A Guide to Emerging Technologies for Large-Scale and Whole-Brain Optical Imaging of Neuronal Activity.

The mammalian brain is a densely interconnected network that consists of millions to billions of neurons. Decoding how information is represented and processed by this neural circuitry requires the ability to capture and manipulate the dynamics of large populations at high speed and high resolution over a large area of the brain. Although the use of optical approaches by the neuroscience community has rapidly increased over the past two decades, most microscopy approaches are unable to record the activity of all neurons comprising a functional network across the mammalian brain at relevant temporal and spatial resolutions. In this review, we survey the recent development in optical technologies for Ca2+ imaging in this regard and provide an overview of the strengths and limitations of each modality and its potential for scalability. We provide guidance from the perspective of a biological user driven by the typical biological applications and sample conditions. We also discuss the potential for future advances and synergies that could be obtained through hybrid approaches or other modalities.

Cumulative Effects of Resting-State Connectivity Across All Brain Networks Significantly Correlate with Attention-Deficit Hyperactivity Disorder Symptoms.

Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.

Pre-acquired Functional Connectivity Predicts Choice Inconsistency.

Economic choice theories usually assume that humans maximize utility in their choices. However, studies have shown that humans make inconsistent choices, leading to suboptimal behavior, even without context-dependent manipulations. Previous studies showed that activation in value and motor networks are associated with inconsistent choices at the moment of choice. Here, we investigated if the neural predispositions, measured before a choice task, can predict choice inconsistency in a later risky choice task. Using functional connectivity (FC) measures from resting-state functional magnetic resonance imaging (rsfMRI), derived before any choice was made, we aimed to predict subjects' inconsistency levels in a later-performed choice task. We hypothesized that rsfMRI FC measures extracted from value and motor brain areas would predict inconsistency. Forty subjects (21 females) completed a rsfMRI scan before performing a risky choice task. We compared models that were trained on FC that included only hypothesized value and motor regions with models trained on whole-brain FC. We found that both model types significantly predicted inconsistency levels. Moreover, even the whole-brain models relied mostly on FC between value and motor areas. For external validation, we used a neural network pretrained on FC matrices of 37,000 subjects and fine-tuned it on our data and again showed significant predictions. Together, this shows that the tendency for choice inconsistency is predicted by predispositions of the nervous system and that synchrony between the motor and value networks plays a crucial role in this tendency.

Severity-Dependent Interhemispheric White Matter Connectivity Predicts Poststroke Neglect Recovery.

Left-sided spatial neglect is a very common and challenging issue after right-hemispheric stroke, which strongly and negatively affects daily living behavior and recovery of stroke survivors. The mechanisms underlying recovery of spatial neglect remain controversial, particularly regarding the involvement of the intact, contralesional hemisphere, with potential contributions ranging from maladaptive to compensatory. In the present prospective, observational study, we assessed neglect severity in 54 right-hemispheric stroke patients (32 male; 22 female) at admission to and discharge from inpatient neurorehabilitation. We demonstrate that the interaction of initial neglect severity and spared white matter (dis)connectivity resulting from individual lesions (as assessed by diffusion tensor imaging, DTI) explains a significant portion of the variability of poststroke neglect recovery. In mildly impaired patients, spared structural connectivity within the lesioned hemisphere is sufficient to attain good recovery. Conversely, in patients with severe impairment, successful recovery critically depends on structural connectivity within the intact hemisphere and between hemispheres. These distinct patterns, mediated by their respective white matter connections, may help to reconcile the dichotomous perspectives regarding the role of the contralesional hemisphere as exclusively compensatory or not. Instead, they suggest a unified viewpoint wherein the contralesional hemisphere can - but must not necessarily - assume a compensatory role. This would depend on initial impairment severity and on the available, spared structural connectivity. In the future, our findings could serve as a prognostic biomarker for neglect recovery and guide patient-tailored therapeutic approaches.

Development of the Fetal Brain Corticocortical Structural Network during the Second-to-Third Trimester Based on Diffusion MRI.

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.

Divergent electroencephalogram resting-state functional network alterations in subgroups of autism spectrum disorder: a symptom-based clustering analysis.

