Hippocampal Resting-state Functional Connectivity Research Articles

Effects of stress-related neuromodulators on amygdala and hippocampus resting state functional connectivity.

The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood. To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC. We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo. We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter. The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147).

Hippocampal Resting State Functional Connectivity Associated with Physical Activity in Periadolescent Children.

Periadolescence is a neurodevelopmental period characterized by structural and functional brain changes that are associated with cognitive maturation. The development of the functional connectivity of the hippocampus contributes to cognitive maturation, especially memory processes. Notably, hippocampal development is influenced by lifestyle factors, including physical activity. Physical activity has been associated with individual variability in hippocampal functional connectivity. However, this relationship has not been characterized in a developmental cohort. In this study, we aimed to fill this gap by investigating the relationship between physical activity and the functional connectivity of the hippocampus in a cohort of periadolescents aged 8-13 years (N = 117). The participants completed a physical activity questionnaire, reporting the number of days per week they performed 60 min of physical activity; then, they completed a resting-state functional MRI scan. We observed that greater physical activity was significantly associated with differences in hippocampal functional connectivity in frontal and temporal regions. Greater physical activity was associated with decreased connectivity between the hippocampus and the right superior frontal gyrus and increased connectivity between the hippocampus and the left superior temporal sulcus. Capturing changes in hippocampal functional connectivity during key developmental periods may elucidate how lifestyle factors including physical activity influence brain network connectivity trajectories, cognitive development, and future disease risk.

4.37 The Relationship Between Serum Brain-Derived Neurotrophic Factor and Hippocampal Resting-State Functional Connectivity in Adolescents With MDD

4.37 The Relationship Between Serum Brain-Derived Neurotrophic Factor and Hippocampal Resting-State Functional Connectivity in Adolescents With MDD

Assessing periadolescent memory ability and characterizing the development of a functional brain network vulnerable to Alzheimer’s disease

AbstractBackgroundIn typically presenting Alzheimer’s disease (AD), pathological changes to the hippocampus (Hc) and its associated functional brain networks result in impaired declarative/relational memory. While it is known that risk factors for AD (genetic, environmental, etc.) can impact hippocampal resting‐state functional connectivity (RSFC) later in life, the development of the hippocampus and its connections to other brain regions may also be influenced by such risk factors. The goal the current study was to characterize the neurodevelopmental changes in this hippocampal network during the periadolescent epoch and determine whether the observed changes were associated with declarative/relational memory ability. Therefore, we utilized a cross‐sectional approach to test whether individual differences in hippocampal RSFC covary with outcomes on a test of relational memory ability in periadolescent children.MethodData were drawn from an ongoing NIA‐funded project: the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. Our analysis was carried out using data from healthy periadolescent participants (N=90; age 8‐13 years). We assessed declarative/relational memory with Cambridge Cognition’s Paired Associates Learning (PAL) task. To conduct the resting‐state functional MRI analyses, we used a seed‐based approach with the bilateral hippocampus as the seed region of interest. We then analyzed the hippocampal RSFC data to and assessed covariance of individual patterns of hippocampal RSFC with memory performance measured with the PAL task.ResultOur preliminary findings, largely consistent with previous work, demonstrate patterns of hippocampal RSFC sharing territory with the ventral and lateral portions of the default mode network (DMN). In addition, we observed evidence of regional covariance between hippocampal RSFC and PAL task performance.ConclusionThe preliminary findings of the ongoing PRANK study indicate that hippocampal RSFC covaries regionally with hippocampal‐dependent memory ability in periadolescent children. Future work from the PRANK study aims to understand whether genetic and polygenic risk factors for AD influence this hippocampal network development. To do so, we will utilize participants’ AD polygenic risk scores, and determine whether those scores are related to individual differences in hippocampal RSFC.

Testing the association of resting‐state functional connectivity of the hippocampus and prefrontal cortex with AD‐vulnerable executive functions in periadolescent children

AbstractBackgroundAlzheimer’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.

