Human Imaging Studies Research Articles

The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models

Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review evidence collected during the past 40-plus years supporting the role of dopamine dysfunction in attention deficit hyperactivity disorder (ADHD). We recapitulate the basic components of dopaminergic signaling in the central nervous system, focusing on core enzymes, transporters and receptors involved in monoaminergic functions, particularly in striatal and cortical regions. We summarize key human brain imaging and genetic studies reporting associations between dopaminergic neurotransmission and behavioral traits, with an emphasis on ADHD. We also consider ADHD in the context of animal models and single gene, metabolic, and neurological disorders with established dysfunction of the dopaminergic system. Examining the evidence in this way leads us to conclude that there is evidence for the involvement of dopamine but limited evidence for a hypo-dopaminergic state per se as a key component of ADHD. We propose a path forward to increase our understanding of dopamine signaling in human behavioral traits and disorders that should particularly focus on its role in clinical subgroups, during brain development and how it interacts with other neurotransmitter systems.

FONDUE: Robust resolution-invariant denoising of MR Images using Nested UNets

Abstract Recent human magnetic resonance imaging (MRI) studies continually push the boundaries of spatial resolution as a means to enhance levels of neuroanatomical detail and increase the accuracy and sensitivity of derived brain morphometry measures. However, acquisitions required to achieve these resolutions have a higher noise floor, potentially impacting segmentation and morphometric analysis results. This study proposes a novel, fast, robust, and resolution-invariant deep learning method to denoise structural human brain MRIs. We explore denoising of T1-weighted (T1w) brain images from varying field strengths (1.5T to 7T), voxel sizes (1.2mm to 250µm), scanner vendors (Siemens, GE, and Phillips), and diseased and healthy participants from a wide age range (young adults to aging individuals). Our proposed Fast-Optimized Network for Denoising through residual Unified Ensembles (FONDUE) method demonstrated stable denoising capabilities across multiple resolutions with performance on par or superior to the state-of-the-art methods while being several orders of magnitude faster at low relative cost when using a dedicated Graphics Processing Unit (GPU). FONDUE achieved the best performance on at least one of the four denoising-performance metrics on all the test datasets used, showing its generalization capabilities and stability. Due to its high-quality performance, robustness, fast execution times, and relatively low-GPU memory requirements, as well as its open-source public availability, FONDUE can be widely used for structural MRI denoising, especially in large-cohort studies. We have made the FONDUE repository and all training and evaluation scripts as well as the trained weights available at https://github.com/waadgo/FONDUE.

Neural Transformation from Retinotopic to Background-Centric Coordinates in the Macaque Precuneus.

Visual information is initially represented in retinotopic coordinates and later in craniotopic coordinates. Psychophysical evidence suggests that visual information is further represented in more general coordinates related to the external world; however, the neural basis of non-egocentric coordinates remains elusive. This study investigates the automatic transformation from egocentric to non-egocentric coordinates in the macaque precuneus (two males, one female), identified by a functional imaging study as a key area for non-egocentric representation. We found that 6.2% of neurons in the precuneus have receptive fields anchored to the background rather than to the retina or the head, while 16% had traditional retinotopic receptive fields. Notably, these two types were not exclusive: many background-centric neurons initially encode a stimulus's position in retinotopic coordinates (up to ∼90 ms from stimulus onset) but later shift to background coordinates, peaking at ∼150 ms. Regarding retinotopic information, the stimulus dominated the initial period, whereas the background dominated the later period. In the absence of a background, there is a dramatic surge in retinotopic information about the stimulus during the later phase, clearly delineating two distinct periods of retinotopic encoding: one focusing on the figure to be attended and another on the background. These findings suggest that the initial retinotopic information of the stimulus is combined with the background retinotopic information in a subsequent stage, yielding a more stable representation of the stimulus relative to the background through time-division multiplexing.Significance Statement According to psychological literature, the location of visual stimuli is automatically positioned against the background of a scene. This representation relative to the background, not being influenced by eye movements, should be important for stabilizing the visual world. A human functional imaging study suggested that the precuneus in the medial cerebral cortex is a strong candidate. This study recorded neural activity from the precuneus of monkeys and demonstrated the existence of background-centered cells with receptive fields fixed relative to the background.

Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids

A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.

The Glymphatic System and its Relationship to Migraine.

We aim to critically review animal and human studies of the glymphatic system in migraine and propose a model for how the glymphatic system may function in migraine, based on the available evidence. Early studies in animal models report migraine attacks temporarily disrupt glymphatic flow. Human imaging studies suggest chronic migraine may be associated with alterations in glymphatic system function, albeit with conflicting results. Presently, it remains unknown whether repetitive migraine attacks or frequent nights of insomnia impair glymphatic system function over time in those with migraine, and whether alterations in glymphatic function could contribute to worsening migraine disability or risk for cognitive disease. Longitudinal studies of glymphatic function in patients with migraine and insomnia, with inclusion of cognitive assessments, may be informative.