Autism spectrum disorder (ASD) is characterized by etiological and phenotypic heterogeneity. Despite efforts to categorize ASD into subtypes, research on specific functional connectivity changes within ASD subgroups based on clinical presentations is limited. This study proposed a symptom-based clustering approach to identify subgroups of ASD based on multiple clinical rating scales and investigate their distinct Electroencephalogram (EEG) functional connectivity patterns. Eyes-opened resting-state EEG data were collected from 72 children with ASD and 63 typically developing (TD) children. A data-driven clustering approach based on Social Responsiveness Scales-Second Edition and Vinland-3 scores was used to identify subgroups. EEG functional connectivity and topological characteristics in four frequency bands were assessed. Two subgroups were identified: mild ASD (mASD, n = 37) and severe ASD (sASD, n = 35). Compared to TD, mASD showed increased functional connectivity in the beta band, while sASD exhibited decreased connectivity in the alpha band. Significant between-group differences in global and regional topological abnormalities were found in both alpha and beta bands. The proposed symptom-based clustering approach revealed the divergent functional connectivity patterns in the ASD subgroups that was not observed in typical ASD studies. Our study thus provides a new perspective to address the heterogeneity in ASD research.

MRI resting-state signature of the propensity to experience meaningful coincidences: a functional coupling analysis.

The propensity to experience meaningful patterns in random arrangements and unrelated events shows considerable interindividual differences. Reduced inhibitory control (over sensory processes) and decreased working memory capacities are associated with this trait, which implies that the activation of frontal as well as posterior brain regions may be altered during rest and working memory tasks. In addition, people experiencing more meaningful coincidences showed reduced gray matter of the left inferior frontal gyrus (IFG), which is linked to the inhibition of irrelevant information in working memory and the control and integration of multisensory information. To study deviations in the functional connectivity of the IFG with posterior associative areas, the present study investigated the fMRI resting state in a large sample of n = 101 participants. We applied seed-to-voxel analysis and found that people who perceive more meaningful coincidences showed negative functional connectivity of the left IFG (i.e. pars triangularis) with areas of the left posterior associative cortex (e.g. superior parietal cortex). A data-driven multivoxel pattern analysis further indicated that functional connectivity of a cluster located in the right cerebellum with a cluster including parts of the left middle frontal gyrus, left precentral gyrus, and the left IFG (pars opercularis) was associated with meaningful coincidences. These findings add evidence to the neurocognitive foundations of the propensity to experience meaningful coincidences, which strengthens the idea that deviations of working memory functions and inhibition of sensory and motor information explain why people experience more meaning in meaningless noise.

Verbal semantic expertise is associated with reduced functional connectivity between left and right anterior temporal lobes.

The left and right anterior temporal lobes (ATLs) encode semantic representations. They show graded hemispheric specialization in function, with the left ATL contributing preferentially to verbal semantic processing. We investigated the cognitive correlates of this organization, using resting-state functional connectivity as a measure of functional segregation between ATLs. We analyzed two independent resting-state fMRI datasets (n = 86 and n = 642) in which participants' verbal semantic expertise was measured using vocabulary tests. In both datasets, people with more advanced verbal semantic knowledge showed weaker functional connectivity between left and right ventral ATLs. This effect was highly specific. It was not observed for within-hemisphere connections between semantic regions (ventral ATL and inferior frontal gyrus (IFG), though it was found for left-right IFG connectivity in one dataset). Effects were not found for tasks probing semantic control, nonsemantic cognition, or face recognition. Our results suggest that hemispheric specialization in the ATLs is not an innate property but rather emerges as people develop highly detailed verbal semantic representations. We speculate that this effect is a consequence of the left ATL's greater connectivity with left-lateralized written word recognition regions, which causes it to preferentially represent meaning for advanced vocabulary acquired primarily through reading.

Familiarity enhances functional connectivity between visual and nonvisual regions of the brain during natural viewing.