Pathological emotionalism following limbic encephalitis: the neural foundations of a novel disorder

ObjectiveWe investigated pathological emotionalism in a large cohort of patients that had presented with autoimmune limbic encephalitis(a-LE).Methods38 patients in the post-acute phase of a-LE completed questionnaires probing emotion regula- tion. They all underwent structural/functional MRI post-acutely, along with age- and sex-matched healthy controls. We investigated correlations of questionnaire scores with demographic, clinical, neuropsycho- logical and brain MRI data across patients. We also compared patients with pathological emotionalism and those without, along with healthy controls, on grey matter volume, resting-state functional connec- tivity and activity.ResultsPathological emotionalism was reported by 50% of the patients. It was not associated with depres- sion, impulsiveness, or memory impairment. However, it correlated with abnormalities in specific emotional brain networks: volume reduction in the anterior hippocampus, fusiform gyrus and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and middle frontal gyrus, and abnormal hemodynamic activity in the fusiform gyrus, inferior parietal lobule, and ventral pons.ConclusionsPathological emotionalism is common following a-LE, is not a manifestation of other neu- ropsychiatric disorders, and reflects abnormalities in networks of emotion regulation including, but not limited to the acute hippocampal focus. This condition provides novel insights into the neural basis of emotion regulation and its dysfunction in disease.christopher.butler@imperial.ac.uk

The relationship between recent PTSD secondary to sexual assault, hippocampal volume and resting state functional connectivity in adolescent girls

ObjectiveImproved understanding of the time course of neural changes associated with adolescent PTSD would elucidate the development of the disorder and could inform approaches to treatment. We compared hippocampal volumes and resting state functional connectivity (RSFC) in adolescent girls with post-traumatic stress disorder (PTSD) secondary to sexual assault, within six months of onset and age- and gender-matched, non-trauma exposed healthy controls (HCs) in São Paulo, Brazil. We also examined the relationship between pre- and post-treatment PTSD symptoms and RSFC. MethodWe collected brain structure, RSFC, and PTSD symptoms in 30 adolescents with PTSD (mean age: 15.7 ± 1.04 years) and 21 HCs (mean age: 16.2 ± 1.21 years) at baseline. We collected repeated measures in 21 participants with PTSD following treatment; 9 participants dropped out. Hippocampal volume and RSFC from hippocampal and default mode network (DMN) seeds were compared between participants with PTSD and HCs. We examined associations between within-subject changes in RSFC and PTSD symptoms following treatment. ResultsNo hippocampal volumetric differences between groups were found. Compared to HCs, adolescents with recent PTSD had reduced RSFC between hippocampus and the lateral parietal node of the DMN, encompassing the angular gyrus, peak coordinates: −38, −54, 16; 116 voxels; peak F1,47 = 31.76; FDR corrected p = 0.038. Improvements in PTSD symptoms were associated with increased RSFC between hippocampus and part of the lateral parietal node of the DMN, peak coordinates: −38, −84, 38; 316 voxels; peak F1,47 = 40.28; FDR corrected p < 0.001. ConclusionAdolescents with recent PTSD had reduced hippocampal-DMN RSFC, while no group differences in hippocampal volume were found, suggesting that hippocampal function, but not structure, is altered early in the course of PSTD. Following treatment, hippocampal-DMN RSFC increased with symptom improvement and may indicate an important neural mechanism related to successful PTSD treatment.

Altered Hippocampal Resting-state Functional Connectivity in Highly Superior Autobiographical Memory

Altered Hippocampal Resting-state Functional Connectivity in Highly Superior Autobiographical Memory

How sleep disturbances affect internet gaming disorder: The mediating effect of hippocampal functional connectivity

