Altered Brain Functional Connectivity Research Articles

Longitudinal functional brain connectivity maturation in premature newborn infants: modulatory influence of early music enrichment

Abstract Premature birth affects brain maturation, illustrated by altered brain functional connectivity at term equivalent age (TEA) and alters neurobehavioral outcome. To correct early developmental differences and improve neurological outcome, music during the NICU stay has been proposed as an auditory enrichment with modulatory effects on functional and structural brain development, but longitudinal effects of such interventions have not been studied so far. We longitudinally investigated resting-state functional connectivity (RS-FC) maturation in preterm infants (n=43). Data-driven Independent Component Analyses (ICA) were performed on scans obtained at 33- and 40-weeks gestational age (GA), determining the presence of distinct RSNs. Connectome analysis ´accordance measure´ quantitively examined the RS-FC both at 33- and 40-weeks GA. Further comparing the internetwork RS-FC at 33- and 40 weeks GA provided a circuitry of interest (COI) for significant maturational changes in which the effects on the RS-FC of a music intervention was tested. The connectome analyses resulted in a COI of RS-FC connections significantly maturing from 33 to 40 weeks GA, namely between the thalamic/brainstem and prefrontal-limbic, salience, sensorimotor, auditory and prefrontal cortical networks; between the prefrontal-limbic and cerebellar, visual and left hemispheric precuneus networks; between the salience and visual, and cerebellar networks; and between the sensorimotor and auditory, and posterior cingulate/precuneus networks. The infants exposed to music exhibited significantly increased maturation in RS-FC between the thalamic/brainstem and salience networks, compared to controls. This study exemplifies that preterm infant RS-FC maturation is modulated through NICU music exposure, highlighting the importance of environmental enrichment for neurodevelopment in premature newborns.

Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection.

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 ± 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI. The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p < 0.001, effect size r = 0.58) and lower functional connectivity in multiple brain regions (mean t = 3.47 ±0.36, p = 0.03, corrected, effect size d = 0.92 to 1.5). Hypo-connectivity of these regions was inversely correlated with subjective cognitive function and directly correlated with fatigue (p < 0.05, corrected). These regions demonstrated significantly reduced local efficiency (p < 0.026, corrected) and altered effective connectivity (p < 0.001, corrected). COVID-19 may have a widespread effect on the functional connectome characterized by lower functional connectivity and altered patterns of information processing efficiency and effective information flow. This may serve as an adaptation to the pathology of SARS-CoV-2 wherein the brain can continue functioning at near expected objective levels, but patients experience lowered efficiency as brain fog.

Resting-State fMRI and Machine Learning as Diagnostic Tools for Alzheimer's Disease

: Alzheimer's disease (AD) presents a significant challenge in healthcare, necessitating accurate and timely diagnosis for effective management. Resting-state functional magnetic resonance imaging (Rs-fMRI) has emerged as a valuable tool for understanding neural correlates and the early detection of AD. This article reviews recent advancements in utilizing Rs-fMRI in combination with machine learning (ML) techniques for early AD diagnosis. First, we discuss the underlying principles of Rs-fMRI, highlighting its ability to detect alterations in brain functional connectivity (FC) patterns associated with AD. We then explore the potential of ML algorithms, particularly support vector machines (SVMs), in analyzing Rs-fMRI data and discriminating between AD patients and healthy controls. We indicate the challenges and opportunities in integrating Rs-fMRI and ML, such as in data preprocessing, feature selection, and model interpretation. We also address the importance of large-scale, multi-site studies to validate the robustness and generalizability of the proposed approaches. Overall, the integration of Rs-fMRI and ML holds great promise as a non-invasive, objective, and sensitive diagnostic tool for AD, potentially enabling early detection and personalized treatment strategies. However, further studies are warranted to optimize methodologies, enhance interpretability, and facilitate clinical translation.

