Biology subjects

Elliott, B. L.

Publications and source records attributed to Elliott, B. L..

8 recordsLinked to original sources

bioRxiv2026

Mapping Mesolimbic Dopamine Projections to Subcortical Circuits Underlying Adaptive Behavior: A Human 7T Diffusion Tractography Atlas

The mesolimbic dopamine system supports broad aspects of adaptive behavior including salience, learning, memory, and decision making, yet the structural organization supporting these functions remains incompletely mapped in humans. Using high-resolution 7T diffusion magnetic resonance imaging (up to N=173), we reconstructed seven bilateral ventral tegmental area (VTA)-subcortical pathways spanning direct mesolimbic projections and the hippocampus-VTA (HPC-VTA) loop regulatory circuit. Projection-endpoint analyses revealed long-axis and subfield organization of VTA-hippocampal pathways and superior-inferior VTA-nucleus accumbens (NAc) topography. Consistent with the HPC-VTA loop framework, neurite density covaried across mesolimbic pathways but not the arcuate fasciculus, demonstrating circuit-level organization. Nodewise analyses identified localized associations between pathway microstructure and delay discounting across VTA-hippocampal, VTA-NAc, and VTA-amygdala pathways. Together, these findings parse the human mesolimbic system into distinct pathways supporting adaptive behavior. The probabilistic atlas, MesoConnect, is freely available with tutorials to facilitate reconstruction and investigation of circuits in independent datasets.

neuroscience↗

bioRxiv2026

Altered Dopamine-Linked Striatal Hemodynamic Latency in Early Psychosis

Key Points Question: Is striatal hemodynamic latency, a novel indirect correlate of dopamine physiology, altered in individuals with early psychosis? Findings: In this cross-sectional study of 105 individuals with early psychosis and 55 healthy comparison participants, early psychosis was associated with significantly lower striatal hemodynamic latency. Differences were observed in the dorsal striatum (caudate and putamen), whereas ventral striatal (nucleus accumbens) latency did not significantly differ between groups. Meaning: These findings support further evaluation of striatal hemodynamic latency as a noninvasive, indirect marker of dopamine-linked physiology in early psychosis. Abstract Importance: Psychosis is strongly associated with striatal dopamine dysfunction, but noninvasive measures that capture variation in dopamine remain limited. Hemodynamic latency, which quantifies the timing of low-frequency blood oxygen level-dependent (BOLD) fluctuations, may provide a way to indirectly probe dopamine dysfunction in psychosis. Objective: To determine whether striatal hemodynamic latency differs between individuals with early psychosis (EP) and healthy control (HC) participants and whether latency is associated with positive or negative symptom severity. Design: Cross-sectional analysis of resting-state functional magnetic resonance imaging (fMRI) data from the Human Connectome Project (HCP)-EP dataset. Setting: Multisite study at 4 sites using 3T Siemens Prisma MRI scanners. Participants: 105 individuals with EP and 55 HC participants with usable resting-state fMRI and hemodynamic latency data. Exposure: EP status. Main Outcomes and Measures: Voxel-wise hemodynamic latency was estimated using RapidTide and summarized within 6 striatal regions: nucleus accumbens core and shell, anterior and posterior caudate and putamen. Group differences were evaluated using linear mixed-effects models accounting for region and subject-level random effects and controlling for age, sex, and mean framewise displacement. Positive symptoms were measured using the Positive and Negative Syndrome Scale positive subscale; negative symptoms using the Clinical Assessment Interview for Negative Symptoms. Associations with symptoms were assessed using nested linear regressions within the EP group. Results: Latency was significantly lower in the dorsal than ventral striatum in HC and EP, with a greater difference in EP (b=-119.46 ms, SE=52.16, p=.022). Follow-up six-subregion models found significant main effects of group F(1,156.55)=7.79, p=.006, and region F(5,2760)=187.99; p< .001, but no group-by-region interaction F(5,2760)=1.74; p=.121. Region-specific contrasts showed lower latency in EP in the anterior caudate (p=.014), posterior caudate (p<.001), anterior putamen (p=.007), and posterior putamen (p=.029), but not NAc core or shell. Striatal latency was not significantly associated with positive or negative symptom severity among participants with EP. Conclusions and Relevance: EP was associated with broadly reduced striatal hemodynamic latency, with the strongest differences in the caudate and putamen. Altered striatal latency in psychosis warrants further evaluation as a noninvasive indirect marker of striatal pathophysiology linked to dopamine.

neuroscience↗

bioRxiv2026

Prenatal Maternal Inflammation Is Associated with Altered Offspring Mesolimbic White Matter Circuitry Observed in Late Midlife

