Human Neuroimaging Studies Research Articles

Associative recognition without hippocampal associations.

Whereas both human and animal lesion and human neuroimaging studies have implicated the hippocampus in memory for associations, some studies find preserved associative memory following hippocampal damage. Starting with a classic summed similarity model of item recognition, we can account for associative recognition without assuming a specific hippocampally-mediated associative process. We add one key assumption: that one item can influence activation of another item's features. Feature-strength patterns, evaluated for each probe item individually, are then diagnostic of whether an item was paired with one item versus another. We suggest that feature-level inference, without explicit storage of associations, may play a critical role in associative recognition tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A neuronal prospect theory model in the brain reward circuitry

Prospect theory, arguably the most prominent theory of choice, is an obvious candidate for neural valuation models. How the activity of individual neurons, a possible computational unit, obeys prospect theory remains unknown. Here, we show, with theoretical accuracy equivalent to that of human neuroimaging studies, that single-neuron activity in four core reward-related cortical and subcortical regions represents the subjective valuation of risky gambles in monkeys. The activity of individual neurons in monkeys passively viewing a lottery reflects the desirability of probabilistic rewards parameterized as a multiplicative combination of utility and probability weighting functions, as in the prospect theory framework. The diverse patterns of valuation signals were not localized but distributed throughout most parts of the reward circuitry. A network model aggregating these signals reconstructed the risk preferences and subjective probability weighting revealed by the animals’ choices. Thus, distributed neural coding explains the computation of subjective valuations under risk.

Angiotensin II Regulates the Neural Expression of Subjective Fear in Humans: A Precision Pharmaco-Neuroimaging Approach

BackgroundRodent models and pharmacological neuroimaging studies in humans have been used to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear, which represents the key symptom that motivates patients to seek treatment. In this study, we used a novel precision pharmacological functional magnetic resonance imaging approach based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (AT1R) antagonist losartan on the subjective experience of fear. MethodsIn a double-blind, placebo-controlled, randomized pharmacological functional magnetic resonance imaging design, healthy participants (N = 87) were administered 50 mg losartan or placebo before they underwent an oddball paradigm that included neutral, novel, and fear oddballs. Effects of losartan on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined. ResultsAT1R blockade selectively reduced neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate communication. Neurofunctional decoding further demonstrated fear-specific effects in that AT1R blockade reduced the neural expression of subjective fear but not of threat or nonspecific negative affect and did not influence reactivity to novel oddballs. ConclusionsThese results show a specific role of the AT1R in regulating the subjective fear experience and demonstrate the feasibility of a precision pharmacological functional magnetic resonance imaging approach to the affective characterization of novel receptor targets for fear in humans.

Topographic organization of the human caudate functional connectivity and age-related changes with resting-state fMRI.

The striatum is postulated to play a central role in gating cortical processing during goal-oriented behavior. While many human neuroimaging studies have treated the striatum as an undivided whole or several homogeneous compartments, some recent studies showed that its circuitry is topographically organized and has more complex relations with the cortical networks than previously assumed. Here, we took a gradient functional connectivity mapping approach that utilizes the entire anatomical space of the caudate nucleus to examine the organization of its functional relationship with the rest of the brain and how its topographic mapping changes with age. We defined the topography of the caudate functional connectivity using three publicly available resting-state fMRI datasets. We replicated and extended previous findings. First, we found two stable gradients of caudate connectivity patterns along its medial-lateral (M-L) and anterior-posterior (A-P) axes, supporting findings from previous tract-tracing studies of non-human primates that there are at least two main organizational principles within the caudate nucleus. Second, unlike previous emphasis of the A-P topology, we showed that the differential connectivity patterns along the M-L gradient of caudate are more clearly organized with the large-scale neural networks; such that brain networks associated with internal vs. external orienting behavior are respectively more closely linked to the medial vs. lateral extent of the caudate. Third, the caudate's M-L organization showed greater age-related reduction in integrity, which was further associated with age-related changes in behavioral measures of executive functions. In sum, our analysis confirmed a sometimes overlooked M-L functional connectivity gradient within the caudate nucleus, with its lateral longitudinal zone more closely linked to the frontoparietal cortical circuits and age-related changes in cognitive control. These findings provide a more precise mapping of the human caudate functional connectivity, both in terms of the gradient organization with cortical networks and age-related changes in such organization.

What is there to know about the effects of progestins on the human brain and cognition?

Progestins are an important component of hormonal contraceptives (HCs) and hormone replacement therapies (HRTs). Despite an increasing number of studies elucidating the effects of HCs and HRTs, little is known about the effects of different types of progestins included in these medications on the brain. Animal studies suggest that various progestins interact differently with sex steroid, mineralocorticoid and glucocorticoid receptors and have specific modulatory effects on neurotransmitter systems and on the expression of neuropeptides, suggesting differential impacts on cognition and behavior. This review focuses on the currently available knowledge from human behavioral and neuroimaging studies pooled with evidence from animal research regarding the effects of progestins on the brain. The reviewed information is highly relevant for improving women’s mental health and making informed choices regarding specific types of contraception or treatment.