Interference of default mode on attention networks in adults with attention-deficit/hyperactivity disorder and its association with genetic variants and treatment outcomes.

Altered brain functional connectivity has been proposed as the neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD), and the default mode interference hypothesis is one of the most popular neuropsychological models. Here, we explored whether this hypothesis is supported in adults with ADHD and the association with high-risk genetic variants and treatment outcomes. Voxel-based whole-brain connectome analysis was conducted on resting-state functional MRI data from 84 adults with ADHD and 89 healthy controls to identify functional connectivity substrates corresponding to ADHD-related alterations. The candidate genetic variants and 12-week cognitive behavioral therapy data were leveraged from the same population to assess these associations. We detected breakdowns of functional connectivity in the precuneus and left middle temporal gyrus in adults with ADHD, with exact contributions from decreased connectivity within the default mode, dorsal and ventral attention networks, as well as increased connectivity among them with the middle temporal gyrus serving as a crucial 'bridge'. Additionally, significant associations between the altered functional connectivity and genetic variants in both MAOA and MAOB were detected. Treatment restored brain function, with the amelioration of connectivity of the middle temporal gyrus, accompanied by improvements in ADHD core symptoms. These findings support the interference of default mode on attention in adults with ADHD and its association with genetic risk variants and clinical management, providing insights into the underlying pathogenesis of ADHD and potential biomarkers for treatment evaluation.

Resting-State Network Analysis Reveals Altered Functional Brain Connectivity in Essential Tremor.

Introduction: Essential tremor (ET) comprises motor and non-motor-related features, whereas the current neuro-pathogenetic basis is still insufficient to explain the etiologies of ET. Although cerebellum-associated circuits have been discovered, the large-scale cerebral network connectivity in ET remains unclear. This study aimed to characterize the ET in terms of functional connectivity as well as network. We hypothesized that the resting-state network (RSN) within cerebrum could be altered in patients with ET. Methods: Resting-state functional magnetic resonance imaging (fMRI) was used to evaluate the inter- and intra-network connectivity as well as the functional activity in ET and normal control. Correlation analysis was performed to explore the relationship between RSN metrics and tremor features. Results: Comparison of inter-network connectivity indicated a decreased connectivity between default mode network and ventral attention network in the ET group (p < 0.05). Differences in functional activity (assessed by amplitude of low-frequency fluctuation, ALFF) were found in several brain regions participating in various RSNs (p < 0.05). The ET group generally has higher degree centrality over normal control. Correlation analysis has revealed that tremor features are associated with inter-network connectivity (|r| = 0.135-0.506), ALFF (|r| = 0.313-0.766), and degree centrality (|r| = 0.523-0.710). Conclusion: Alterations in the cerebral network of ET were detected by using resting-state fMRI, demonstrating a potentially useful approach to explore the cerebral alterations in ET.

Disrupted dynamic brain functional connectivity in male cocaine use disorder: Hyperconnectivity, strongly-connected state tendency, and links to impulsivity and borderline traits

Cocaine use is a major public health problem with serious negative consequences at both the individual and societal levels. Cocaine use disorder (CUD) is associated with cognitive and emotional impairments, often manifesting as alterations in brain functional connectivity (FC). This study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine dynamic FC in 38 male participants with CUD and 31 matched healthy controls. Using group spatial independent component analysis (group ICA) combined with sliding window approach, we identified two recurring distinct connectivity states: the strongly-connected state (state 1) and weakly-connected state (state 2). CUD patients exhibited significant increased mean dwell and fraction time in state 1, and increased transitions from state 2 to state 1, demonstrated significant strongly-connected state tendency. Our analysis revealed abnormal FC patterns that are state-dependent and state-shared in CUD patients. This study observed hyperconnectivity within the default mode network (DMN) and between DMN and other networks, which varied depending on the state. Furthermore, after adjustment for multiple comparisons, we found significant correlations between these altered dynamic FCs and clinical measures of impulsivity and borderline personality disorder. The disrupted FC and repetitive effects of precuneus and angular gyrus across correlations suggested that they might be the important hub of neural circuits related behaviorally and mentally in CUD. In summary, our study highlighted the potential of these disrupted FC as neuroimaging biomarkers and therapeutic targets, and provided new insights into the understanding of the neurophysiologic mechanisms of CUD.