BackgroundStudies have revealed that sleep disturbances lead to an increased risk of Internet gaming disorder (IGD). However, the neural underpinnings of this feature remain unknown. Exploring this issue would be valuable in understanding the relationship between sleep and psychiatric disorders. MethodsGiven the impact of sleep on reward circuitry, we examined nucleus accumbens (NAcc) and hippocampal resting-state functional connectivity (rsFC) differences between 41 IGD subjects and 59 healthy controls. Significant connections were determined and used to examine correlations with clinical variables. Finally, we explored the relationship between neuroimaging findings, IGD severity and sleep disturbances through a mediation model. ResultsWe observed the connection deviation between the hippocampus and a wide range of cerebral cortexes in IGD subjects, including the prefrontal, parietal and temporal lobes. More importantly, the right posterior hippocampus (pHIP)-left caudate rsFC was positively correlated with both the Pittsburgh Sleep Quality Index (PSQI) and Internet Addiction Test scores and mediated the relationship between the two. For the NAcc, a difference between groups was only observed in the rsFC between the shell partition of the NAcc and the inferior orbitofrontal cortex, but this connectivity was not related to the PSQI score. ConclusionsIGD subjects showed a wide range of abnormal connections in the hippocampus, involving memory, reward motivation, and cognitive control. Here we emphasized the potential of the hippocampus in studying sleep disturbances in IGD, especially the coupling between the pHIP and caudate nucleus, which could provide novel insight into how sleep interacts with motivational systems in IGD subjects.

Measuring the developmental relationship between memory ability and organization of a functional brain network vulnerable to Alzheimer’s disease: Preliminary findings from the PRANK study

AbstractBackgroundThe hallmark memory impairments of typically presenting Alzheimer’s disease (AD) are associated with pathological changes of the hippocampus. While it is known that the hippocampus is necessary for normal relational memory performance, the development of functional brain networks associated with the hippocampus is not well characterized, particularly in the periadolescent epoch. The development of the hippocampus and its associated functional brain network may be influenced by genetic, environmental, or other risk factors for AD, potentially creating vulnerabilities to AD in later life. This project explores the neurodevelopment of this hippocampal network to determine how individual differences in functional connectivity impact relational memory abilities during the periadolescent epoch. Here, we utilized preliminary data from the NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study, which aims to improve insight regarding how brain and cognitive development is affected by polygenic risk for Alzheimer’s disease. Our continuing study is recruiting healthy periadolescent individuals (8‐13 years of age). Here we report preliminary cross‐sectional findings from the PRANK study exploring how individual differences in hippocampal resting‐state functional connectivity (RSFC) covary with declarative/relational memory ability.MethodAnalyses were conducted on preliminary data from healthy periadolescent participants (n=40). Declarative/relational memory performance was measured with Cambridge Cognition’s Paired Associates Learning (PAL) task. Resting‐state functional MRI data was analyzed using a seed‐based approach with the bilateral hippocampus as the seed region of interest. RSFC data were analyzed to determine their covariance with relational memory ability (operationalized as PAL performance).ResultOur analysis revealed patterns of hippocampal RSFC that were broadly consistent with prior work, sharing the territory of the default mode network (DMN). We also observed regional covariance between hippocampal RSFC and performance on the PAL task.ConclusionThe present work describes preliminary findings of the ongoing PRANK study. Our preliminary observations are consistent with the perspective that hippocampal RSFC covaries with hippocampal‐dependent declarative/relation memory ability among periadolescent children. To understand whether this hippocampal network development is susceptible to genetic risk factors for AD, future work from the PRANK study will utilize participants’ AD polygenic risk scores to determine whether those scores are related to individual differences of hippocampal RSFC.

Altered Hippocampal Resting-state Functional Connectivity in Highly Superior Autobiographical Memory

Individuals with Highly Superior Autobiographical Memory (HSAM) provide the opportunity to investigate the neurobiological substrates of enhanced memory performance. While previous studies started to assess the neural correlates of memory retrieval in HSAM, here we assessed for the first time the intrinsic connectivity of a core memory region, the hippocampus, with the whole brain, in 8 HSAM subjects (HSAMs) and 21 controls during resting-state functional neuroimaging. We found in HSAMs vs. controls disrupted hippocampal resting-state functional connectivity (rsFC) with high-level control regions belonging to the saliency network (the anterior cingulate cortex and the left and right insulae), and to the ventral fronto-parietal attentional network (the temporo-parietal junction and the inferior frontal gyrus), also involved with salience detection. Conversely, HSAMs showed enhanced hippocampal rsFC with sensory regions along the fusiform gyrus and the inferior temporal cortex. This altered pattern of hippocampal rsFC might be interpreted as a reduced capability of HSAMs to discriminate and select salient information, with a subsequent increase in the probability to encode and consolidate sensory information irrespective of their task-relevancy. Ultimately, these findings provide evidence that HSAM might be paradoxically enabled by an altered hippocampal rsFC that bypasses regions involved with salience detection in favor of specialized sensory regions.