Explicit and Implicit Emotion Processing in the Cerebellum: A Meta-analysis and Systematic Review.

The cerebellum's role in affective processing is increasingly recognized in the literature, but remains poorly understood, despite abundant clinical evidence for affective disruptions following cerebellar damage. To improve the characterization of emotion processing and investigate how attention allocation impacts this processing, we conducted a meta-analysis on task activation foci using GingerALE software. Eighty human neuroimaging studies of emotion including 2761 participants identified through Web of Science and ProQuest databases were analyzed collectively and then divided into two categories based on the focus of attention during the task: explicit or implicit emotion processing. The results examining the explicit emotion tasks identified clusters within the posterior cerebellar hemispheres (bilateral lobule VI/Crus I/II), the vermis, and left lobule V/VI that were likely to be activated across studies, while implicit tasks activated clusters including bilateral lobules VI/Crus I/II, right Crus II/lobule VIII, anterior lobule VI, and lobules I-IV/V. A direct comparison between these categories revealed five overlapping clusters in right lobules VI/Crus I/Crus II and left lobules V/VI/Crus I of the cerebellum common to both the explicit and implicit task contrasts. There were also three clusters activated significantly more for explicit emotion tasks compared to implicit tasks (right lobule VI, left lobule VI/vermis), and one cluster activated more for implicit than explicit tasks (left lobule VI). These findings support previous studies indicating affective processing activates both the lateral hemispheric lobules and the vermis of the cerebellum. The common and distinct activation of posterior cerebellar regions by tasks with explicit and implicit attention demonstrates the supportive role of this structure in recognizing, appraising, and reacting to emotional stimuli.

The effects of probiotics on risk and time preferences

Animal models, human neuroimaging and lesion studies revealed that the gut microbiota can influence the interaction between the central and the enteric nervous systems via the gut–brain axis (GBA) and can affect brain regions linked to basic emotional and cognitive processes. The role of the gut microbiota in decision-making in healthy humans thus far remains largely unknown. Our study establishes a functional relationship between the gut microbiota and healthy humans’ decisions that involve risk and time. We conducted a between subjects’ placebo-controlled double-blinded design, with two groups and two sessions separated by 28 days, during which participants received daily doses of probiotics or a placebo. We investigated whether the prolonged and controlled intake of probiotics affects risk-taking behavior and intertemporal choices using incentivized economic tasks. We found a significant decrease in risk-taking behavior and an increase in future-oriented choices in the probiotics group as compared to the placebo group. These findings provide the first direct experimental evidence suggesting a potential functional role on the part of the microbiota-gut-brain axis in decision-making, creating a path for potential clinical applications and allowing for a better understanding of the underlying neural mechanisms of risk-taking behavior and intertemporal choices.

The Neurobiological Basis of Love: A Meta-Analysis of Human Functional Neuroimaging Studies of Maternal and Passionate Love.

Maternal and passionate love are both crucial for reproduction and involve attachment behaviors with high rewards. Neurobiological studies of attachment in animal and human neuroimaging studies have suggested that the coordination of oxytocinergic and vasopressinergic pathways, coupled with the dopaminergic reward system, contribute to the formation and maintenance of maternal and passionate love. In the present study, we carried out a quantitative meta-analysis of human neuroimaging to identify common and dissociable neural substrates associated with maternal and passionate love, using the activation likelihood estimation (ALE) approach. The ALE results showed significant activation of the brain regions in the left ventral tegmental area (VTA), right thalamus, left substantia nigra, and the left putamen for maternal love, but in the bilateral VTA for passionate love. The meta-analytic neuroimaging evidence suggests the greater involvement of cognitive–affective regulation in maternal attachment and the greater desire to combine liking and wanting in romantic love behaviors. The conjunction analysis highlights the functional convergence of the VTA across the two types of human love, indicating a shared neurobiological mechanism of maternal and passionate love with evolutionary roots. Our findings suggest that the processing of both maternal and passionate love involve the affective and motivational regulation associated with dopaminergic systems; our neuroimaging evidence supports the notion that maternal and passionate love share a common evolutionary origin and neurobiological basis in the human brain.

Temporally and anatomically specific contributions of the human amygdala to threat and safety learning

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Open-label study of androgen receptor inhibition with darolutamide plus androgen-deprivation therapy (ADT) versus ADT in men with metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC).