BackgroundExposure to prenatal maternal inflammation (PNMI) has been linked to neurodevelopmental alterations in human offspring. Preclinical studies suggest that PNMI disrupts reward circuitry, particularly within mesolimbic circuits. However, the effects of PNMI on mesolimbic circuits (i.e, ventral tegmental area (VTA) projections to the hippocampus (VTA-H) and limbic striatum (VTA-LS)) in humans are not yet known. MethodsData for PNMI biomarkers [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor-II (sTNF-RII)] from first trimester (T1) and second trimester (T2) maternal sera, and offspring MRI brain scans in late midlife (aged 57-63 years), were available for 89 mother-offspring dyads. Probabilistic tractography delineated bilateral VTA-H and VTA-LS tracts. Macrostructural tract measures were examined using hierarchical linear regressions. Microstructural integrity was assessed using neurite orientation dispersion and density imaging, and permutation-based cluster analyses. ResultsHigher T2 IL-1ra was associated with increased macrostructure (left VTA-H tract), whereas higher T2 sTNF-RII was associated with reduced macrostructure (right VTA-H and VTA-LS tracts) and higher T2 IL-8 (bilateral VTA-LS tracts). Microstructurally, higher T2 IL-6 was associated with increased neurite density (distal cluster, right VTA-H tract), while higher T1 IL-8 was associated with reduced neurite density (near the hippocampus in the left VTA-H tract, near the VTA in bilateral VTA-LS tracts). ConclusionsPNMI was associated with altered mesolimbic reward circuitry in offspring. This suggests that prenatal inflammation may contribute to affective and motivational disorders in offspring via alterations in mesolimbic circuitry.

neuroscience↗

bioRxiv2024

Synergistic Neural Circuits for Novelty and Goal-Directed Behavior

The ability to adapt to a dynamic world relies on detecting, learning, and responding to environmental changes. The detection of novelty serves as a critical indicator of such changes, priming mechanisms to detect and respond to goal-relevant information. However, neural regions that support novelty detection (hippocampus) and goal-directed behavior (dopaminergic midbrain [VTA] and prefrontal cortex [PFC]) have yet to be described as a sequential process that unfolds over time. Using a forward-prediction functional magnetic resonance imaging (fMRI) model, we explored interactions between the hippocampus, VTA, and PFC in humans performing a novelty-imbued target-detection task. Hippocampal novelty activation predicted subsequent VTA target activation, enhancing readiness to detect goal-relevant information. Concurrently, goal-directed PFC activation modulated VTA target activation, refining focus on behaviorally significant cues. These circuits function both synergistically and independently, promoting subsequent hippocampal activity during target trials. This work provides new insights into how distributed circuits coordinate to optimize adaptive behavior. Significance StatementSurviving in dynamic environments requires coordinated neural mechanisms to detect, learn from, and respond to change. However, neural regions that support novelty detection and goal-oriented behavior have yet to be described as a sequential process that unfolds over time. Using a novel forward-prediction functional magnetic resonance imaging (fMRI) model, we show that hippocampal activation during novelty predicts ventral tegmental area (VTA) readiness to process goal-relevant information. Concurrently, goal-directed prefrontal cortex activity modulates VTA responses, sharpening focus on behaviorally significant cues. Furthermore, these synergistic and independent circuits enhance hippocampal sensitivity for future adaptive responses, offering novel insights into integration of brain mechanisms critical for learning, motivation, and executive function.

neuroscience↗

bioRxiv2024

Decreased hippocampal neurite density in middle-aged/aging adults following prenatal exposure to higher levels of maternal inflammation

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interests neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes. Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early mid-gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of prenatal insults in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.

immunology↗

bioRxiv2023

Cerebellum-Midbrain Reward Circuitry in Humans: an in vivo dissection

Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in humans using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections from the cerebellum to the VTA predominantly originate in the right hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.

neuroscience↗

bioRxiv2023

In Vivo Structural Connectivity of the Reward System Along the Hippocampal Long-Axis

Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N=628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (VTA) showed stronger connectivity with the anterior versus posterior hippocampus, the vmPFC showed stronger connectivity with the posterior hippocampus. The nucleus accumbens (NAc) showed a more homogeneous connectivity profile along the hippocampal long-axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.

neuroscience↗

bioRxiv2022

Midbrain-Hippocampus Structural Integrity Selectively Predicts Motivated Memory Encoding

Motivation is a powerful driver of learning and memory. Functional MRI studies show that interactions between the dopaminergic midbrain (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. However, it is not known if these effects are transient and purely functional, or if individual differences in the structure of this circuit underlie motivated memory encoding. To quantify individual differences in structure, diffusion-weighted MRI and probabilistic tractography were used to quantify SN/VTA-striatum and SN/VTA-hippocampus pathways associated with motivated memory encoding in humans. Participants completed a motivated source memory paradigm. During encoding, words were randomly assigned to one of three conditions: reward ($1.00), control ($0.00), or punishment (-$1.00). During retrieval, participants were asked to retrieve item and source information of the previously studied words and were rewarded or penalized according to their performance. Source memory for words assigned to both reward and punishment conditions was greater than control words, while there were no differences in item memory based on value. Anatomically, probabilistic tractography results revealed a heterogeneous, topological arrangement of the SN/VTA. Tract density measures of SN/VTA-hippocampus pathways were positively correlated with individual differences in reward and punishment modulated memory performance, while density of SN/VTA-striatum pathways showed no association. This novel finding suggests that pathways emerging from the human SV/VTA are anatomically separable and functionally heterogeneous. Individual differences in structural connectivity of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding. Significance StatementFunctional MRI studies show that interactions between the dopaminergic midbrain (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. This has led to competing theories that posit either SN/VTA-NAc reward prediction errors or SN/VTA-hippocampus signals underlie motivated memory encoding. Additionally, it is not known if these effects are transient and purely functional, or if individual differences in the structure of these circuits underlie motivated memory encoding. Using diffusion-weighted MRI and probabilistic tractography, we show that tract density measures of SN/VTA-hippocampus pathways are positively correlated with motivated memory performance, while density of SN/VTA-striatum pathways show no association. This finding suggests that anatomical individual differences of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.

neuroscience↗