Effects of walking exercise training on learning and memory and hippocampal neuroimaging outcomes in MS: A targeted, pilot randomized controlled trial

PurposeThe current pilot study involved a single-blind, randomized controlled trial (RCT) on the effects of treadmill walking exercise training compared with an active control condition on learning and memory (L/M) and hippocampal neuroimaging outcomes in 11 fully-ambulatory persons with multiple sclerosis (MS) who demonstrated impairments in new learning. MethodsThe study protocol is registered at clinicaltrials.gov: NCT03319771 (February 2018). Eleven fully-ambulatory persons with MS-related impairments in new learning were randomly assigned into either 12-weeks of supervised, treadmill walking exercise training or 12-weeks of low-intensity resistive exercise (active control condition). Participants underwent neuropsychological tests of L/M and hippocampal neuroimaging before and after the 12-week study period; outcomes were administered by treatment-blinded assessors. ResultsThere were moderate-to-large intervention effects on measures of verbal L/M (ηp2 = 0.11, d = 0.63, 95% CI: −0.61, 1.83), whereby those in the intervention condition demonstrated improvement in California Verbal Learning Test-II (CVLT-II) scores compared with the control condition. There were smaller effects on a composite L/M measure (ηp2 = 0.02, d = 0.28, 95% CI: −0.93, 1.46). There were large intervention effects on normalized hippocampal volume (ηp2 = 0.36, d = 1.13, 95% CI: 0.09, 2.82), whereby hippocampal volume was preserved in the intervention condition, compared with hippocampal atrophy in the control condition. By comparison, there were no intervention effects on hippocampal resting-state functional connectivity. ConclusionsCollectively, this study provides initial proof-of-concept data for further examining treadmill walking exercise training as a possible behavioral approach for managing L/M impairment and preserving hippocampal volume as common and debilitating manifestations of MS.

Hippocampal resting-state functional connectivity with the mPFC and DLPFC moderates and mediates the association between education level and memory function in subjective cognitive decline

Objective: This study aims to determine the relationship between education level, memory function, and hippocampus functional and structural alterations in subjective cognitive decline (SCD). Methods: Seventy-five participants with SCD were divided into high education (HE) and low education (LE) level groups. A Wechsler Memory Scale–Chinese Revision test and functional and structural MRI were performed within 1 week after participant recruitment. The bilateral hippocampus resting-state functional connectivity (rsFC), gray matter volume (GMV) of brain regions identified by rsFC analysis, and moderating and mediating effects were assessed. Results: Compared with the LE group, HE individuals showed 1) higher memory quotient (MQ) and Digit Span subscore, 2) decreased hippocampal rsFC with the right medial prefrontal cortex (mPFC) and dorsolateral prefrontal cortex (DLPFC), and 3) increased GMV in the right mPFC and DLPFC. The bilateral hippocampus–right DLPFC rsFC significantly associated with the MQ and the bilateral hippocampus–right mPFCrsFC with the Digit Span subscore in each group. The bilateral hippocampus–right DLPFC rsFC moderated the relationship between the education level and MQ. The bilateral hippocampus–right mPFC rsFC mediated the relationship between the education level and Digit Span subscore in all subjects. Conclusion: The hippocampal rsFC with the right mPFC and DLPFC contributes to the education level effect on memory function in SCD.