TPS5111 Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARI) that significantly improved metastasis-free survival by ̃2 years and reduced the risk of death by 31% vs placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Darolutamide has a favorable safety and tolerability profile, with only ≤2% difference vs placebo for most adverse events (AEs) of interest (falls, fractures, hypertension, mental impairment). Fatigue was the only AE with > 10% incidence in the darolutamide arm (13.2%; placebo, 8.3%). Darolutamide has shown lower blood–brain barrier penetration than other ARIs in preclinical models (supported by human neuroimaging studies), which may lead to a lower risk of central nervous system-related AEs and has a low potential for drug–drug interactions. For patients with metastatic hormone-sensitive prostate cancer (mHSPC), the combination of darolutamide and ADT is expected to offer a favorable benefit–risk profile. ARASEC will evaluate the efficacy and safety of darolutamide plus ADT in mHSPC in the US (NCT05059236) and complement the data in the ongoing ARANOTE study (NCT04736199). Methods: ARASEC is a US-based, phase 2, open-label, single-arm study with an external control arm. Eligible patients will have confirmed adenocarcinoma of the prostate, radiologic evidence of metastatic disease by conventional imaging, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Patients with mHSPC will receive darolutamide 600 mg twice daily plus ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The control arm for ARASEC will be derived from the 393 patients with mHSPC treated with ADT alone in the CHAARTED trial. Patients in the active arm will be matched 1:1 to patients in the control arm using important baseline characteristics such as age, ECOG PS, extent of disease defined as low or high volume according to CHAARTED, and presence of bone and visceral metastases. Study duration was defined as the time from the first patient’s first visit until either the event count threshold triggering the primary endpoint analysis has been met or all patients have been followed for ≥2 years after enrollment, whichever occurs later. The primary endpoint is progression-free survival (PFS), defined in CHAARTED as the time from enrollment to prostate-specific antigen (PSA) progression, clinical progression (including radiological or symptomatic progression or clinical deterioration), or death, whichever occurs first. Secondary endpoints are overall survival, radiographic PFS, time to CRPC, complete PSA response rate at 6 months, and safety. Patient recruitment is in progress. Clinical trial information: NCT05059236.

Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity

Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.

Aversive conditioning: Principles of memory storage in sensory cortex

Sensory cortices exhibit plasticity after aversive learning and may have a crucial role in memory storage. A human neuroimaging study has now addressed neural principles underlying olfactory disgust conditioning.

Neuroimaging Recovery in Human Drug Addiction: An Eye Towards Intervention Development

Drug addiction is on the rise during these COVID-19 times that intensify the factors contributing to relapse and overdose across drugs of abuse and continents. Using a multimodal approach (neuropsychology, fMRI, ERP), human neuroimaging studies in my lab have elucidated core mechanisms underlying drug addiction, with a focus on the role of the dopaminergic mesocorticolimbic circuit, especially the prefrontal cortex, in higher-order cognitive and emotional dysfunction in this population. Our theoretical model is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex (and other cortical regions underlying higher order executive function), contribute to the core clinical symptoms in addiction. Specifically, our program of research is guided by the working hypothesis that drug addicted individuals disproportionately attribute salience and value to their drug of choice at the expense of other reinforcing stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. Our complex and multifaceted dataset has allowed us to study the impact of abstinence on recovery in these brain-behavior compromises in treatment-seeking addicted individuals, where non-linear relationships exemplify incubation of craving while other trajectories of change, including in white matter tracks and for small subcortical regions (such as the habenula), are also explored. Novel paradigm shifts in the lab include the use of naturalistic and dynamic stimuli for enhanced generalizability and validity, in addition to development of effective neurorehabilitation strategies (including cognitive reappraisal, mindfulness, and transcranial direct current stimulation) in drug addiction.

P684. Diurnal Fluctuations in Testosterone Tied to Variation in Intrinsic Functional Connectivity in a Densely Sampled Male

Sex hormones are powerful neuromodulators of learning and memory, influencing the brain at the level of microscopic intracellular events to macroscopic brain organization. A central feature of the mammalian endocrine system is that hormone secretion varies over time. Human neuroimaging studies that densely sample individuals over timescales of days, weeks, and months provide unique insight into the role our endocrine system plays in regulating the dynamic properties of the human brain. For example, we recently established estrogen’s ability to drive widespread patterns of connectivity and enhance the global efficiency of large-scale brain networks in a densely-sampled female (Pritschet et al., 2020). In men, sex hormone production follows a sinusoidal pattern with a peak in testosterone between 6-7am and nadir between 7-8pm.

P84. Reproductive Status Shapes Working Memory Circuitry in Midlife Women

Sex steroid hormones are neuromodulators of learning and memory. Yet, human neuroimaging studies of the aging brain typically focus on neurocognitive changes brought on by chronological aging, leaving much less known about the effects of endocrine aging.