Brain functional connectivity alterations in patients with anterior cruciate ligament injury

Recent advancements in neuroimaging have illustrated that anterior cruciate ligament (ACL) injuries could impact the central nervous system (CNS), causing neuroplastic changes in the brain beyond the traditionally understood biomechanical consequences. While most of previous functional magnetic resonance imaging (fMRI) studies have focused on localized cortical activity changes post-injury, emerging research has suggested disruptions in functional connectivity across the brain. However, these prior investigations, albeit pioneering, have been constrained by two limitations: a reliance on small-sample participant cohorts, often limited to two to three patients, potentially limiting the generalizability of findings, and an adherence to region of interest based analysis, which may overlook broader network interactions. To address these limitations, our study employed resting-state fMRI to assess whole-brain functional connectivity in 15 ACL-injured patients, comparing them to matched controls using two distinct network analysis methods. Using Network-Based Statistics, we identified widespread reductions in connectivity that spanned across multiple brain regions. Further modular connectivity analysis showed significant decreases in inter-modular connectivity between the sensorimotor and cerebellar modules, and intra-modular connectivity within the default-mode network in ACL-injured patients. Our results thus highlight a shift from localized disruptions to network-wide dysfunctions, suggesting that ACL injuries induce widespread CNS changes. This enhanced understanding has the potential to stimulate the development of strategies aiming to restore functional connectivity and improve recovery outcomes.

Alterations in brain functional connectivity in patients with mild cognitive impairment: A systematic review and meta-analysis of functional near-infrared spectroscopy studies.

Emerging evidences suggest that cognitive deficits in individuals with mild cognitive impairment (MCI) are associated with disruptions in brain functional connectivity (FC). This systematic review and meta-analysis aimed to comprehensively evaluate alterations in FC between MCI individuals and healthy control (HC) using functional near-infrared spectroscopy (fNIRS). Thirteen studies were included in qualitative analysis, with two studies synthesized for quantitative meta-analysis. Overall, MCI patients exhibited reduced resting-state FC, predominantly in the prefrontal, parietal, and occipital cortex. Meta-analysis of two studies revealed a significant reduction in resting-state FC from the right prefrontal to right occipital cortex (standardized mean difference [SMD]=-.56; p<.001), left prefrontal to left occipital cortex (SMD=-.68; p<.001), and right prefrontal to left occipital cortex (SMD=-.53; p<.001) in MCI patients compared to HC. During naming animal-walking task, MCI patients exhibited enhanced FC in the prefrontal, motor, and occipital cortex, whereas a decrease in FC was observed in the right prefrontal to left prefrontal cortex during calculating-walking task. In working memory tasks, MCI predominantly showed increased FC in the medial and left prefrontal cortex. However, a decreased in prefrontal FC and a shifted in distribution from the left to the right prefrontal cortex were noted in MCI patients during a verbal frequency task. In conclusion, fNIRS effectively identified abnormalities in FC between MCI and HC, indicating disrupted FC as potential markers for the early detection of MCI. Future studies should investigate the use of task- and region-specific FC alterations as a sensitive biomarker for MCI.

Distinct Functional Connectivity Patterns for Intermittent Vs Constant Neuropathic Pain Phenotypes in Persistent Spinal Pain Syndrome Type 2 Patients.

