Defining optimal memory modulation windows: isolating the causal role of distinct post-learning awake periods to human memory consolidation

Memory abnormalities are a core feature of psychiatric and neurological disorders, as well as in aging. Persistent negative memories are a hallmark of Post-Traumatic Stress Disorder (PTSD) and are prevalent in anxiety disorders, while memory retention can be impaired in aging and other conditions. Thus, effective approaches to strategically modulate memory strength would enhance mental health and cognition across broad populations. Memory consolidation mechanisms represent a key opportunity for targeted memory modulation. While traditionally studied during sleep, recent research highlights the importance of consolidation during wakefulness, providing a new window of opportunity for strategic memory modulation. However, most human studies on awake consolidation focus on narrow time periods immediately post-learning and a single state (rest), making it unclear when consolidation peaks during wakefulness and thus when interventions should be applied for maximum effectiveness. Yet, recent work suggests that consolidation may peak: 1) multiple hours, not minutes, after learning and 2) during internally-oriented rather than externally-oriented states of high vigilance. The central goal of this research is to determine when memory consolidation maximally occurs during wakefulness, identifying effective time windows and cognitive states for memory modulation. Based on the emerging literature, we test the overarching hypothesis that memory consolidation varies across wakefulness. In two Aims, we systematically decompose awake post-learning periods to determine when memory consolidation is maximal across two key factors: extended time window (Aim 1) and cognitive state (Aim 2). In each Aim, we use an innovative combination of advanced fMRI methods and causal manipulations to measure and test the differential contribution of distinct time windows (Aim 1) and cognitive states (Aim 2) to consolidation. To determine when consolidation is maximal over time, in Aim 1A, we will measure consolidation across multiple extended post-learning time windows using cutting-edge fMRI methods, thus isolating windows with the strongest and weakest consolidation evidence. We will then test whether causal disruption of the strongest vs. weakest time windows differentially impairs memory using a combined Transcranial Magnetic Stimulation (TMS)+fMRI approach (Aim 1B). In Aim 2A, to test whether consolidation is most prevalent during internally focused states, we will measure consolidation evidence via fMRI while attention is directed internally vs. externally using a validated task paradigm. We will then test whether causal induction of consolidation (via cued reactivation) and its impact on memory is more robust during internally vs. externally-oriented states (Aim 2B). The proposed work will collectively characterize how consolidation varies across wakefulness, resulting in the identification of time windows and cognitive states to target for strategic memory intervention. This will enable future work to probe the potential of impacting memory consolidation in clinical and non-clinical populations, moving towards the goal of strategic memory modulation in stress and trauma research. Project Number: 1R01MH138766-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Arielle Tambini | Institution: NATHAN S. KLINE INSTITUTE FOR PSYCH RES, ORANGEBURG, NY | Award Amount: $745,840 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ICN-P (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298597