High schizotypy traits are associated with reduced hippocampal resting state functional connectivity

Altered hippocampal functioning is proposed to play a critical role in the development of schizophrenia-spectrum disorders. Previous resting state functional Magnetic Resonance Imaging (rs-fMRI) studies report disrupted hippocampal connectivity in patients with psychosis and in individuals with clinical high risk, yet hippocampal connectivity has not been investigated in people with high schizotypy traits. Here we used rs-fMRI to examine hippocampal connectivity in healthy people with low (LS, n = 23) and high levels (HS, n = 22) of schizotypal traits assessed using the Schizotypy Personality Questionnaire. Using a bilateral hippocampal seed region, we examined resting state functional connectivity (RSFC) between hippocampus and striatal, thalamic and prefrontal cortex regions of interest. Compared to LS, HS participants showed lower RSFC between hippocampus and striatum and between hippocampus and thalamus. Whilst the group effect of reduced hippocampal RSFC in striatal and thalamic regions was driven by total schizotypy scores, positive schizotypy subfactor scores were significantly positively correlated with hippocampus-caudate/thalamus RSFC. Group differences in RSFC were not observed between hippocampus and prefrontal cortex. These results demonstrate that subclinical schizotypal traits are associated with altered hippocampal connectivity in striatal and thalamic regions and provide further support that hippocampal dysconnectivity confers risk for schizophrenia spectrum disorders.

Hippocampal Functional Connectivity Mediates the Impact of Acceptance on Posttraumatic Stress Symptom Severity.

Investigation in posttraumatic stress disorder (PTSD) shows a negative association between patients’ degrees of acceptance (the willingness to face unwanted private experiences while pursuing one’s values and goals) and those of clinical symptom severity, suggesting that experiential acceptance is a protective factor of symptoms or an early indicator of resilience after trauma. However, neural mechanisms involved in the relationship between these two variables have yet to be elucidated. Thus, we here investigate whether there are neural mechanisms mediating such relationship using whole-brain voxel-level mediation analysis with seed-based resting-state functional connectivity (RSFC) maps generated by hippocampal subregion seeds in accident survivors (n = 33). We found that the correlation between patients’ acceptance and symptom severity was mediated by the RSFC strength between left hippocampal body and left lateral occipital cortex adjacent to superior parietal cortex, the areas related to flashbacks. Our result provides novel evidence that hippocampal RSFC mediates the effect of experiential acceptance on posttraumatic stress symptom severity. If further refined and validated, the finding may aid to the identification of biomarkers to intervention and prevention programs for patients with PTSD.

Hippocampal Resting-State Functional Connectivity Patterns are More Closely Associated with Severity of Subjective Memory Decline than Whole Hippocampal and Subfield Volumes.

The goal of this study was to examine whether hippocampal volume or resting-state functional connectivity (rsFC) patterns are associated with subjective memory decline (SMD) in cognitively normal aged adults. Magnetic resonance imaging data from 53 participants (mean age: 71.9 years) of the Boston University Alzheimer’s Disease Center registry were used in this cross-sectional study. Separate analyses treating SMD as a binary and continuous variable were performed. Subfield volumes were generated using FreeSurfer v6.0, and rsFC strength between the head and body of the hippocampus and the rest of the brain was calculated. Decreased left whole hippocampal volume and weaker rsFC strength between the right body of the hippocampus and the default mode network (DMN) were found in SMD+. Cognitive Change Index score was not correlated with volumetric measures but was inversely correlated with rsFC strength between the right body of the hippocampus and 6 brain networks, including the DMN, task control, and attentional networks. These findings suggest that hippocampal rsFC patterns reflect the current state of SMD in cognitively normal adults and may reflect subtle memory changes that standard neuropsychological tests are unable to capture.

Hippocampal Resting State Functional Connectivity in Patients With Schizophrenia and Unaffected Family Members.

The hippocampus is an important candidate region in the study of functional connectivity alterations in schizophrenia (SZ) given its role as a functional hub for multiple brain networks. Although studies have implicated the hippocampus in SZ, no studies have compared hippocampal functional connectivity in healthy participants, patients with SZ, and unaffected family members (UAFMs). Patients and UAFM likely share biomarkers associated with susceptibility to SZ; the study of UAFM may also reveal compensatory markers. Patients with SZ, UAFM, and healthy control (HC) participants underwent resting state magnetic resonance imagingty and completed the Wisconsin Card Sort Task (WCST) as a measure of general cognitive function. We compared functional coupling with a hippocampus seed across the three groups. SZ and UAFM groups shared reductions in connectivity between the hippocampus and the striatum relative to HC. We also identified a significant positive correlation between WCST errors and hippocampal-striatal connectivity in the UAFM group. Hippocampal-striatal rsFC may be associated with familial susceptibility to SZ and with subtle cognitive deficits in the UAFM of individuals with SZ.

