Michael A. Yassa

Puberty is a period of profound behavioral reorganization that recalibrates social motivation, risk-taking, and sexual behavior in ways that shape lifelong human health. Yet its characterization in population-based studies relies largely on self-report, which reflects perceived physical changes rather than the neuroendocrine substrates driving the transition. The pituitary gland sits at the center of this reorganization, coordinating hypothalamic-pituitary axes that orchestrate puberty. Leveraging 11,818 adolescents (ABCD Study; 30,276 MRI observations), we show that pituitary volume is a precise, scalable marker of pubertal progression carrying non-redundant information beyond chronological age, salivary hormones, and self-reported stage. Sex-specific non-linear trajectories, accelerated expansion anchored to menarche, and distinct patterns across menarche timing subgroups capture both the timing and tempo of puberty at population scale. Pituitary volume was further associated with ACEs and decreased within-person growth following hormonal contraception initiation, positioning it as a sensitive index of the biological embedding of exogenous exposures known to influence pubertal maturation.

Anhedonia – the diminished capacity to experience or anticipate pleasure – is among the most common consequences of early-life unpredictability, yet how these co-occurring conditions jointly shape real-world decision-making remains unknown. Here, we use a sequential foraging-under-threat task to probe motivational conflict decisions in 357 individuals varying in early-life unpredictability and anhedonia symptoms. We find that unpredictability and anhedonia exert opposing influences on choice: unpredictability shifts behavior away from the survival-optimal policy in a sex-dependent manner, while anhedonia promotes adherence to it, partly through heightened sensitivity to unexpected threatening outcomes. A mediation analysis reveals that anhedonia partially buffers the deleterious effects of unpredictability on decision quality. These results demonstrate that co-occurring conditions can mask one another’s behavioral signatures and suggest that the heterogeneous expression of transdiagnostic constructs like anhedonia may reflect context-dependent adaptations to distinct underlying etiologies.

Women face twice the lifetime risk of Alzheimer's disease (AD) compared with men. Inflammatory burden is widely implicated in AD, but whether sex-differentiated vulnerability is determined by cytokine levels or by the brain’s sensitivity to those signals remains unclear. Here, we examined sex-specific associations between peripheral inflammatory markers, medial temporal lobe (MTL) white matter microstructure using NODDI diffusion MRI, and hippocampal-dependent memory in 121 cognitively unimpaired older adults. Women exhibited widespread alterations in MTL white matter microstructure relative to men. In women, peripheral cytokines (TNFα, IL-10) were associated with microstructural variation in hippocampal-prefrontal tracts, whereas these associations were absent in men. An indirect association between TNFα and memory through hippocampal cingulum neurite density was observed only in women. Despite these microstructural and coupling differences, cytokine levels were comparable between sexes, indicating that risk may be better captured by the coupling between peripheral immune signals and circuit integrity than by cytokine levels alone. These findings identify a sex-specific pattern of immune-brain coupling that reframes inflammatory risk in AD as a property of circuit-level sensitivity rather than overall inflammatory burden.

The synapse is the fundamental unit of communication in the nervous system. Determining how information is transferred across the synaptic interface is one of the most complex endeavors in neuroscience, owing to the large number of contributing factors and events. An approach to solving this problem involves collapsing across these complexities to derive concise mathematical formulas that fully capture the governing dynamics of synaptic transmission. We investigated the feasibility of deriving such a formula – an input-output transformation function for the CA3 to CA1 node of the hippocampus – using the Volterra expansion technique for non-linear system identification. The timecourse of the fEPSP in the apical dendrites of mouse brain slices was described with >94% accuracy by a 2nd order equation that captured the linear and non-linear influence of past inputs on current outputs. This function generalized to cases not included in its derivation and uncovered previously undetected timing rules. The basal dendrites expressed a substantially different transfer function and evidence was obtained that, unlike the apical system, a 3rd order system or higher will be needed for complete characterization. At scale, the approach will also provide information needed for the construction of biologically realistic models of brain networks.

Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting-edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe (MTL) WM than traditional tensor metrics. In total, 199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75 years; 60% female; cognitively unimpaired, n = 121; cognitively impaired MCI/dementia, n = 77) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate). A subset of participants received 18F-florbetapir or 18F-florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F-flortaucipir to measure tau (n = 135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR-SB) and memory composite score (ADNI-MEM). NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures. For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus and the uncinate, and with ODI in the fornix ST. Both ODI and NDI across the majority of tracts were associated with CDR-SB and ADNI-MEM. In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid-beta, while MD in MTL tracts showed limited correlations with pathology or cognition. NDI partially mediated the relationship between AD pathology (entorhinal tau, meta temporal tau, or Aβ) and the memory composite score. Random forest modeling showed that a combination of NODDI metrics and DTI had the strongest estimates of memory performance and clinical impairment. NODDI metrics offer more sensitive insights about MTL WM integrity in AD that could have been previously missed due to the limitations of DTI analyses. Additionally, combining NODDI with DTI yielded the strongest predictive performance for memory and clinical impairment, suggesting that the two approaches are complementary. The use of advanced diffusion acquisitions such as multishell which allows for analyses such as NODDI is crucial for the future development of disease identification and structural understanding.

