Cortical structural and functional coupling during development and implications for attention deficit hyperactivity disorder

Unprecedented 4D spatiotemporal infant regional cerebral blood flow framework and region-specific physiology–function coupling across infancy were elucidated, highlighting strong physiology–function coupling specifically at the default-mode network to meet extraneuronal metabolic demand for network emergence.

ObjectivesThere is an ongoing debate about the restrictive inattentive (RI) presentation of attention deficit hyperactivity disorder (ADHD). The current study aimed to systematically investigate the clinical, neuropsychological, and brain functional characteristics of children with ADHD restrictive inattentive presentation.MethodsA clinical sample of 789 children with or without ADHD participated in the current study and finished clinical interviews, questionnaires, and neuropsychological tests. Those individuals with a diagnosis of ADHD were further divided into three subgroups according to the presentation of inattentive and/or hyperactive/impulsive symptoms, the ADHD-RI, the ADHD-I (inattentive), and the ADHD-C (combined) groups. Between-group comparisons were carried out on each clinical and neuropsychological measure using ANCOVA, with age and sex as covariates. Bonferroni corrections were applied to correct for multiple comparisons. Two hundred twenty-seven of the subjects also went through resting-state functional magnetic resonance imaging scans. Five ADHD-related brain functional networks, including the default mode network (DMN), the dorsal attention network (DAN), the ventral attention network, the executive control network, and the salience network, were built using predefined regions of interest (ROIs). Voxel-based group-wise comparisons were performed.ResultsCompared with healthy controls, all ADHD groups presented more clinical problems and weaker cognitive function. Among the ADHD groups, the ADHD-C group had the most clinical problems, especially delinquent and aggressive behaviors. Regarding cognitive function, the ADHD-RI group displayed the most impaired sustained attention, and the ADHD-C group had the worst response inhibition function. In terms of brain functional connectivity (FC), reduced FC in the DMN was identified in the ADHD-C and the ADHD-I groups but not the ADHD-RI group, compared to the healthy controls. Subjects with ADHD-I also presented decreased FC in the DAN in contrast to the control group. The ADHD-RI displayed marginally significantly lower FC in the salience network compared to the ADHD-I and the control groups.ConclusionThe ADHD-RI group is distinguishable from the ADHD-I and the ADHD-C groups. It is characterized by fewer externalizing behaviors, worse sustained attention, and better response inhibition function. The absence of abnormally high hyperactive/impulsive symptoms in ADHD-RI might be related to less impaired brain function in DMN, but potentially more impairment in the salience network.

IntroductionResponse inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.MethodsResponse inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).ResultsControl subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.DiscussionSubjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Attention-deficit hyperactivity disorder (ADHD) has a high prevalence of co-occurring impaired self-regulation (dysregulation), exacerbating adverse outcomes. Neural correlates underlying impaired self-regulation in ADHD remain inconclusive. We aimed to investigate the impact of dysregulation on intrinsic functional connectivity (iFC) in children with ADHD and the correlation of iFC with dysregulation among children with ADHD relative to typically developing controls (TDC). Resting-state functional MRI data of 71 children with ADHD (11.38 ± 2.44years) and 117 age-matched TDC were used in the final analysis. We restricted our analyses to resting-state networks (RSNs) of interest derived from independent component analysis. Impaired self-regulation was estimated based on the Child Behavioral Checklist-Dysregulation Profile. Children with ADHD showed stronger iFC than TDC in the left frontoparietal network, somatomotor network (SMN), visual network (VIS), default-mode network (DMN), and dorsal attention network (DAN) (FWE-corrected alpha < 0.05). After adding dysregulation levels as an extra regressor, the ADHD group only showed stronger iFC in the VIS and SMN. ADHD children with high dysregulation had higher precuneus iFC within DMN than ADHD children with low dysregulation. Angular gyrus iFC within DMN was positively correlated with dysregulation in the ADHD group but negatively correlated with dysregulation in the TDC group. Functional network connectivity showed ADHD had a greater DMN-DAN connection than TDC, regardless of the dysregulation level. Our findings suggest that DMN connectivity may contribute to impaired self-regulation in ADHD. Impaired self-regulation should be considered categorical and dimensional moderators for the neural correlates of altered iFC in ADHD.