Chronic low backpain (cLBP) has been associated with alterations in brain functional connectivity (FC) butbased upon heterogeneous populations and single network analyses. Our goal is to study a more homogeneous cLBP population and focus on multiple cross-network (CN) connectivity analysis. We hypothesize that within this population: 1) altered CNFC, involving emotion and reward/aversion functions are related to their pain levels and 2) altered relationships are dependent upon pain phenotype (constant neuropathic vs intermittent pain). In this case series, resting state fcMRI scans were obtained over a study duration of 60 months from 23 patients (13 constant neuropathic and 10 intermittent pain) with Persistent Spinal Pain Syndrome (PSPS Type 2) being considered for spinal cord stimulation (SCS) therapy at a single academic center. Images were acquired using a Discovery MR750 GE scanner. During the resting state acquisitions, they were asked to close their eyes and relax. The CNanalysis was performed on 7 brain networksand compared to age-matched controls. Linear regression was used to test the correlation between CN connectivity and pain scores. CNFCinvolving emotion networks (STM: striatum network index) was significantly lower than controls in all patients, regardless of pain phenotype (P < 0.003). Pain levels were positively correlated with emotional FCfor intermittent painbut negatively correlated for constant pain. This is thefirst report of 1) altered CN FCinvolving emotion/reward brain circuitry in 2) a homogeneous population of cLBPpatients with 3) two different pain phenotypes (constant vs intermittent) in PSPS Type 2 patients being considered for SCS. FC patterns were altered in cLBPpatients as compared to controls and were characteristic for each pain phenotype. Thesedata supportfcMRI as a potential and objective tool in assessing pain levels in cLBP patients with different painphenotypes.

Functional connectivity subtypes of MDD and their associations with gene expression profile, neurotransmitter, and cognition

IntroductionThere’s large heterogeneity present in major depressive disorder (MDD) and controversial evidence on alterations of brain functional connectivity (FC), making it hard to elucidate the neurobiological basis of MDD. Subtyping is one promising solution to characterize this heterogeneity.ObjectivesTo identify neurophysiological subtypes of MDD based on FC derived from resting-state functional magnetic resonance imaging using large multisite data and investigate the differences in genetic mechanisms and neurotransmitter basis of FC alterations, and the differences of FC-related cognition between each subtype.MethodsConsensus clustering of FC patterns was applied to a population of 829 MDD patients from REST-Meta-MDD database after data cleaning and image quality control. Gene transcriptomic data derived from Allen Human Brain Atlas and neurotransmitter receptor/transporter density data acquired by using neuromap toolbox were used to characterize the molecular mechanism underlying each FC-based subtype by identifying the gene set and neurotransmitters/transporters showing high spatial similarity with the profiles of FC alterations between each subtype and 770 healthy controls. The FC-related cognition in each subtype was also selected by lasso regression.ResultsTwo stable neurophysiological MDD subtypes were found and labeled as hypoconnectivity (n=527) and hyperconnectivity (n=299) characterized by the FC differences in each subtype relative to controls, respectively. The two subtypes did not differ in age, sex, and scores of Hamilton Depression/Anxiety Scale.The genes related to FC alterations were enriched in ion transmembrane transport, synaptic transmission/organization, axon development, and regulation of neurotransmitter level for both subtypes, but specifically enriched in glial cell differentiation for hypoconnectivity subtype, while enriched in regulation of presynaptic membrane and regulation of neuron differentiation for hyperconnectivity subtype.FC alterations were associated with the density of 5-HT2a receptor in both subtypes. For hyperconnectivity subtype, FC alterations were also correlated with the density of norepinephrine transporter, glutamate receptor, GABA receptor, 5-HT1b receptor, and cannabinoid receptor.Both subtypes showed correlations between FC and categorization, motor inhibition, and localization. The FC in hypoconnectivity subtype correlated with response inhibition, selective attention, face recognition, sleep, empathy, expertise, uncertainty, and anticipation, while that was related to inference, speech perception, and reward anticipation in hyperconnectivity subtype.ConclusionsOur findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypo or hyper-connectivity. The two subtypes had both shared and distinct genetic mechanisms, neurotransmitter receptor/transporter profiles, and cognition types.Disclosure of InterestNone Declared

Abnormal intrinsic brain functional network dynamics in first-episode drug-naïve adolescent major depressive disorder.

Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients. Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls. Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks. Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

Commentary: Early-in-life Isoflurane Exposure Alters Resting-State Functional Connectivity in Juvenile Non-human Primates - a Role for Neuroinflammation?

The concern about anesthesia-induced developmental neurotoxicity (AIDN) in infants and young children arises from animal studies indicating potential long-term neurobehavioral impairments following early-in-life anesthesia exposure. While initial clinical studies provided ambiguous results, recent prospective assessments in children indicate associations between early-in-life anesthesia exposure and later behavioral alterations. Ethical constraints and confounding factors in clinical studies pose challenges in establishing a direct causal link and in investigating its mechanisms. This commentary on a recent study in non-human primates (NHPs) focuses on exploring the role of neuroinflammation and alterations in brain functional connectivity in the behavioral impairments following early-in-life anesthesia exposure. In juvenile NHPs, chronic astrogliosis in the amygdala correlates with alterations in functional connectivity between this area with other regions of the brain and with the behavioral impairments, suggesting a potential mechanism for AIDN. Despite acknowledging the study's limitations, these findings emphasize the need for further research with larger cohorts to confirm these associations and to establish a causal link between the neuroinflammation and the behavioral alterations associated with early-in-life anesthesia exposure.

Altered brain functional connectivity in patients with resistance to thyroid hormone ß.

To investigate changes in brain network organization and possible neurobehavioral similarities to attention-deficit hyperactivity disorder (ADHD), we measured changes in brain resting-state functional connectivity (rs-fMRI) and cognitive domains in patients with resistance to thyroid hormone β (RTHβ) and compared them with those in healthy control subjects. In this prospective case-control study, twenty-one participants with genetically confirmed RTHβ were matched with 21 healthy controls. The Adult ADHD Self-Report Scale (ASRS-v1.1) and ADHD Rating Scale-IV were used to assess self-reported symptoms of ADHD. A voxel-wise and atlas-based approach was used to identify changes in the brain networks. The RTHβ group reported behavioral symptoms similar to those of ADHD. We found evidence of weaker network integration of the lingual and fusiform gyri in the RTHβ group, which was mainly driven by weaker connectivity to the bilateral insula and supplementary motor cortex. Functional connectivity between regions of the default mode network (angular gyrus/middle temporal gyrus) and regions of the cognitive control network (bilateral middle frontal gyrus) was increased in RTHβ patients compared to healthy controls. Increased connectivity between regions of the default mode network and the dorsolateral prefrontal cortex is frequently reported in ADHD and is interpreted to be associated with deficits in attention. Our finding of weaker connectivity of the lingual gyrus to the bilateral insula (salience network) in RTHβ patients has also been reported previously in ADHD and may reflect decreased habituation to visual stimuli and increased distractibility. Overall, our observations support the notion of neuropsychological similarities between RTHβ and ADHD.

Altered Brain Functional and Effective Connectivity Induced by Electroacupuncture in Rats Following Anterior Cruciate Ligament Transection.

The chronic pain arising from knee osteoarthritis (KOA) is a prevalent clinical manifestation. As a traditional Chinese approach, electroacupuncture (EA) has a positive influence in relieving chronic pain from KOA. The study aims to explore functional connectivity (FC) and effective connectivity (EC) alterations induced by EA in anterior cruciate ligament transection (ACLT) rat model of KOA using resting-state functional magnetic resonance imaging (fMRI). After the establishment of ACLT, rats were randomly divided into the EA group and the sham-EA group. The EA group received EA intervention while the sham-EA group received sham-intervention for 3 weeks. Mechanical pain threshold (MPT) assessment was performed before and after intervention, and fMRI was conducted after intervention. EA intervention effectively relieved pain in post-ACLT rats. Results of rest-state functional connectivity (rs-FC) analysis revealed that compared with the sham-EA group, the EA group had higher FC between the right raphe and the left auditory cortex, the left caudate_ putamen and the left internal capsule (IC), as well as the right zona incerta (ZI) and the left piriform cortex, but lower FC between the right raphe and the left hippocampus ventral, as well as the right septum and the left septum. Furthermore, Granger causality analysis (GCA) found the altered EC between the right septum and the left septum, as well as the left IC and the right septum. The results confirmed the effect of EA on analgesia in post- ACLT rats. The alterations of FC and EC, mainly involving basal ganglia and limbic system neural connections, might be one of the neural mechanisms underlying the effect of EA, providing novel information about connectomics plasticity of EA following ACLT.