We explored the neural correlates of familiarity with people and places using a naturalistic viewing paradigm. Neural responses were measured using functional magnetic resonance imaging, while participants viewed a movie taken from Game of Thrones. We compared inter-subject correlations and functional connectivity in participants who were either familiar or unfamiliar with the TV series. Higher inter-subject correlations were found between familiar participants in regions, beyond the visual brain, that are typically associated with the processing of semantic, episodic, and affective information. However, familiarity also increased functional connectivity between face and scene regions in the visual brain and the nonvisual regions of the familiarity network. To determine whether these regions play an important role in face recognition, we measured responses in participants with developmental prosopagnosia (DP). Consistent with a deficit in face recognition, the effect of familiarity was significantly attenuated across the familiarity network in DP. The effect of familiarity on functional connectivity between face regions and the familiarity network was also attenuated in DP. These results show that the neural response to familiarity involves an extended network of brain regions and that functional connectivity between visual and nonvisual regions of the brain plays an important role in the recognition of people and places during natural viewing.

Functionality of arousal-regulating brain circuitry at rest predicts human cognitive abilities.

Arousal state is regulated by subcortical neuromodulatory nuclei, such as locus coeruleus, which send wide-reaching projections to cortex. Whether higher-order cortical regions have the capacity to recruit neuromodulatory systems to aid cognition is unclear. Here, we hypothesized that select cortical regions activate the arousal system, which, in turn, modulates large-scale brain activity, creating a functional circuit predicting cognitive ability. We utilized the Human Connectome Project 7T functional magnetic resonance imaging dataset (n = 149), acquired at rest with simultaneous eye tracking, along with extensive cognitive assessment for each subject. First, we discovered select frontoparietal cortical regions that drive large-scale spontaneous brain activity specifically via engaging the arousal system. Second, we show that the functionality of the arousal circuit driven by bilateral posterior cingulate cortex (associated with the default mode network) predicts subjects' cognitive abilities. This suggests that a cortical region that is typically associated with self-referential processing supports cognition by regulating the arousal system.

Differential neural correlates underlying visuospatial versus semantic reasoning in autistic children.

While fronto-posterior underconnectivity has often been reported in autism, it was shown that different contexts may modulate between-group differences in functional connectivity. Here, we assessed how different task paradigms modulate functional connectivity differences in a young autistic sample relative to typically developing children. Twenty-three autistic and 23 typically developing children aged 6 to 15 years underwent functional magnetic resonance imaging (fMRI) scanning while completing a reasoning task with visuospatial versus semantic content. We observed distinct connectivity patterns in autistic versus typical children as a function of task type (visuospatial vs. semantic) and problem complexity (visual matching vs. reasoning), despite similar performance. For semantic reasoning problems, there was no significant between-group differences in connectivity. However, during visuospatial reasoning problems, we observed occipital-occipital, occipital-temporal, and occipital-frontal over-connectivity in autistic children relative to typical children. Also, increasing the complexity of visuospatial problems resulted in increased functional connectivity between occipital, posterior (temporal), and anterior (frontal) brain regions in autistic participants, more so than in typical children. Our results add to several studies now demonstrating that the connectivity alterations in autistic relative to neurotypical individuals are much more complex than previously thought and depend on both task type and task complexity and their respective underlying cognitive processes.

The mediating role of trait impulsivity in the relation between cue-induced craving and functional connectivity within the salience network among abstinent patients with methamphetamine use disorder.

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Dysfunction of thalamocortical circuits in early-onset schizophrenia.

Previous studies have demonstrated that the thalamus is involved in multiple functional circuits in participants with schizophrenia. However, less is known about the thalamocortical circuit in the rare subtype of early-onset schizophrenia. A total of 110 participants with early-onset schizophrenia (47 antipsychotic-naive patients) and 70 matched healthy controls were recruited and underwent resting-state functional and diffusion-weighted magnetic resonance imaging scans. A data-driven parcellation method that combined the high spatial resolution of diffusion magnetic resonance imaging and the high sensitivity of functional magnetic resonance imaging was used to divide the thalamus. Next, the functional connectivity between each thalamic subdivision and the cortex/cerebellum was investigated. Compared to healthy controls, individuals with early-onset schizophrenia exhibited hypoconnectivity between subdivisions of the thalamus and the frontoparietal network, visual network, ventral attention network, somatomotor network and cerebellum, and hyperconnectivity between subdivisions of thalamus and the parahippocampal and temporal gyrus, which were included in limbic network. The functional connectivity between the right posterior cingulate cortex and 1 subdivision of the thalamus (region of interest 1) was positively correlated with the general psychopathology scale score. This study showed that the specific thalamocortical dysconnection in individuals with early-onset schizophrenia involves the prefrontal, auditory and visual cortices, and cerebellum. This study identified thalamocortical connectivity as a potential biomarker and treatment target for early-onset schizophrenia.