IntroductionRecent evidence suggests that attention deficit hyperactivity disorder (ADHD) is associated with a range of brain functional connectivity abnormalities, with one of the most prominent being reduced inhibition of the default mode network (DMN) while performing a cognitive task. In this study, we examine the effects of a methylphenidate dose on brain functional connectivity in boys diagnosed with ADHD while they performed a cognitive task.MethodBrain functional connectivity was estimated using steady‐state visual evoked potential partial coherence before and 90 min after the administration of a methylphenidate dose to 42 stimulant drug‐naïve boys newly diagnosed with ADHD while they performed the A‐X version of the continuous performance task (CPT A‐X).ResultsMethylphenidate robustly reversed the transient functional connectivity increase in the A‐X interval seen premedication to a postmedication decrease during this interval. In addition, methylphenidate‐induced reductions in individual reaction time were correlated with corresponding reductions in functional connectivity.ConclusionThese findings suggest that methylphenidate suppresses the increased functional connectivity observed in ADHD and that such suppression is associated with improved performance. Our findings support the suggestion that the increased functional connectivity we have observed in ADHD is associated with abnormal DMN activity. In addition, we comment on the significance of specific frequency channels mediating top‐down communication within the cortex and the extent to which our findings are selectively sensitive to top‐down intracortical communication.

Functional connectomics is a popular approach to investigate the neural underpinnings of developmental disorders of which attention deficit hyperactivity disorder (ADHD) is one of the most prevalent. Nonetheless, neuronal mechanisms driving the aberrant functional connectivity resulting in ADHD symptoms remain largely unclear. Whereas resting state activity reflecting intrinsic tonic background activity is only vaguely connected to behavioral effects, naturalistic neuroscience has provided means to measure phasic brain dynamics associated with overt manifestation of the symptoms. Here we collected functional magnetic resonance imaging (fMRI) data in three experimental conditions, an active virtual reality (VR) task where the participants execute goal-directed behaviors, a passive naturalistic Video Viewing task, and a standard Resting State condition. Thirty-nine children with ADHD and thirty-seven typically developing (TD) children participated in this preregistered study. Functional connectivity was examined with network-based statistics (NBS) and graph theoretical metrics. During the naturalistic VR task, the ADHD group showed weaker task performance and stronger functional connectivity than the TD group. Group differences in functional connectivity were observed in widespread brain networks: particularly subcortical areas showed hyperconnectivity in ADHD. More restricted group differences in functional connectivity were observed during the Video Viewing, and there were no group differences in functional connectivity in the Resting State condition. These observations were consistent across NBS and graph theoretical analyses, although NBS revealed more pronounced group differences. Furthermore, during the VR task and Video Viewing, functional connectivity in TD controls was associated with task performance during the measurement, while Resting State activity in TD controls was correlated with ADHD symptoms rated over six months. We conclude that overt expression of the symptoms is correlated with aberrant brain connectivity in ADHD. Furthermore, naturalistic paradigms where clinical markers can be coupled with simultaneously occurring brain activity may further increase the interpretability of psychiatric neuroimaging findings.

In children with attention deficit hyperactivity disorder (ADHD) difficulty maintaining task focus may relate to the coordinated, negatively correlated activity between brain networks that support the initiation and maintenance of task sets (task positive networks) and networks that mediate internally directed processes (i.e., the default mode network). Here, resting-state functional connectivity MRI between these networks was examined in ADHD, across development, and in relation to attention. Children with ADHD had reduced negative connectivity between task positive and task negative networks (p = 0.002). Connectivity continues to become more negative between these networks throughout development (7–15 years of age) in children with ADHD (p = 0.005). Regardless of group status, females had increased negative connectivity (p = 0.003). In regards to attentional performance, the ADHD group had poorer signal detection (d′) on the continuous performance task (CPT) (p < 0.0001), more so on easy than difficult d′ trials (p < 0.0001). The reduced negative connectivity in children with ADHD also relates to their attention, where increased negative connectivity is related to better performance on the d′ measure of the CPT (p = 0.008). These results highlight and further strengthen prior reports underscoring the role of segregated system integrity in ADHD.

