BACKGROUND: Treating memory and cognitive deficits requires knowledge about anatomical sites and neural activities to be targeted with particular therapies. Emerging technologies for local brain stimulation offer attractive therapeutic options but need to be applied to target specific neural activities, at distinct times, and in specific brain regions that are critical for memory formation. METHODS: The areas that are critical for successful encoding of verbal memory as well as the underlying neural activities were determined directly in the human brain with intracranial electrophysiological recordings in epilepsy patients. We recorded a broad range of spectral activities across the cortex of 135 patients as they memorised word lists for subsequent free recall. FINDINGS: The greatest differences in the spectral power between encoding subsequently recalled and forgotten words were found in low theta frequency (3-5 Hz) activities of the left anterior prefrontal cortex. This subsequent memory effect was proportionally greater in the lower frequency bands and in the more anterior cortical regions. We found the peak of this memory signal in a distinct part of the prefrontal cortex at the junction between the Broca's area and the frontal pole. The memory effect in this confined area was significantly higher (Tukey-Kramer test, p<0.05) than in other anatomically distinct areas. INTERPRETATION: Our results suggest a focal hotspot of human verbal memory encoding located in the higher-order processing region of the prefrontal cortex, which presents a prospective target for modulating cognitive functions in the human patients. The memory effect provides an electrophysiological biomarker of low frequency neural activities, at distinct times of memory encoding, and in one hotspot location in the human brain. FUNDING: Open-access datasets were originally collected as part of a BRAIN Initiative project called Restoring Active Memory (RAM) funded by the Defence Advanced Research Project Agency (DARPA). CT, ML, MTK and this research were supported from the First Team grant of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Mayo Clinic Rochester MN USA; Czech Institute of Informatics Robotics and Cybernetics Czech Technical University Prague Prague Czech Republic

Department of Neurology Mayo Clinic Rochester MN USA; Department of Physiology and Biomedical Engineering Mayo Clinic USA

Gdansk University of Technology Faculty of Electronics Telecommunications and Informatics Multimedia Systems Department BioTechMed Center Gdansk Poland; Department of Neurology Mayo Clinic Rochester MN USA

Gdansk University of Technology Faculty of Electronics Telecommunications and Informatics Multimedia Systems Department BioTechMed Center Gdansk Poland; Department of Neurology Mayo Clinic Rochester MN USA; Department of Physiology and Biomedical Engineering Mayo Clinic USA

Gdansk University of Technology Faculty of Electronics Telecommunications and Informatics Multimedia Systems Department BioTechMed Center Gdansk Poland; Department of Neurology Mayo Clinic Rochester MN USA; Laboratory of Neuroinformatics Nencki Institute of Experimental Biology of the Polish Academy of Sciences Warsaw Poland

Graduate School of Biomedical Sciences Mayo Clinic USA

University of Illinois Department of Electrical and Computer Engineering Urbana Champaign IL USA

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High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?