Human memory systems are imperfect recording devices that are affected by age and disease, but recent findings suggest that the performance of these systems may be modifiable through interventions using non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). The translational potential of these rTMS interventions is clear: memory problems are the most common cognitive complaint associated with healthy aging, while pathological conditions such as Alzheimer’s disease are often associated with severe deficits in memory. Therapies to improve memory or treat memory loss could enhance independence while reducing costs for public health systems. Despite this promise, several important factors limit the generalizability and translational potential of rTMS interventions for memory. Heterogeneity of protocol design, rTMS parameters, and outcome measures present significant challenges to interpretation and reproducibility. However, recent advances in cognitive neuroscience, including rTMS approaches in addition to a new understanding of functional brain networks and related insights, may offer methodological tools necessary to design new interventional studies with enhanced experimental rigor, improved reproducibility, and greater likelihood of successful translation to clinical settings. In this review, we first discuss the current state of the literature on memory modulation with rTMS, then offer a commentary on developments in cognitive neuroscience that are relevant to rTMS interventions, and finally close by offering several recommendations for the design of future investigations using rTMS to modulate human memory performance.

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Background Aging processes — healthy and pathological — contribute to age‐related memory decline, and current treatments offer limited remediation. Targeted non‐invasive brain stimulation (NBS) of memory networks vulnerable to Alzheimer’s disease is a novel approach which can enhance memory in healthy young adults by 20% (Wang et al., 2014). To test generalizability of this finding, we are administering a clinical trial (ClinicalTrials.gov #alz045244) applying targeted NBS to healthy young adults, healthy older adults, and patients with amnestic mild cognitive impairment (aMCI). Here, we report preliminary findings from the trial arm studying healthy young adults. Method Our approach replicates methods from Wang et al. (2014). Healthy young adults (N = 16) completed two interventions which combined pre/post‐stimulation brain and cognitive measurement with NBS (treatment or sham for five consecutive days) in the form of repetitive transcranial magnetic stimulation (rTMS). The two interventions were identical except for rTMS parameters. Pre‐/post‐stimulation, brain measures included structural and resting‐state functional MRI data; cognitive measures included cognitive abilities (e.g., hippocampal‐dependent memory). Intervention formats applied rTMS using β‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min; the stimulation location was constant (left lateral parietal cortex coactive with a hippocampus‐centered network). Stimulation intensity was tailored to participants’ resting motor threshold (RMT) and varied by condition: treatment, 100% RMT; sham, 10% RMT. Participants completed both conditions in a counterbalanced order. Result We successfully mapped hippocampus‐centered functional networks in each participant and localized left lateral parietal targets for rTMS. Furthermore, we observed changes in brain and cognitive measures related to the stimulation condition. Brain measures including resting‐state functional connectivity (RSFC) revealed changes in patterns of RSFC between several areas of the hippocampus‐centered network targeted with rTMS in the treatment condition. Conclusion Our ongoing clinical trial measures changes in brain and cognitive variables associated with NBS of a functional brain network supporting memory. The current trial arm focused on healthy young adults, and we found evidence consistent with plasticity in the intrinsic brain network supporting memory. Findings from the remaining arms (older adults, healthy or aMCI) will inform the generalizability of our observations to populations vulnerable to Alzheimer’s disease.

Background Individual variability in Alzheimer’s disease (AD) risk is greatly affected by genetic factors, and those factors may exert early influence on brain development. Specifically, genetic/genomic AD risk factors may bias brain development toward vulnerability to late onset AD. We are conducting a five‐year study (funded by the National Institute on Aging) to test the hypothesis that polygenic AD risk alters neurodevelopment of brain systems most affected by AD in ways that increase vulnerability to late‐onset AD. If true, then properties of AD‐vulnerable brain structures (e.g., hippocampus) and AD‐vulnerable brain networks (e.g., default mode network) will vary with polygenic AD risk even during youth. Here, we describe our study aims, approach, and predictions. Methods We have implemented our project as the Polygenic Risk of Alzheimer’s disease in Nebraska Kids (PRANK) study. The PRANK study will measure neurodevelopmental effects of AD polygenic risk scores (ADPRS) with three aims: 1) measure effects of ADPRS on development of AD‐vulnerable brain regions; 2) quantify how ADPRS affects development of functional brain networks vulnerable to AD; and 3) evaluate effects of ADPRS on development of AD‐vulnerable cognitive abilities. To address these aims, we are developing a new dataset which combines neuroimaging (brain structure/function), neuropsychology (cognition), and genomics (ADPRS) in a longitudinal design. Our study is currently enrolling healthy youth age 8‐13 years; our multi‐year recruitment goal is N = 270. Participants will return for follow‐up two years after initial participation. Results Our study is ongoing, but we will discuss our design and preliminary findings. We predict that higher ADPRS in otherwise typically developing youth will be associated with: 1) smaller hippocampal volume and decreased cortical thickness in AD‐related ROIs; 2) lower connectivity in functional brain networks and less brain activity in memory tasks; 3) lower scores on measures of AD‐related cognitive abilities (e.g., memory and executive functions) after accounting for IQ. Conclusions Findings from the PRANK study will improve the field’s understanding of how developmental effects of ADPRS relate to clinical and epidemiological challenges of AD. Measuring how genetic/genomic factors associated with late‐onset AD affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention.