Impact of pathogenic variants of the Ras-mitogen-activated protein kinase pathway on major white matter tracts in the human brain.

Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

An Updated Review on Possible Therapeutic Role of Vincamine Via 5-HT Receptors in the Treatment of Depression

Background: Serotonin is a neurotransmitter that regulates neuronal activity and a variety of cognitive functions, and medicines that target serotonin receptors are frequently utilized in psychiatry and neurology. Clinical and preclinical research on the role of serotonin in major depressive disorder is growing. These findings demonstrate the intricacy of serotonin transmission across multiple receptors, in a variety of brain areas, and across the lifespan. The serotonin transporter's significance in major depressive disorder has been highlighted in geneenvironment association studies, as well as its participation in the mechanism of the most successful antidepressant medications, selective serotonin reuptake inhibitors. While most of the 15 known serotonin receptors have been linked to depression or depressive-like behaviour, the serotonin 1A (5-HT) and 1B (5-HT) receptors have received the most attention. Objectives: The primary goal of this study is to review the antidepressant effect of herbal medications by modifying serotonin receptors in the future. Result: Human brain imaging and genetic studies suggest that 5-HT and 5-HT receptors play a role in major depressive disorder and antidepressant treatment response. The availability of tissue-specific and inducible knockout mice lines in rodents has allowed for the detection of 5- HT and 5-HT receptor involvement throughout development and in cell-type specific ways. It may be found that herbal drugs will be effective as the serotonin reuptake inhibitors. Conclusion: This and other future preclinical pharmacology studies show that these receptors' autoreceptor and heteroreceptor populations play different roles in modulating depressionrelated behaviour and antidepressant responses, as well as having different functions during early postnatal development versus adulthood. According to analysis of our research findings, alkaloids may have some therapeutic promise as natural antidepressants. Given their widespread distribution in nature, alkaloids might be a cheap way to treat depression.

Sex and mental health are related to subcortical brain microstructure

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

Neuronal tuning and population representations of shape and category in human visual cortex

Object recognition and categorization are essential cognitive processes which engage considerable neural resources in the human ventral visual stream. However, the tuning properties of human ventral stream neurons for object shape and category are virtually unknown. We performed large-scale recordings of spiking activity in human Lateral Occipital Complex in response to stimuli in which the shape dimension was dissociated from the category dimension. Consistent with studies in nonhuman primates, the neuronal representations were primarily shape-based, although we also observed category-like encoding for images of animals. Surprisingly, linear decoders could reliably classify stimulus category even in data sets that were entirely shape-based. In addition, many recording sites showed an interaction between shape and category tuning. These results represent a detailed study on shape and category coding at the neuronal level in the human ventral visual stream, furnishing essential evidence that reconciles human imaging and macaque single-cell studies.

Human Brain Magnetic Resonance Imaging Studies for Psychiatric Disorders: The Current Progress and Future Directions.

With the prevalence of psychiatric disorders and the limitations of the diagnostic scheme and treatment options of these disorders, magnetic resonance imaging (MRI) studies play a significant role in uncovering the pathological basis of psychiatric disorders and potentially using biological markers in clinical settings. The use of MRI in clinical research has grown over the past three decades, and current MRI research continues to provide an avenue to guide the development of diagnostic approaches and therapeutic solutions. However, the current shortcomings of MRI studies derive not only from technical limitations (i.e., the range of contrasts that MRI probes or sensors can create) but also from confounding factors in the current methodological approaches of case-control studies for psychiatric disorders. Thus, by reviewing the recent literature on MRI research on psychiatric disorders, we explain the current progress and limitations of brain MRI methodologies used to study psychiatric disorders. We consider the growing use of cross-disorder methods to identify shared and disease-specific pathological features across psychiatric disorders. In addition, we need to outline healthy developmental and aging changes of the brain and investigate the disorder difference as a deviation of the trajectory. Although these methods have provided us with new insights, the demarcation between psychiatric disorders based on a definitive set of pathologies remains limited. This challenge of disease stratification is further complicated by the presence of multiple different sets of disorder pathologies within a single disorder and the different progressive timelines of different disorders. As such, we introduce the ongoing research projects in Japan, namely, the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) and the Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond). These collaborative research initiatives across Japan use neuroimaging and travel-subject harmonization to conduct nationwide MRI studies capable of providing large-scale coherent results, which may address the current limitations of MRI psychiatric disorder research.

A Cross-Sectional and Longitudinal Integrated Study on Brain Functional Changes in a Neuropathic Pain Rat Model.

Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions and even causes mental dysfunctions such as depression and anxiety disorders. In this article, we conducted a multimodal study cross-sectionally and longitudinally, to evaluate how neuropathic pain affects the brain. Using the spared nerve injury (SNI) model which promotes long-lasting mechanical allodynia, results showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 2 weeks after injury. There are significant changes in the activity of the left thalamus (Th_L) and left olfactory bulb (OB_L) brain regions after SNI, as evidenced by both the blood oxygen level-dependent (BOLD) signal and c-Fos expression. Importantly, these changes were closely related to mechanical pain behavior of rats. However, it is worth noting that after morphine administration for analgesia, only the increased activity in the TH region is reversed, while the decreased activity in the OB region becomes more prominent. Functional connectivity (FC) and c-Fos correlation analysis further showed these two regions of interest (ROIs) exhibit different FC patterns with other brain regions. Our study comprehensively revealed the adaptive changes of brain neural networks induced by nerve injury in both cross-sectional and longitudinal dimensions and emphasized the abnormal activity and FC of Th_L and OB_L in the pathological condition. It provides reliable assistance in exploring the intricate mechanisms of diseases.

Intrinsic Functional Connectivity between the Anterior Insular and Retrosplenial Cortex as a Moderator and Consequence of Cocaine Self-Administration in Rats.

While functional brain imaging studies in humans suggest that chronic cocaine use alters functional connectivity (FC) within and between key large-scale brain networks, including the default mode network (DMN), the salience network (SN), and the central executive network (CEN), cross-sectional studies in humans are challenging to obtain brain FC prior to cocaine use. Such information is critical to reveal the relationship between individual's brain FC and the subsequent development of cocaine dependence and brain changes during abstinence. Here, we performed a longitudinal study examining functional magnetic resonance imaging (fMRI) data in male rats (n = 7), acquired before cocaine self-administration (baseline), on 1 d of abstinence following 10 d of cocaine self-administration, and again after 30 d of experimenter-imposed abstinence. Using repeated-measures analysis of variance (ANOVA) with network-based statistics (NBS), significant connectivity changes were found between anterior insular cortex (AI) of the SN, retrosplenial cortex (RSC) of the DMN, somatosensory cortex, and caudate-putamen (CPu), with AI-RSC FC showing the most robust changes between baseline and 1 d of abstinence. Additionally, the level of escalated cocaine intake is associated with AI-RSC and AI-CPu FC changes between 1 d and 30 d of abstinence; further, the subjects' AI-RSC FC prior to cocaine intake is a significant moderator for the AI-RSC changes during abstinence. These results provide novel insights into the roles of AI-RSC FC before and after cocaine intake and suggest this circuit to be a potential target to modulate large-scale network and associated behavioral changes in cocaine use disorders.

Development and evaluation of a new high-TOF-resolution all-digital brain PET system

Objective. Time-of-flight (TOF) capability and high sensitivity are essential for brain-dedicated positron emission tomography (PET) imaging, as they improve the contrast and the signal-to-noise ratio (SNR) enabling a precise localization of functional mechanisms in the different brain regions. Approach. We present a new brain PET system with transverse and axial field-of-view (FOV) of 320 mm and 255 mm, respectively. The system head is an array of 6 × 6 detection elements, each consisting of a 3.9 × 3.9 × 20 mm3 lutetium–yttrium oxyorthosilicate crystal coupled with a 3.93 × 3.93 mm2 SiPM. The SiPMs analog signals are individually digitized using the multi-voltage threshold (MVT) technology, employing a 1:1:1 coupling configuration. Main results. The brain PET system exhibits a TOF resolution of 249 ps at 5.3 kBq ml−1, an average sensitivity of 22.1 cps kBq−1, and a noise equivalent count rate (NECR) peak of 150.9 kcps at 8.36 kBq ml−1. Furthermore, the mini-Derenzo phantom study demonstrated the system’s ability to distinguish rods with a diameter of 2.0 mm. Moreover, incorporating the TOF reconstruction algorithm in an image quality phantom study optimizes the background variability, resulting in reductions ranging from 44% (37 mm) to 75% (10 mm) with comparable contrast. In the human brain imaging study, the SNR improved by a factor of 1.7 with the inclusion of TOF, increasing from 27.07 to 46.05. Time-dynamic human brain imaging was performed, showing the distinctive traits of cortex and thalamus uptake, as well as of the arterial and venous flow with 2 s per time frame. Significance. The system exhibited a good TOF capability, which is coupled with the high sensitivity and count rate performance based on the MVT digital sampling technique. The developed TOF-enabled brain PET system opens the possibility of precise kinetic brain PET imaging, towards new quantitative predictive brain diagnostics.

