Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans

Abstract

People often forget information because they fail to effectively encode it. Here, we test the hypothesis that targeted electrical stimulation can modulate neural encoding states and subsequent memory outcomes. Using recordings from neurosurgical epilepsy patients with intracranially implanted electrodes, we trained multivariate classifiers to discriminate spectral activity during learning that predicted remembering from forgetting, then decoded neural activity in later sessions in which we applied stimulation during learning. Stimulation increased encoding-state estimates and recall if delivered when the classifier indicated low encoding efficiency but had the reverse effect if stimulation was delivered when the classifier indicated high encoding efficiency. Higher encoding-state estimates from stimulation were associated with greater evidence of neural activity linked to contextual memory encoding. In identifying the conditions under which stimulation modulates memory, the data suggest strategies for therapeutically treating memory dysfunction.

Keywords: deep brain stimulation; epilepsy; episodic memory; free recall; intracranial EEG; local field potential; multivariate classification.

Figure 1.. Experimental Design and Analysis

(A) Subjects performed delayed free recall while intracranially implantedelectrodes recorded local field potentials simultaneously across multiple regions of the brain. (B) The electrode frequency pattern of spectral power for each word-encodingperiod was used as input (X) to fit a classifier to discriminate recalled from forgotten patterns (resulting weight; w). We assessed classifier performance using area under the receiver-operating characteristic curve (AUC). See also Figure S1.

Figure 2.. Classifier Performance

(A and C) Classifier output probability for an eight-list period of the delayed free recall task in two example subjects. Dashed lines indicate the optimal decisionthreshold dividing recalled from forgotten trials. Red, later recalled words; blue, later forgotten words. (A) Example patient 1. (C) Example patient 2. (B and D) AUC for both subjects was significantly greater than chance. (B) Example patient 1. (D) Example patient 2. (E) Individual receiver-operating characteristic (ROC) curves plotted for all subjects. (F) Forward-model-derived estimates of classification importance for each electrode region × frequency feature, grouped into anatomical regions of interest. (G) Subsequent memory analysis contrasting encoding power for later recalled words with later not recalled words. (F and G) IFG, inferior frontal gyrus; MFG, middle frontal gyrus; SFG, superior frontal gyrus; MTLC, medial temporal lobe cortex; Hipp, hippocampus; TC, temporal cortex; IPC, inferior parietal cortex; SPC, superior parietal cortex; OC, occipital cortex. Data are multiple comparisons corrected using false discovery rate (FDR) at q = 0.05. See also Figures S2 and S3.

Figure 3.. Classifier Output Predicts the Effect of Stimulation on Memory

(A) We applied stimulation across alternating pairs of words on Stim lists;NoStim lists were devoid of stimulation. (B) The effect of stimulation on memory performance varied across subjects(SD 22.5%); mean, red dashed line. (C and D) Recall probability as a function of serial position (C) and inter-item lag (D) does not significantly differ as a function of stimulation condition. See also Table S1.

Figure 4.. The Effect of Stimulation Depends on Brain State

(A) Classifier decoding prior to stimulation onset allowed us to analyze memory performance based on pre-stimulation brain state. (B) Spectral power prior to stimulation onset was significantly lower at high frequencies in frontal, temporal, parietal, and occipital cortex (FDR corrected at q = 0.05). (C) Recall performance increased if stimulation was delivered when the brain was in a low encoding state (p < 0.03) and decreased if delivered in a high encoding state (p < 0.05). The difference between low and high stimulation was also significant (p < 0.003). Red bars show mean SE of the difference. (D) Stimulation significantly increased classifier output when delivered at low encoding states (p < 0.01). (E) Stimulation significantly decreased classifier output when delivered at high encoding states (p < 0.001). See also Table S2.

Figure 5.. Correlation between the Stimulation-Related Change in Classifier Output and the Spectral Tilt Effect: (High-Frequency Activity t Stat) –(Low-Frequency Activity t Stat)