The ability to discriminate similar visual stimuli has been used as an important index of memory function. This ability is widely thought to be supported by expanding the dimensionality of relevant neural codes, such that neural representations for the similar stimuli are maximally distinct, or "separated." An alternative hypothesis is that discrimination is supported by lossy compression of visual inputs, efficiently coding sensory information by discarding seemingly irrelevant details. A benefit of compression, relative to expansion, is that it allows the individual to efficiently retain fewer essential dimensions underlying stimulus variation---a process linked to higher-order visual processing---without hindering discrimination. Under the compression hypothesis, pattern separation is facilitated when more information from similar stimuli can be discarded, rather than preserving more information about distinct stimulus dimensions. We test the compression versus expansion hypotheses by predicting performance on the canonical mnemonic similarity task. First, we train neural networks to compress perceptual and semantic factors of stimuli, and measure lossiness of those representations using the mathematical framework underlying compression. Consistent with the compression hypothesis, and not the expansion hypothesis, we find that greater lossiness predicts the ease and performance of lure discrimination, particularly in later layers of convolutional neural networks shown to predict brain activity in the higher-order visual stream. We then empirically confirm these predictions across two sets of images, four behavioral datasets, and alternative metrics of lossiness. Finally, using task fMRI data, we identify signatures of lossy compression---neural dimensionality reduction and information loss---in the higher-order visual stream regions V4 and IT as well as hippocampal subregions dentate gyrus/CA3 and CA1 associated with lure discrimination performance. These results suggest lossy compression may support mnemonic discrimination behavior by discarding redundant and overlapping information.

Animal studies have demonstrated that physical exercise enhances neural plasticity, particularly in the hippocampal dentate gyrus (DG), and improves learning and memory. Notably, these effects are more pronounced with light-intensity exercise compared to higher-intensity exercise. Recent advancements have enabled the investigation of hippocampal memory in humans, especially DG-dependent pattern separation, providing a bridge between animal and human research. In this chapter, we outline the methodological approaches for assessing hippocampal pattern separation using mnemonic discrimination tasks and high-resolution MRI, and we review key studies examining the effects of aerobic exercise on human DG function. Evidence from cross-sectional, acute, and chronic exercise intervention studies supports the positive impact of exercise and physical activity, with some findings aligning with the exercise hormesis observed in animals. However, further research is needed to determine the optimal exercise conditions for enhancing hippocampal memory and to elucidate the underlying neural mechanisms.

Age-related structural brain changes may be better captured by assessing complex spatial geometric differences rather than isolated changes to individual regions. We applied an analytic method to quantify age-related changes to the spatial anatomy of the brain by measuring expansion and compression of global brain shape and the distance between cross-hemisphere homologous regions. To test how global brain shape and regional distances are affected by aging, we analyzed 2603 structural MRIs (range: 30−97 years). Increasing age was associated with global expansion across inferior-anterior gradients, global compression across superior-posterior gradients, and regional expansion between frontotemporal homologues. Specific patterns of global and regional expansion and compression were further associated with clinical impairment and distinctly related to deficits in various cognitive domains. These findings suggest that changes to the complex spatial anatomy and geometry of the aging brain may be associated with reduced efficiency and cognitive dysfunction in older adults.

Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and functional loss in older adults. Obstructive sleep apnea (OSA) is common in older adults, can increase cerebrovascular disease risk, and is linked to medial temporal lobe (MTL) degeneration and cognitive impairment. However, the interaction between OSA features and CSVD burden and their combined effect on MTL structure and function are not well understood. This study tested the hypothesis that CSVD burden is a candidate mechanism linking OSA to MTL degeneration and impaired memory in older adults. Cognitively unimpaired older adults from the Biomarker Exploration in Aging, Cognition, and Neurodegeneration cohort were recruited for an observational, in-lab overnight polysomnography (PSG) study with emotional mnemonic discrimination ability assessed before and after sleep. Participants had no neurologic or psychiatric disorders and were not on sleep-affecting medications. PSG-derived OSA variables included apnea-hypopnea index (AHI), total arousal index, and minimum SpO₂. MRI was used to assess global and lobar white matter hyperintensity (WMH) volumes and MTL structure (hippocampal volume; entorhinal cortex [ERC] thickness) at an earlier time point. Regressions were implemented while adjusting for age, sex, and concurrent use of antihyperlipidemic and/or antihypertensive medication. Minimum SpO₂ was transformed into a Hypoxemia Severity Index for normality, in which lower SpO₂ values indicated more severe hypoxemia. Thirty-seven older adults were included in the study (age 72.5 ± 5.6 years, 23 women, AHI = 13.8 ± 18.0 [range 0-80]). Hypoxemia measures significantly predicted global WMH volume (b_minSpO2 = 0.141 [0.001-0.282], b_{duration = 0.008 [0.000-0.016]). This relationship was driven by hypoxemia severity during REM sleep (bREMminSpO2 = 0.143 [0.003-0.284]), which also predicted frontal (bREMminSpO2 = 0.101 [0.004-0.198]) and parietal (bREMminSpO2 = 0.121 [0.024-0.219]) WMH burden. Greater frontal WMH burden indirectly mediated the relationship between REM sleep hypoxemia and ERC thickness (indirect effect = -0.043, 95% CI -0.1174 to -0.00015). Reduced ERC thickness was, in turn, associated with worse overnight mnemonic discrimination ability (bleftERCthickness = 0.112 [0.014-0.211]). These findings identify CSVD as a candidate mechanism linking OSA-related hypoxemia to MTL degeneration and impaired sleep-dependent memory in older adults, specifically implicating hypoxic events during REM sleep.}