Neurogenesis-independent mechanisms of MRI-detectable hippocampal volume increase following electroconvulsive stimulation

Electroconvulsive therapy (ECT) is one of the most effective psychiatric treatments but the underlying mechanisms are still unclear. In vivo human magnetic resonance imaging (MRI) studies have consistently reported ECT-induced transient hippocampal volume increases, and an animal model of ECT (electroconvulsive stimulation: ECS) was shown to increase neurogenesis. However, a causal relationship between neurogenesis and MRI-detectable hippocampal volume increases following ECT has not been verified. In this study, mice were randomly allocated into four groups, each undergoing a different number of ECS sessions (e.g., 0, 3, 6, 9). T2-weighted images were acquired using 11.7-tesla MRI. A whole brain voxel-based morphometry analysis was conducted to identify any ECS-induced brain volume changes. Additionally, a histological examination with super-resolution microscopy was conducted to investigate microstructural changes in the brain regions that showed volume changes following ECS. Furthermore, parallel experiments were performed on X-ray-irradiated mice to investigate the causal relationship between neurogenesis and ECS-related volume changes. As a result, we revealed for the first time that ECS induced MRI-detectable, dose-dependent hippocampal volume increase in mice. Furthermore, increased hippocampal volumes following ECS were seen even in mice lacking neurogenesis, suggesting that neurogenesis is not required for the increase. The comprehensive histological analyses identified an increase in excitatory synaptic density in the ventral CA1 as the major contributor to the observed hippocampal volume increase following ECS. Our findings demonstrate that modification of synaptic structures rather than neurogenesis may be the underlying biological mechanism of ECT/ECS-induced hippocampal volume increase.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.

Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study.

It is well known that there are significant differences in the prevalence of chronic pain between males and females. Human and animal imaging studies have shown that chronic pain profoundly alters the structure and function of brain regions. However, there is limited research on the sex-specific mechanisms underlying the brain plasticity and adaptive changes associated with chronic pain. In this article, we conducted a multimodal study to evaluate how nerve injury-induced chronic pain affects the brain. Male and female Sprague-Dawley (SD) rats with spared nerve injury (SNI) model underwent resting-state functional magnetic resonance imaging (rs-fMRI) (male sham group: n = 18; male SNI group: n = 18; female sham group: n = 20; female SNI group: n = 18) and magnetic resonance diffusion tensor imaging (DTI) (male sham group: n = 23; male SNI group: n = 21; female sham group: n = 20; female SNI group: n = 21) scanning. ICA method, Fractional amplitude of low-frequency fluctuations (fALFF), immunofluorescence staining, and graph theory analysis was utilized to extract the rs-fMRI changes of brain regions of each group. Using SNI model, which promotes long-lasting mechanical allodynia, we found that neuropathic pain deeply modified the intrinsic organization of the brain functional network in male and female rats (main effect of operation: F = 298.449, P < 0.001). 64 independent components (ICs) in the brain were divided and assigned to 16 systems. In male rats, we observed significant alterations in the microstructure of the hippocampal cornu ammonis 1 and cornu ammonis 2 (CA1/CA2) region, as indicated by increased mean diffusivity (MD) (CA1_L: P = 0.02; CA1_R: P = 0.031; CA2_L: P = 0.035; CA2_R: P = 0.015) and radial diffusivity (RD) (CA1_L: P = 0.028; CA1_R: P = 0.033; CA2_L: P = 0.037; CA2_R: P = 0.038) values, along with enhanced activating transcription factor 3 (ATF3) expression. Conversely, in female rats, we found significant increases in the fractional amplitude of low frequency fluctuations (fALFF) value within the hippocampal dentate gyrus (DG) (F = 5.419, P = 0.023), accompanied by elevated c-Fos signal (F = 6.269, P = 0.031). Furthermore, graph theory analysis revealed notable differences in the small-world network of the hippocampal system in female rats, characterized by reduced small-world attributes and increased inter-nodal transmission efficiency. Our study indicates sex differences in structural and functional alterations in the hippocampal system in rats under chronic pain conditions. The results suggest that the hippocampus system plays an important role in the different mechanisms of chronic pain in different sexes. These findings provide reliable insights to explore the complex mechanisms underlying sex differences in chronic pain.

To improve big data, we need small-scale human imaging studies

To improve big data, we need small-scale human imaging studies

Scene-selectivity in CA1/subicular complex: Multivoxel pattern analysis at 7T

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category selectivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside posteromedial (including retrosplenial) and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus.

Anatomy of the auditory cortex then and now.

Using neuroanatomical investigations in the macaque, Deepak Pandya and his colleagues have established the framework for auditory cortex organization, with subdivisions into core and belt areas. This has aided subsequent neurophysiological and imaging studies in monkeys and humans, and a nomenclature building on Pandya's work has also been adopted by the Human Connectome Project. The foundational work by Pandya and his colleagues is highlighted here in the context of subsequent and ongoing studies on the functional anatomy and physiology of auditory cortex in primates, including humans, and their relevance for understanding cognitive aspects of speech and language.