<bold>Objective</bold> To observe the differences in brain network activation and functional connectivity of patients with post-stroke cognitive impairment (PSCI) of different severity using functional near-infrared spectroscopy (fNIRS). <bold>Methods</bold> A total of 40 stroke patients in the outpatient and inpatient Rehabilitation Department in the Pudong District of Huashan Hospital, Fudan University from April to November 2020 were recruited and divided into normal group (<italic>n</italic>=14), mild to moderate group (<italic>n</italic>=11) and severe group (<italic>n</italic>=15) according to the mini-mental state examination (MMSE) score. Fugl-Meyer assessment scale (FMA) and functional comprehensive assessment (FCA) were used to evaluate the motor function of upper and lower limbs; 64-channel fNIRS functional imaging device was used to collect the resting-state brain network data of patients. The whole brain functional connectivity was analyzed based on oxyhemoglobin (HbO₂) and deoxyhemoglobin (HbR). Differences in functional connectivity strengths between homologous and heterologous brain networks in dorsal attention network (DAN), sensorimotor network (SEN), ventral attention network (VAN), frontoparietal network (FPN), default mode network (DMN) and visual network (VIS) regions were analyzed. <bold>Results</bold> (1) Motor function: there was no significant difference in FMA and FCA scores in three groups (<italic>P</italic>&gt;0.05). (2) Whole brain functional connectivity and strength of homologous brain network functional connectivity: there was no significant difference in whole brain functional connectivity based on HbO₂ and HbR in three groups (<italic>P</italic>&gt;0.05). Compared with the normal group, there were significant differences in the strength of functional connectivity of the in the SEN and FPN regions of the HbO₂-based homologous brain network in the severe group (<italic>P</italic>&lt;0.05), but there were no significant differences in the regions of interest of the HbR-based homologous brain network in the three groups (<italic>P</italic>&gt;0.05). (3) Functional connectivity strength of heterologous brain networks: compared with the normal group, the functional connectivity of SEN-VAN, SEN-DMN, SEN-FPN, VAN-FPN and DMN-FPN in the severe group decreased significantly, and the differences were statistically significant (<italic>P</italic>&lt;0.05). Compared with the mild to moderate group, the functional connectivity of SEN-DAN and SEN-FPN in the severe group decreased significantly, and the differences were statistically significant (<italic>P</italic>&lt;0.05). There was no significant difference of strength of functional connectivity based on HbR in the three groups (<italic>P</italic>&gt;0.05). (4) Correlation analysis between SEN-FPN heterologous functional connectivity and MMSE, FCA scores: MMSE score (<italic>r</italic>=0.32, <italic>P</italic>&lt;0.05) and FCA score (<italic>r</italic>=0.38, <italic>P</italic>&lt;0.05) were positively correlated with SEN-FPN functional connectivity. <bold>Conclusion</bold> The SEN-FPN functional connectivity may play an important role in the cognitive function of stroke patients. Altered functional connectivity patterns of SEN-FPN may be closely related to the occurrence and progression of PSCI, and changes in functional connectivity strength of SEN-FPN may be a potential imaging indicator of PSCI.

Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability.

Abnormal functional connectivity between the anterior cingulate and the default mode network in drug-naïve boys with attention deficit hyperactivity disorder

Dynamic functional connectivity changes of resting-state brain network in attention-deficit/hyperactivity disorder

Thyroid-associated ophthalmopathy (TAO) is a prevalent autoimmune disease characterized by ocular symptoms like eyelid retraction and exophthalmos. Prior neuroimaging studies have revealed structural and functional brain abnormalities in TAO patients, along with central nervous system symptoms such as cognitive deficits. Nonetheless, the changes in the static and dynamic functional network connectivity of the brain in TAO patients are currently unknown. This study delved into the modifications in static functional network connectivity (sFNC) and dynamic functional network connectivity (dFNC) among thyroid-associated ophthalmopathy patients using independent component analysis (ICA). Thirty-two patients diagnosed with thyroid-associated ophthalmopathy and 30 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. ICA method was utilized to extract the sFNC and dFNC changes of both groups. In comparison to the HC group, the TAO group exhibited significantly increased intra-network functional connectivity (FC) in the right inferior temporal gyrus of the executive control network (ECN) and the visual network (VN), along with significantly decreased intra-network FC in the dorsal attentional network (DAN), the default mode network (DMN), and the left middle cingulum of the ECN. On the other hand, FNC analysis revealed substantially reduced connectivity intra- VN and inter- cerebellum network (CN) and high-level cognitive networks (DAN, DMN, and ECN) in the TAO group compared to the HC group. Regarding dFNC, TAO patients displayed abnormal connectivity across all five states, characterized by notably reduced intra-VN connectivity and CN connectivity with high-level cognitive networks (DAN, DMN, and ECN), alongside compensatory increased connectivity between DMN and low-level perceptual networks (VN and basal ganglia network). No significant differences were observed between the two groups for the three dynamic temporal metrics. Furthermore, excluding the classification outcomes of FC within VN (with an accuracy of 51.61% and area under the curve of 0.35208), the FC-based support vector machine (SVM) model demonstrated improved performance in distinguishing between TAO and HC, achieving accuracies ranging from 69.35 to 77.42% and areas under the curve from 0.68229 to 0.81667. The FNC-based SVM classification yielded an accuracy of 61.29% and an area under the curve of 0.57292. In summary, our study revealed that significant alterations in the visual network and high-level cognitive networks. These discoveries contribute to our understanding of the neural mechanisms in individuals with TAO, offering a valuable target for exploring future central nervous system changes in thyroid-associated eye diseases.

