Focal electrical stimulation of the brain incites a cascade of neural activity that propagates from the stimulated region to both nearby and remote areas, offering the potential to control the activity of brain networks. Understanding how exogenous electrical signals perturb such networks in humans is key to its clinical translation. To investigate this, we applied electrical stimulation to subregions of the medial temporal lobe in 26 neurosurgical patients fitted with indwelling electrodes. Networks of low-frequency (5–13 Hz) spectral coherence predicted stimulation-evoked increases in theta (5–8 Hz) power, particularly when stimulation was applied in or adjacent to white matter. Stimulation tended to decrease power in the high-frequency broadband (HFB; 50–200 Hz) range, and these modulations were correlated with HFB-based networks in a subset of subjects. Our results demonstrate that functional connectivity is predictive of causal changes in the brain, capturing evoked activity across brain regions and frequency bands.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

In humans, brain oscillations support critical features of memory formation. However, understanding the molecular mechanisms underlying this activity remains a major challenge. We measured memory-sensitive oscillations using intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. When these patients undergo resection subsequently, we employ transcriptomics on the temporal cortex to link gene expression with brain oscillations, identifying genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated oscillatory signature-specific modules associated with neuropsychiatric disorders as well as ion channel activity, with highly correlated genes exhibiting strong connectivity within these modules. Using single-nuclei transcriptomics, we further revealed that these modules are enriched for specific classes of both excitatory and inhibitory neurons, and immunohistochemistry confirmed expression of highly correlated genes. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding.

Phase amplitude coupling (PAC) between theta and gamma oscillations represents a key neurophysiological mechanism that promotes the temporal organization of oscillatory activity. For this reason, PAC has been implicated in item/context integration for episodic processes, including coordinating activity across multiple cortical regions. While data in humans has focused principally on PAC within a single brain region, data in rodents has revealed evidence that the phase of the hippocampal theta oscillation modulates gamma oscillations in the cortex (and vice versa). This pattern, termed cross‐regional PAC (xPAC), has not previously been observed in human subjects engaged in mnemonic processing. We use a unique dataset with intracranial electrodes inserted simultaneously into the hippocampus and seven cortical regions across 40 human subjects to (1) test for the presence of significant cross‐regional PAC (xPAC), (2) to establish that the magnitude of xPAC predicts memory encoding success, (3) to describe specific frequencies within the broad 2–9 Hz theta range that govern hippocampal‐cortical interactions in xPAC, and (4) compare anterior versus posterior hippocampal xPAC patterns. We find that strong functional xPAC occurs principally between the hippocampus and other mesial temporal structures, namely entorhinal and parahippocampal cortices, and that xPAC is overall stronger for posterior hippocampal connections. We also show that our results are not confounded by alternative factors such as inter‐regional phase synchrony, local PAC occurring within cortical regions, or artifactual theta oscillatory waveforms.