P272. Diminished ‘Punishment Learning’ in Patients with Treatment-Resistant Depression

Human neuroimaging studies demonstrate diminished reward learning in dopaminergic regions known to encode prediction errors between expected and experienced rewards in patients with depression. However, differences in punishment learning and how these may vary in patients responsive or not to antidepressants is unclear. We utilized a novel valence-partitioned reinforcement learning model to examine cohort-specific differences in punishment learning.

Fatty acid amide hydrolase levels in brain linked with threat-related amygdala activation

BackgroundPreclinical evidence suggests that increasing levels of the major endocannabinoid anandamide decreases anxiety and fear responses potentially through its effects in the amygdala. Here we used neuroimaging to test the hypothesis that lower fatty acid amide hydrolase (FAAH), the main catabolic enzyme for anandamide, is associated with a blunted amygdala response to threat. MethodsTwenty-eight healthy participants completed a positron emission tomography (PET) scan with the radiotracer for FAAH, [11C]CURB, as well as a block-design functional magnetic resonance imaging session during which angry and fearful faces meant to activate the amygdala were presented. Results[11C]CURB binding in the amygdala as well as in the medial prefrontal cortex, cingulate and hippocampus correlated positively with blood-oxygen-level-dependent (BOLD) signal during processing of angry and fearful faces (pFWE < 0.05). ConclusionOur finding that lower levels of FAAH in amygdala, medial prefrontal cortex, cingulate and hippocampus was associated with a dampened amygdala response to a threatening social cue aligns with preclinical and neuroimaging studies in humans and suggests the involvement of FAAH in modulating stress and anxiety in humans. The current neuroimaging study also lends support for the potential use of FAAH inhibitors to control amygdala hyperactivity, which is known to be involved in the pathophysiology of anxiety and trauma-related disorders.

Myeloarchitectonic plasticity in elite golf players' brains.

Human neuroimaging studies have demonstrated that exercise influences the cortical structural plasticity as indexed by gray or white matter volume. It remains elusive, however, whether exercise affects cortical changes at the finer‐grained myelination structure level. To answer this question, we scanned 28 elite golf players in comparison with control participants, using a novel neuroimaging technique—quantitative magnetic resonance imaging (qMRI). The data showed myeloarchitectonic plasticity in the left temporal pole of the golf players: the microstructure of this brain region of the golf players was better proliferated than that of control participants. In addition, this myeloarchitectonic plasticity was positively related to golfing proficiency. Our study has manifested that myeloarchitectonic plasticity could be induced by exercise, and thus, shed light on the potential benefits of exercise on brain health and cognitive enhancement.

What Is the Brainstem Control of Locomotion?

Locomotion in humans is defined as bipedal progression through stages of a gait cycle to move from one place to another while maintaining balance and posture. Locomotion can be categorized in temporal phases (initiation, actual locomotive episode/execution, and termination) or in behavioral categories (slow exploratory and fast speed locomotion). The motivation behind a locomotive episode may be driven by internal needs (goal driven from the motor cortex or emotion driven from the limbic system) or external environmental cues. Locomotion is mediated by a spinal central pattern generator (CPG) under the influence of the brainstem reticular formation and is integrated with control of muscle tone and posture. Control of gait, muscle tone, and posture involves complex interactions among the sensorimotor cortex, basal ganglia, basal forebrain, cerebellum, brainstem, and spinal cord.1-3 Pioneering studies in cats4 and monkeys5,6 and more recently in rodents7-12 have contributed to elucidate the brainstem mechanisms controlling locomotion. This information, together with indirect evidence from human electrophysiologic and functional neuroimaging studies, provides testable pathophysiologic hypotheses and potential therapeutic targets for gait control disorders. The focus of this review is on brainstem mechanisms controlling locomotion. The role of other CNS areas in control of gait and posture and their abnormalities in disorders such as Parkinson disease (PD) have been extensively reviewed1 and are only briefly discussed here.

Risk Factors for Brain Health in Agricultural Work: A Systematic Review.

Certain exposures related to agricultural work have been associated with neurological disorders. To date, few studies have included brain health measurements to link specific risk factors with possible neural mechanisms. Moreover, a synthesis of agricultural risk factors associated with poorer brain health outcomes is missing. In this systematic review, we identified 106 articles using keywords related to agriculture, occupational exposure, and the brain. We identified seven major risk factors: non-specific factors that are associated with agricultural work itself, toluene, pesticides, heavy metal or dust exposure, work with farm animals, and nicotine exposure from plants. Of these, pesticides are the most highly studied. The majority of qualifying studies were epidemiological studies. Nigral striatal regions were the most well studied brain area impacted. Of the three human neuroimaging studies we found, two focused on functional networks and the third focused on gray matter. We identified two major directions for future studies that will help inform preventative strategies for brain health in vulnerable agricultural workers: (1) the effects of moderators such as type of work, sex, migrant status, race, and age; and (2) more comprehensive brain imaging studies, both observational and experimental, involving several imaging techniques.