Brain functional connectivity (FC) changes and microstructural abnormalities are reported in infants born moderate and late preterm (MLPT). We evaluated the effect of low-grade (grades I, II) intraventricular hemorrhage (IVH) in MLPT babies on brain structural connectivity (SC) and FC. Babies born MLPT between January 2014 and May 2017 underwent brain ultrasound (US) at 72h and 7days after birth, and MRI at around term equivalent. The MRI protocol comprised T1- and T2-weighted sequences, diffusion tensor imaging (DTI), and resting-state functional MRI (fMRI). SC and FC were assessed using graph analysis. Of 350 MLPT neonates, 15 showed low-grade IVH on US at 72h, for which brain MRI was available in 10. These 10 infants, with mean gestational age (GA) 34.0 ± 0.8weeks, comprised the study group, and 10 MLPT infants of mean GA 33.9 ± 1.1weeks, with no abnormalities on brain US and MRI, were control subjects. All study subjects presented modularity, small world topology, and rich club organization for both SC and FC. The patients with low-grade IVH had lower FC rich club coefficient and lower SC betweenness centrality in the left frontoparietal operculum, and lower SC rich club coefficient in the right superior orbitofrontal cortex than the control subjects. Topological and functional properties of mature brain connectivity are present in MLPT infants. IVH in these infants was associated with structural and functional abnormalities in the left frontoparietal operculum and right orbitofrontal cortex, regions related to language and cognition.

Neuroimaging studies have confirmed that acupuncture can promote static functional reorganization in poststroke patients with motor dysfunction. But its effect on dynamic brain networks remains unclear. This study is aimed at investigating how acupuncture affected the brain's dynamic functional network connectivity (dFNC) after ischemic stroke. We conducted a single-center, randomised controlled neuroimaging study in ischemic stroke patients. A total of 53 patients were randomly divided into the true acupoint treatment group (TATG) and the sham acupoint treatment group (SATG) at a ratio of 2 : 1. Clinical assessments and magnetic resonance imaging (MRI) scans were performed on subjects before and after treatment. We used dFNC analysis to estimate distinct dynamic connectivity states. Then, the temporal properties and strength of functional connectivity (FC) matrix were compared within and between the two groups. The correlation analysis between dynamic characteristics and clinical scales was also calculated. All functional network connectivity (FNC) matrices were clustered into 3 connectivity states. After treatment, the TATG group showed a reduced mean dwell time and found attenuated FC between the sensorimotor network (SMN) and the frontoparietal network (FPN) in state 3, which was a sparsely connected state. The FC between the dorsal attention network (DAN) and the default mode network (DMN) was higher after treatment in the TATG group in state 1, which was a relative segregated state. The SATG group preferred to increase the mean dwell time and FC within FPN in state 2, which displayed a local tightly connected state. In addition, we found that the FC value increased between DAN and right frontoparietal network (RFPN) in state 1 in the TATG group after treatment compared to the SATG group. Correlation analyses before treatment showed that the Fugl-Meyer Assessment (FMA) lower score was negatively correlated with the mean dwell time in state 3. FMA score showed positive correlation with FC in RFPN-SMN in state 3. FMA-lower score was positively correlated with FC in DAN-DMN and DAN-RFPN in state 1. Acupuncture has the potential to modulate abnormal temporal properties and promote the balance of separation and integration of brain function. True acupoint stimulation may have a more positive effect on regulating the brain's dynamic function. Clinical Trial Registration. This trial is registered with Chinese Clinical Trials Registry (ChiCTR1800016263).