Distinctive modulation patterns of functional brain connectivity of the default mode network by negative social emotions are associated with Alzheimer’s disease biomarkers in community‐dwelling older adults – cross‐sectional findings from the Age‐Well trial

AbstractBackgroundRecent evidence in Alzheimer’s diseases suggests that early dysfunction of emotional processing may precede the onset of cognitive decline and dementia. Altered functional brain connectivity patterns also occur along with other brain changes many years before clinical AD symptoms.MethodWe combined baseline multimodal neuroimaging data from cognitively healthy older adults (N = 125) enrolled in the Age‐Well trial of the Medit‐Ageing study. The aim was to elucidate the relationship of five AD risk factors (amyloid‐beta depositions and hypoperfusion with AV45‐PET, hippocampal atrophy, cognition with PACC‐5, cardiovascular risk with CAIDE) with carry‐over effects of social emotions and related brain functions. Using k‐means clustering analysis with the AD risk factors, we first defined participants with higher or lower preclinical risk for AD. We then used functional Magnetic Resonance Imaging to probe functional brain connectivity in resting periods following negative socio‐emotional videos in the SoVT‐Rest paradigm.ResultParticipants with a higher preclinical AD risk showed reduced positivity bias in affect ratings and reduced connectivity patterns between control‐related frontal brain regions and emotion‐related limbic regions (amygdala). In particular, this fronto‐limbic connectivity was associated with higher cardiovascular risk on the CAIDE composite score.ConclusionWe find evidence for changes in post‐emotion functional recovery patterns in fronto‐limbic brain networks in at‐risk individuals for AD. These changes might reflect impaired emotion regulation processes.

Associations Between Brain-Gut Axis and Psychological Distress in Fibromyalgia: A Microbiota and Magnetic Resonance Imaging Study

An altered brain-gut axis is suspected to be one of the pathomechanisms in fibromyalgia (FM). This cross-sectional study investigated the associations among altered microbiota, psychological distress, and brain functional connectivity (FC) in FM. We recruited 25 FM patients and 25 healthy people in the present study. Psychological distress was measured using standardized questionnaires. Microbiota analysis was performed on the participants' stools. Functional magnetic resonance imaging data were acquired, and seed-based resting-state FC (rs-FC) analysis was conducted with the salience network nodes as seeds. Linear regression and mediation analyses evaluated microbiota, symptoms, and rs-FCs associations. We found altered microbiota diversity in FM, of which Phascolarctobacterium and Lachnoclostridium taxa increased the most and Faecalibacterium taxon decreased the most compared to controls. The Phascolarctobacterium abundance significantly predicted Beck depression inventory (BDI-II) scores in FM (β = 6.83; P = .033). Rs-FCs from salience network nodes were reduced in FM, of which rs-FCs from the right lateral rostral prefrontal cortex (RPFC) to the lateral occipital cortex, superior division right (RPFC-sLOC) could be predicted by BDI-II scores in patients (β = −.0064; P = .0054). In addition, the BDI-II score was a mediator in the association between Phascolarctobacterium abundance and rs-FCs of RPFC-sLOC (ab = −.06; 95% CI: −.16 to −9.10-3). In conclusion, microbial dysbiosis might be associated with altered neural networks mediated by psychological distress in FM, emphasizing the critical role of the brain-gut axis in FM's non-pain symptoms and supporting further analysis of mechanism-targeted therapies to reduce FM symptoms. PerspectiveOur study suggests microbial dysbiosis might be associated with psychological distress and the altered salience network, supporting the role of brain-gut axis dysfunction in fibromyalgia pathomechanisms. Further targeting therapies for microbial dysbiosis should be investigated to manage fibromyalgia patients in the future.