Distinguishable neural circuit mechanisms associated with the clinical efficacy of rTMS in aMCI patients.

Repetitive transcranial magnetic stimulation is used in early-stage Alzheimer's disease to slow progression, but heterogeneity in response results in different treatment outcomes. The mechanisms underlying this heterogeneity are unclear. This study used resting-state neuroimaging to investigate the variability in episodic memory improvement from angular gyrus repetitive transcranial magnetic stimulation and tracked the neural circuits involved. Thirty-four amnestic mild cognitive impairment patients underwent angular gyrus repetitive transcranial magnetic stimulation (4 weeks, 20 Hz, 100% resting motor threshold) and were divided into high-response and low-response groups based on minimal clinically important differences in auditory verbal learning test scores. Baseline and pre/post-treatment neural circuit activities were compared. Results indicated that the orbital middle frontal gyrus in the orbitofrontal cortex network and the precuneus in the default mode network had higher local activity in the low-response group. After treatment, changes in local and remote connectivity within brain regions of the orbitofrontal cortex, default mode network, visual network, and sensorimotor network showed opposite trends and were related to treatment effects. This suggests that the activity states of brain regions within the orbitofrontal cortex and default mode network could serve as imaging markers for early cognitive compensation in amnestic mild cognitive impairment patients and predict the aftereffects of repetitive transcranial magnetic stimulation response.

Sex differences in aberrant functional connectivity of three core networks and subcortical networks in medication-free adolescent-onset major depressive disorder.

Major depressive disorder demonstrated sex differences in prevalence and symptoms, which were more pronounced during adolescence. Yet, research on sex-specific brain network characteristics in adolescent-onset major depressive disorder remains limited. This study investigated sex-specific and nonspecific alterations in resting-state functional connectivity of three core networks (frontoparietal network, salience network, and default mode network) and subcortical networks in adolescent-onset major depressive disorder, using seed-based resting-state functional connectivity in 50 medication-free patients with adolescent-onset major depressive disorder and 56 healthy controls. Irrespective of sex, compared with healthy controls, adolescent-onset major depressive disorder patients showed hypoconnectivity between bilateral hippocampus and right superior temporal gyrus (default mode network). More importantly, we further found that females with adolescent-onset major depressive disorder exhibited hypoconnectivity within the default mode network (medial prefrontal cortex), and between the subcortical regions (i.e. amygdala, striatum, and thalamus) with the default mode network (angular gyrus and posterior cingulate cortex) and the frontoparietal network (dorsal prefrontal cortex), while the opposite patterns of resting-state functional connectivity alterations were observed in males with adolescent-onset major depressive disorder, relative to their sex-matched healthy controls. Moreover, several sex-specific resting-state functional connectivity changes were correlated with age of onset, sleep disturbance, and anxiety in adolescent-onset major depressive disorder with different sex. These findings suggested that these sex-specific resting-state functional connectivity alterations may reflect the differences in brain development or processes related to early illness onset, underscoring the necessity for sex-tailored diagnostic and therapeutic approaches in adolescent-onset major depressive disorder.

The characteristic pattern of functional connectivity density influenced by postmenopausal females in the preclinical stage of dementia.

Subjective cognitive decline (SCD) is considered an early indicator of Alzheimer's disease. Previous evidence suggests that postmenopausal females are at heightened risk for developing dementia. However, the potential effects of gender (i.e. postmenopausal female) on functional connectivity density (FCD) in individuals with SCD are not well understood. A total of 56 healthy controls and 57 subjects with SCD were included. The short-range and long-range FCD (srFCD and lrFCD) mapping of each participant was calculated. The interactive effect of gender × diagnosis on the FCD was explored by two-way analysis of variance. The interaction effect of gender × diagnosis on lrFCD was primarily in the right middle frontal gyrus (MFG). The older males with SCD exhibited significantly enhanced lrFCD in the right MFG relative to other subgroups. The lrFCD of the right MFG was positively associated with cognitive performance in older females with SCD. Cognition-related functional terms were significantly related to the right MFG. Decreased lrFCD of the right MFG in cognitively normal older women may explain why postmenopausal females have a higher risk for progression to dementia than men. Furthermore, this altered pattern could be applied to identify individuals with a high risk for dementia.