The Role of Hippocampal Functional Connectivity on Multisystem Subclinical Abnormalities in Schizophrenia.

Schizophrenia is associated with excess medical mortality: patients have an average life expectancy one to two decades shorter than the general population. This study investigates the relationship between aberrant hippocampal resting-state functional connectivity in schizophrenia and cumulative subclinical effects of chronic stress on metabolic, cardiovascular, and immune function using the allostatic load index. Cumulative stress was estimated using allostatic load total score (range, 0-13) in 46 patients with schizophrenia and 31 controls matched for age and sex (patients: age = 36.1 [13.7] years, sex = 32/14 male/female; controls: age = 35.5 [14.1], sex = 21/10 male/female). Hippocampal functional connectivity was assessed using resting-state functional magnetic resonance imaging; hippocampal structural connectivity was assessed using fornix fractional anisotropy. Linear regression analysis was used a) to test the hypothesis that aberrant hippocampal resting-state functional connectivity in schizophrenia (identified in analysis of schizophrenia - control differences) is associated with elevated allostatic load scores in patients and b) to determine the association between fornix fractional anisotropy with allostatic load. In patients, higher allostatic load was significantly associated with reduced resting functional connectivity between the left hippocampus and right cingulate cortex and left precentral gyrus, but higher connectivity between the right hippocampus and left cerebellum lobe VI (corrected p values <. 05). In controls, reductions in both hippocampal structural connectivity and hippocampal-cingulate functional connectivity were associated with higher allostatic load scores. These findings support basic neuroscience evidence that cumulative stress and hippocampal function are closely connected and suggest that abnormal hippocampal functional communication in schizophrenia may be related to elevated multisystem subclinical medical issues in patients as indexed by allostatic load.

Pathologic tearfulness after limbic encephalitis: A novel disorder and its neural basis.

ObjectiveWe investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE).MethodsWe recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity.ResultsPathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons.ConclusionsPathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease.

Kaempferol Treatment after Traumatic Brain Injury during Early Development Mitigates Brain Parenchymal Microstructure and Neural Functional Connectivity Deterioration at Adolescence.

Targeting mitochondrial ion homeostasis using Kaempferol, a mitochondrial Ca2+ uniporter channel activator, improves energy metabolism and behavior soon after a traumatic brain injury (TBI) in developing rats. Because of broad TBI pathophysiology and brain mitochondrial heterogeneity, Kaempferol-mediated early-stage behavioral and brain metabolic benefits may accrue from diverse sources within the brain. We hypothesized that Kaempferol influences TBI outcome by differentially impacting the neural, vascular, and synaptic/axonal compartments. After TBI at early development (P31), functional magnetic resonance imaging and diffusion tensor imaging (DTI) were applied to determine imaging outcomes at adolescence (2 months post-injury). Vehicle and Kaempferol treatments were made at 1, 24, and 48 h post-TBI, and their effects were assessed at adolescence. A significant increase in neural connectivity was observed after Kaempferol treatment as assessed by the spatial extent and strength of the somatosensory cortical and hippocampal resting-state functional connectivity (RSFC) networks. However, no significant RSFC changes were observed in the thalamus. DTI measures of fractional anisotropy (FA) and apparent diffusion coefficient, representing synaptic/axonal and microstructural integrity, showed significant improvements after Kaempferol treatment, with highest changes in the frontal and parietal cortices and hippocampus. Kaempferol treatment also increased corpus callosal FA, indicating measurable improvement in the interhemispheric structural connectivity. TBI prognosis was significantly altered at adolescence by early Kaempferol treatment, with improved neural connectivity, neurovascular coupling, and parenchymal microstructure in select brain regions. However, Kaempferol failed to improve vasomotive function across the whole brain, as measured by cerebrovascular reactivity. The differential effects of Kaempferol treatment on various brain functional compartments support diverse cellular-level mitochondrial functional outcomes in vivo.