Disentangling the Individual-Shared and Individual-Specific Subspace of Altered Brain Functional Connectivity in Autism Spectrum Disorder

BackgroundDespite considerable effort toward understanding the neural basis of autism spectrum disorder (ASD) using case-control analyses of resting-state functional magnetic resonance imaging data, findings are often not reproducible, largely due to biological and clinical heterogeneity among individuals with ASD. Thus, exploring the individual-shared and individual-specific altered functional connectivity (AFC) in ASD is important to understand this complex, heterogeneous disorder. MethodsWe considered 254 individuals with ASD and 295 typically developing individuals from the Autism Brain Imaging Data Exchange to explore the individual-shared and individual-specific subspaces of AFC. First, we computed AFC matrices of individuals with ASD compared with typically developing individuals. Then, common orthogonal basis extraction was used to project AFC of ASD onto 2 subspaces: an individual-shared subspace, which represents altered connectivity patterns shared across ASD, and an individual-specific subspace, which represents the remaining individual characteristics after eliminating the individual-shared altered connectivity patterns. ResultsAnalysis yielded 3 common components spanning the individual-shared subspace. Common components were associated with differences of functional connectivity at the group level. AFC in the individual-specific subspace improved the prediction of clinical symptoms. The default mode network–related and cingulo-opercular network–related magnitudes of AFC in the individual-specific subspace were significantly correlated with symptom severity in social communication deficits and restricted, repetitive behaviors in ASD. ConclusionsOur study decomposed AFC of ASD into individual-shared and individual-specific subspaces, highlighting the importance of capturing and capitalizing on individual-specific brain connectivity features for dissecting heterogeneity. Our analysis framework provides a blueprint for parsing heterogeneity in other prevalent neurodevelopmental conditions.

Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway

Major depressive disorder (MDD), a common psychiatric condition, adversely affects patients’ moods and quality of life. Despite the development of various treatments, many patients with MDD remain vulnerable and inadequately controlled. Since anhedonia is a feature of depression and there is evidence of leading to metabolic disorder, deep brain stimulation (DBS) to the nucleus accumbens (NAc) might be promising in modulating the dopaminergic pathway. To determine whether NAc-DBS alters glucose metabolism via mitochondrial alteration and neurogenesis and whether these changes increase neural plasticity that improves behavioral functions in a chronic social defeat stress (CSDS) mouse model. The Lab-designed MR-compatible neural probes were implanted in the bilateral NAc of C57BL/6 mice with and without CSDS, followed by DBS or sham stimulation. All animals underwent open-field and sucrose preference testing, and brain resting-state functional MRI analysis. Meanwhile, we checked the placement of neural probes in each mouse by T2 images. By confirming the placement location, mice with incorrect probe placement (the negative control group) showed no significant therapeutic effects in behavioral performance and functional connectivity (FC) after receiving electrical stimulation and were excluded from further analysis. Western blotting, seahorse metabolic analysis, and electron microscopy were further applied for the investigation of NAc-DBS. We found NAc-DBS restored emotional deficits in CSDS-subjected mice. Concurrent with behavioral amelioration, the CSDS DBS-on group exhibited enhanced FC in the dopaminergic pathway with increased expression of BDNF- and NeuN-positive cells increased dopamine D1 receptor, dopamine D2 receptors, and TH in the medial prefrontal cortex, NAc, ventral hippocampus, ventral tegmental area, and amygdala. Increased pAMPK/total AMPK and PGC-1α levels, functions of oxidative phosphorylation, and mitochondrial biogenesis were also observed after NAc-DBS treatment. Our findings demonstrate that NAc-DBS can promote BDNF expression, which alters FC and metabolic profile in the dopaminergic pathway, suggesting a potential strategy for ameliorating emotional processes in individuals with MDD.

