A child's death is a profound loss for mothers and affects hundreds of thousands of women. Mothers report inconsolable and progressive grief that is distinct from depression and impacts daily emotions and functions. The brain mechanisms responsible for this relatively common and profound mental health problem are unclear, hampering its clinical recognition and care. In an initial exploration of this condition, we used resting state functional MRI (fMRI) scans to examine functional connectivity in key circuits, and task-based fMRI to examine brain network activity in grieving mothers in response to pictures of their deceased child and as well as recognizable deceased celebrities and unfamiliar individuals. We compared nine mothers who had lost an adult child and aged-matched control mothers with a living child of a similar age. Additionally, we collected diffusion imaging scans to probe structural connectivity and complemented the imaging studies with neuropsychological assessments. Increased functional activation in Ventral Attention/Salience Networks accompanied by a reduced activation in the medial prefrontal cortex in response to the deceased child's picture robustly distinguished the grieving mothers from controls. Heightened resting-state functional connectivity between the paraventricular thalamic nucleus (PVT) and the amygdala distinguished the grieving mothers from the controls and correlated with subjective grief severity. Structurally, maternal grief and its severity were associated with alterations in corticolimbic white matter tracts. Finally, grieving mothers performed worse than controls on neuropsychological tests of learning, memory, and executive function, linked with grief severity. Reduced activation in cortical regions inhibiting emotions and changes in the PVT circuitry-a region involved in long-term emotional memories and decision making under conflict-distinguish grieving mothers from controls. Notably, the magnitude of neurobiological changes correlates with the subjective severity of grief. Together, these new discoveries delineate a prevalent and under-recognized mental health syndrome and chart a path for its appreciation and care.

Oxidative stress has long been implicated in the pathophysiology and progression of Huntington's disease (HD). Uric acid (UA) is a naturally occurring antioxidant that is present in the brain and periphery. Growing evidence has implicated UA as a molecular biomarker for several neurodegenerative diseases, most notably Parkinson's disease (PD). In this study, we investigated UA levels in clinical samples from HD patients and normal controls (NCs) and assessed potential relationships between UA levels and disease and clinical data. UA levels were measured in plasma (n = 107) and saliva (n = 178) samples from premanifest (pre-HD) and manifest HD patients and control subjects. Gender effects of UA levels were observed in both biofluids, with male patients showing higher UA levels compared to female patients. Comparisons of UA levels across diagnostic groups, separated by gender, revealed that both plasma and salivary UA levels were significantly lower in female pre-HD and manifest HD patients compared to NCs. Salivary levels of UA were also significantly lower in male manifest HD patients versus controls, but not in plasma. Correlations of peripheral UA levels to clinical data also showed differences according to gender. In male HD patients, both plasma and salivary UA levels were significantly negatively correlated with total functional capacity (TFC), while positive correlations were observed with total motor score (TMS). Female HD patients showed a significant positive correlation between plasma UA levels and TMS, while salivary UA levels from female patients were significantly correlated to disease burden. Finally, in a separate cohort, we show that UA levels are decreased in postmortem prefrontal cortical samples (n = 20) from HD subjects compared to matched controls. These findings suggest that decreased levels of UA in the brains of HD patients can be reflected in peripheral fluids, with salivary measures of UA particularly offering significant promise as a potentially relevant, non-invasive biomarker of disease symptoms and burden. Our findings further highlight the impact of sexual dimorphism in HD pathophysiology.

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington's disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30-40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

BACKGROUND: Major Depressive Disorder, characterized by cognitive affective biases, is a considerable public health challenge. Past work has shown that higher depressive symptoms are associated with augmented memory of negative stimuli. In contrast, anxiety symptoms have been associated with overgeneralization of emotional memories. Given the high comorbidity of depression and anxiety, it is critical to understand how cognitive affective biases are differentially associated with clinical symptoms. METHOD: We used continuous measures of depression (Beck Depression Inventory [BDI-II]) and anxiety (Beck Anxiety Inventory [BAI]) to evaluate an adult sample (N = 79; 18-41 years old, 58 female). Emotional memory discrimination and recognition memory were tested using an emotional discrimination task. We applied exploratory factor analysis to questions from the BAI and BDI-II to uncover latent constructs consisting of negative affect, anhedonia, somatic anxiety, and cognitive anxiety. RESULTS: We report evidence that anxious symptoms were associated with impaired recognition of negative items after accounting for age and sex. Our exploratory factor analysis revealed that impaired negative item recognition is largely associated with somatic and cognitive anxiety factors. LIMITATIONS: Interpretations in a mixed pathology sample, especially given collinearity among factors, may be difficult. CONCLUSIONS: We provide evidence that somatic and cognitive anxiety are related to impaired recognition memory for negative stimuli. Future clinical investigations should uncover the neurobiological basis supporting the link between recognition of negative stimuli and somatic/cognitive symptoms of anxiety.

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway - the uncinate fasciculus - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

Medial temporal lobe (MTL) atrophy is a core feature of age-related cognitive decline and Alzheimer's disease (AD). While regional volumes and thickness are often used as a proxy for neurodegeneration, they lack the sensitivity to serve as an accurate diagnostic test and indicate advanced neurodegeneration. Here, we used a submillimeter resolution diffusion weighted MRI sequence (ZOOMit) to quantify microstructural properties of hippocampal subfields in older adults (63-98 years old) using tensor derived measures: fractional anisotropy (FA) and mean diffusivity (MD). We demonstrate that the high-resolution sequence, and not a standard resolution sequence, identifies dissociable profiles for CA1, dentate gyrus (DG), and the collateral sulcus. Using ZOOMit, we show that advanced age is associated with increased MD of the CA1 and DG as well as decreased FA of the DG. Increased MD of the DG, reflecting decreased cellular density, mediated the relationship between age and word list recall. Further, increased MD in the DG, but not DG volume, was linked to worse spatial pattern separation. Our results demonstrate that ultrahigh-resolution diffusion imaging enables the detection of microstructural differences in hippocampal subfield integrity and will lead to novel insights into the mechanisms of age-related memory loss.

The perforant path, the white matter bundle connecting the entorhinal cortex (ERC) with the hippocampal formation deteriorates with age-related cognitive decline. Previous investigations using diffusion-weighted MRI to quantify perforant path integrity in-vivo have been limited due to image resolution or have quantified the perforant path using methods susceptible to partial volume effects such as the tensor model and without consideration of its 3-dimensional morphology. In this investigation, we use quantitative-anisotropy informed tractography derived from ultra-high resolution diffusion imaging (ZOOMit) to investigate structural connectivity of the perforant path and other medial temporal lobe (MTL) pathways in older adults (63 to 98 years old, n = 51). We show that graph density within the MTL declines with age and is associated with lower delayed recall performance. We also show that older age and poorer delayed recall are associated with reduced streamlines connecting the ERC and dentate gyrus of the hippocampus (the putative perforant path). This work suggest that intra-MTL connectivity may new candidate biomarkers for age-related cognitive decline.

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.