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BackgroundDuring childhood development, particularly the periadolescent epoch, significant changes in cognition and brain structure are known to occur. The development of spatial working memory (SWM), for example, continues throughout the teenage years. The hippocampus is necessary for normal SWM, as seen by the substantial memory deficits seen in patients with Alzheimer's disease (AD) and their associated hippocampal pathology. It is hypothesized that vulnerability to AD could be modulated by early brain development, so understanding the developmental relationship between hippocampal volume (HV) and SWM would provide a key baseline for comparison of different trajectories. Our ongoing study, Polygenetic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK; R01 AG064247), measures brain structure/function, cognitive abilities, and Alzheimer’s polygenetic risk score in periadolescent children (age 8‐13). Here, we report preliminary data from PRANK measuring the association between HV, age, and SWM.MethodUsing preliminary data from the PRANK project, we investigated the association between SWM, age, and HV. Our sample included children (N=80, age 8‐13 years), recruited from the community and tested at University of Nebraska Medical Center; demographics were consistent with the recruitment area. SWM was measured using the Spatial Working Memory task between errors term from the Cambridge Neuropsychological Battery. Structural MRI data were collected using a 3T Siemens Prisma instrument. HV was measured using automated segmentation in Freesurfer.ResultSWM was associated with age, r(80) = ‐.334, p = .002, such that older children showed fewer spatial working memory errors than younger children. HV was not significantly associated with SWM, controlling for age, r(77) = ‐.027, p = .813. However, the direction of the relationship between HV and SWM (larger HV associated with fewer SWM errors) was consistent with previous literature (Faridi et al., 2015).ConclusionThese preliminary results suggest that increasing age is associated with better SWM in typical childhood; findings for HV were non‐significant. We anticipate that our study’s full sample will provide appropriate statistical power to test the association of SWM with HV. In future efforts, we will investigate this association as it relates to polygenic risk for Alzheimer’s disease and whether these results generalize to children with Down syndrome.

BackgroundAlzheimer’s disease (AD) is an insidious disease process that is frequently diagnosed following complaints of memory loss. The AD‐related decline in memory abilities has been attributed to functional and pathological changes in the hippocampus and distributed functional networks supporting hippocampal‐dependent memory. Although AD manifests in late life, lifelong risk factors for AD may be influenced by childhood brain development. The default mode network (DMN) is one functional network associated with the hippocampus and has been well‐characterized in adulthood. However, there is a gap in the literature regarding the connection between DMN network properties and relational memory abilities in childhood. Here we report preliminary findings from our ongoing study (Polygenic Risk of Alzheimer’s disease in Nebraska Kids, PRANK). The PRANK study collects functional MRI, cognitive measures, and AD polygenic risk scores from periadolescent children in Nebraska (age 8‐13 years). Here, we report the current findings measuring the relationship between brain network measures and cognitive outcomes from the PRANK study.MethodTo assess the relationship between intrinsic functional networks of the brain and hippocampal‐dependent memory, we applied brain and cognitive measures from a preliminary sample of periadolescent children (N=90) from the PRANK study. Cognitive assessments measured hippocampal‐dependent memory and other cognitive domains. Brain measures included both structural and resting‐state functional MRI data. Two properties of brain networks were measured, modularity and participation coefficient. These measures were derived from resting‐state MRI data with help of the Human Connectome Project’s Connectome Workbench tool. For comparison, brain and cognitive measures were also collected from a separate dataset of healthy young adults.ResultOur analysis observed differences between the PRANK and young adult datasets. The observed between‐group differences included graph theoretic measures of network architecture, particularly modularity. The relationship between relational memory performance and the network properties PRANK participants was also assessed.ConclusionThe ongoing PRANK study seeks to determine the association of brain measures and cognitive performance. Here, our preliminary analysis measured the relationship between brain and cognitive measures in periadolescent children with a focus on brain network properties and relational memory.

BackgroundAlzheimer’s disease (AD) is an insidious neurodegenerative disease that is frequently associated with deficits in both memory and executive functions (EFs). EFs consist of a diverse range of cognitive processes, including inhibition, working memory, and cognitive flexibility. In AD and other disorders, dysfunction in EFs can result in attention deficits, decreased inhibition, and impaired decision‐making abilities. EFs have been historically linked to the prefrontal regions of the brain, but recent studies of brain networks and their functional connectivity have broadened these links to include brain regions such as the hippocampus (Hc). Building upon prior work, the current project investigated the association between decision making and hippocampal resting state functional connectivity (rs‐FC) in periadolescent children.MethodA cohort of healthy periadolescent children aged 8‐13 (N = 80) was sampled from the ongoing NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. PRANK participants completed an array of cognitive and behavioral measures, in addition to an MRI of the brain. Decision making ability was assessed via the NIH Toolbox Dimensional Change Card Sorting (DCCS) task. The rs‐FC between the Hc and regions of the prefrontal cortex (PFC) was measured, and its covariance with DCCS was assessed.Resultrs‐FC of the Hc covaried with performance on the DCCS in the left dorsolateral prefrontal cortex (dlPFC) and dorsal anterior cingulate cortex (dACC). These anatomical regions are in line with larger intrinsic brain networks, such as the frontoparietal network (FPN) and the cingulo‐opercular network (CON).ConclusionThese preliminary results suggest the Hc is associated with anatomical regions and intrinsic brain networks that are important for EFs. A better characterization of the process by which EF occurs within the brain may drive further research that can assess ways to limit the decline of these cognitive abilities associated with healthy aging or brain pathology such as AD.