The brain functional connectivity alterations in traumatic patients with olfactory disorder after low-level laser therapy demonstrated by fMRI.

Low-level laser therapy (LLLT) has been clinically accepted to accelerate the nerve regeneration process after a nerve injury or transection. We aimed to investigate the neuronal basis and the influence of LLLT on brain functional networks in traumatic patients with olfactory dysfunction. Twenty-four Patients with traumatic anosmia/hyposmia were exposed to pleasant olfactory stimuli during a block-designed fMRI session. After a 10-week period, patients as control group and patients who had completed the sessions of LLLT were invited for follow-up testing using the same fMRI protocol. Two-sample t-tests were conducted to explore group differences in activation responding to odorants (p-FDR-corrected <0.05). Differences of functional connectivity were compared between the two groups and the topological features of the olfactory network were calculated. Correlation analysis was performed between graph parameters and TDI score. Compared to controls, laser-treated patients showed increased activation in the cingulate, rectus gyrus, and some parts of the frontal gyrus. Shorter pathlength (p = 0.047) and increased local efficiency (p = 0.043) within the olfactory network, as well as decreased inter-network connectivity within the whole brain were observed in patients after laser surgery. Moreover, higher clustering and local efficiency were related to higher TDI score, as manifested in increased sensitivity to identify odors. The results support that low-level laser induces neural reorganization process and make new connections in the olfactory structures. Furthermore, the connectivity parameters may serve as potential biomarkers for traumatic anosmia or hyposmia by revealing the underlying neural mechanisms of LLLT.

Altered dynamic brain activity and functional connectivity in thyroid-associated ophthalmopathy.

Although previous neuroimaging evidence has confirmed the brain functional disturbances in thyroid-associated ophthalmopathy (TAO), the dynamic characteristics of brain activity and functional connectivity (FC) in TAO were rarely concerned. The present study aims to investigate the alterations of temporal variability of brain activity and FC in TAO using resting-state functional magnetic resonance imaging (rs-fMRI). Forty-seven TAO patients and 30 age-, gender-, education-, and handedness-matched healthy controls (HCs) were enrolled and underwent rs-fMRI scanning. The dynamic amplitude of low-frequency fluctuation (dALFF) was first calculated using a sliding window approach to characterize the temporal variability of brain activity. Based on the dALFF results, seed-based dynamic functional connectivity (dFC) analysis was performed to identify the temporal variability of efficient communication between brain regions in TAO. Additionally, correlations between dALFF and dFC and the clinical indicators were analyzed. Compared with HCs, TAO patients displayed decreased dALFF in the left superior occipital gyrus (SOG) and cuneus (CUN), while showing increased dALFF in the left triangular part of inferior frontal gyrus (IFGtriang), insula (INS), orbital part of inferior frontal gyrus (ORBinf), superior temporal gyrus (STG) and temporal pole of superior temporal gyrus (TPOsup). Furthermore, TAO patients exhibited decreased dFC between the left STG and the right middle occipital gyrus (MOG), as well as decreased dFC between the left TPOsup and the right calcarine fissure and surrounding cortex (CAL) and MOG. Correlation analyses showed that the altered dALFF in the left SOG/CUN was positively related to visual acuity (r = .409, p = .004), as well as the score of QoL for visual functioning (r = .375, p = .009). TAO patients developed abnormal temporal variability of brain activity in areas related to vision, emotion, and cognition, as well as reduced temporal variability of FC associated with vision deficits. These findings provided additional insights into the neurobiological mechanisms of TAO.