Medial to lateral frontal functional connectivity mapping reveals the organization of cingulate cortex.

The functional organization of the frontal lobe is a source of debate, focusing on broad functional subdivisions, large-scale networks, or local refined specificities. Multiple neurocognitive models have tried to explain how functional interactions between cingulate and lateral frontal regions contribute to decision making and cognitive control, but their neuroanatomical bases remain unclear. We provide a detailed description of the functional connectivity between cingulate and lateral frontal regions using resting-state functional MRI in rhesus macaques. The analysis focuses on the functional connectivity of the rostral part of the cingulate sulcus with the lateral frontal cortex. Data-driven and seed-based analysis revealed three clusters within the cingulate sulcus organized along the rostro-caudal axis: the anterior, mid, and posterior clusters display increased functional connectivity with, respectively, the anterior lateral prefrontal regions, face-eye lateral frontal motor cortical areas, and hand lateral frontal motor cortex. The location of these clusters can be predicted in individual subjects based on morphological landmarks. These results suggest that the anterior cluster corresponds to the anterior cingulate cortex, whereas the posterior clusters correspond to the face-eye and hand cingulate motor areas within the anterior midcingulate cortex. These data provide a comprehensive framework to identify cingulate subregions based on functional connectivity and local organization.

Structural connectivity changes in unilateral hearing loss.

Network connectivity, as mapped by the whole brain connectome, plays a crucial role in regulating auditory function. Auditory deprivation such as unilateral hearing loss might alter structural network connectivity; however, these potential alterations are poorly understood. Thirty-seven acoustic neuroma patients with unilateral hearing loss (19 left-sided and 18 right-sided) and 19 healthy controls underwent diffusion-weighted and T1-weighted imaging to assess edge strength, node strength, and global efficiency of the structural connectome. Edge strength was estimated by pair-wise normalized streamline density from tractography and connectomics. Node strength and global efficiency were calculated through graph theory analysis of the connectome. Pure-tone audiometry and word recognition scores were used to correlate the degree and duration of unilateral hearing loss with node strength and global efficiency. We demonstrate significantly stronger edge strength and node strength through the visual network, weaker edge strength and node strength in the somatomotor network, and stronger global efficiency in the unilateral hearing loss patients. No discernible correlations were observed between the degree and duration of unilateral hearing loss and the measures of node strength or global efficiency. These findings contribute to our understanding of the role of structural connectivity in hearing by facilitating visual network upregulation and somatomotor network downregulation after unilateral hearing loss.

The functional connectivity between right insula and anterior cingulate cortex underlying the association between future self-continuity and delay discounting.

Delay discounting refers to the tendency of individuals to devalue future rewards as the delay in their receipt increases over time. Previous studies have indicated that future self-continuity correlates with delay discounting rates. However, the neural basis underlying the relationship between future self-continuity and delay discounting is not clear. To address this question, we used voxel-based morphometry and resting-state functional connectivity analyses to investigate the neural basis underlying the association between future self-continuity and delay discounting. Behavioral result showed that future self-continuity was positively associated with delay discounting. Voxel-based morphometry analysis result indicated that gray matter volume in the right dorsal anterior insula was positively correlated with future self-continuity. Resting-state functional connectivity analysis found that functional connectivity between the right dorsal anterior insula and anterior cingulate cortex was positively associated with future self-continuity. Mediation analysis showed that the right dorsal anterior insula-right anterior cingulate cortex functional connectivity partially mediated the relationship between future self-continuity and delay discounting. These results suggested that right dorsal anterior insula-right anterior cingulate cortex functional connectivity could be the neural basis underlying the association between future self-continuity and delay discounting. In summary, the study provided novel insights into how future self-continuity affected delay discounting and offers new explanations from a neural perspective.