Serious Games for the Elderly: An fMRI Functional Connectivity Assessment

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls.We conducted resting state fMRI functional connectivity analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1.Functional connectivity analyses showed a significant increase of resting state FC in 4 networks in alcoholics compared to controls (p<0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (p<0.05, corrected), but not controls.Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

<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.

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Functional connectivity (FC) is commonly defined as the temporal coincidence of neurophysiological events, often quantified by the statistical dependency among signals from different brain regions and measured by Pearson’s correlation coefficient in fMRI. However, Pearson’s r captures only linear dependencies, potentially overlooking nonlinear interactions. Recently, Multiscale Graph Correlation (MGC) was introduced to measure statistical dependencies of both linear and nonlinear relationships across multiple scales, offering an “optimal scale” at which such dependencies can be inferred. In this study, we systematically compared FC measurements by Pearson’s r and MGC across datasets, evaluating their reliability, sensitivity to data quantity, and ability to capture distinct experimental conditions (deeper anesthesia in macaques) and brain-behavior association. Results showed highly similar spatial connectivity patterns and strong alignment between Pearson’s r and MGC for within-network FC, where optimal scales were frequently global. However, local optimal scales emerged between networks, suggesting the presence of nonlinear dependencies of FC. Reliability was higher for Pearson’s r overall, but both measurements improved as the quantity of data increased. Notably, MGC revealed variability in the optimal scales under altered brain states in deeper anesthesia, highlighting its potential for detecting local-scale dependencies across states. Despite these advantages, MGC required greater computational resources and did not outperform Pearson’s r in detecting brain-behavior associations. Consequently, Pearson’s r remains a sufficient and reliable measure for many standard applications, whereas MGC can offer more nuanced insights in scenarios where nonlinear dynamics are of particular interest. Researchers should, therefore, balance the potential gains from MGC against its added complexity and computational cost when selecting methods to quantify FC.

Executive control functions are associated with frontal, parietal, cingulate, and insular brain regions that interact through distributed large-scale networks. Here, we discuss how fMRI functional connectivity can shed light on the organization of control networks and how they interact with other parts of the brain. In the first section of our review, we present convergent evidence from fMRI functional connectivity, activation, and lesion studies that there are multiple dissociable control networks in the brain with distinct functional properties. In the second section, we discuss how graph theoretical concepts can help illuminate the mechanisms by which control networks interact with other brain regions to carry out goal-directed functions, focusing on the role of specialized hub regions for mediating cross-network interactions. Again, we use a combination of functional connectivity, lesion, and task activation studies to bolster this claim. We conclude that a large-scale network perspective provides important neurobiological constraints on the neural underpinnings of executive control, which will guide future basic and translational research into executive function and its disruption in disease.

The present study utilized a multimodal approach encompassing connectome networks combined with brain volume analysis, and assessment of cortical excitability to provide novel insights into amyotrophic lateral sclerosis (ALS) pathogenesis. Magnetic resonance images were acquired using a 3.0-Tesla Signa HDx scanner (GE Healthcare, Milwaukee, WI, USA), using an eight-channel head coil. Magnetic resonance images for the resting-state scan were acquired using an echo-planar imaging magnetic resonance sequence, acquiring 40 contiguous axial/oblique slices. Structural magnetic resonance imaging three-dimensional T1-weighted images were acquired in the sagittal plane using three-dimensional spoiled gradient echo sequences. For structural imaging, a T1-weighted high-resolution (3.0-Tesla) magnetic resonance imaging scan was used. Cortical excitability was assessed by using the threshold-tracking transcranial magnetic stimulation paradigm. Network-based statistics and whole-brain functional topology (using graph theoretical approaches) assessed functional connectivity. Using a global network-based statistical analysis approach, functional connectivity was increased in 12 network edges connecting 14 nodes (P < 0.05) within the frontal, temporal, parietal and subcortical regions. Analysis of local connectedness disclosed dichotomous effects with reduced connectivity in frontal regions and increased connectivity in occipital regions in ALS. Cortical hyperexcitability was evident in patients with ALS, negatively correlated with functional connectivity changes in the pre-central gyrus (P < 0.01). Connectivity changes in the frontal regions were negatively associated with functional disability (P < 0.05). Multimodal assessment of cortical function in patients with ALS identified deficits in functional connectivity associated with cortical hyperexcitability that correlated with patient disability. Novel integration of functional brain assessment further contributes to the understanding of disease pathogenesis in ALS.

In previous studies, resting-state functional connectivity (FC) metrics of specific brain regions or networks based on prior hypotheses have been correlated with cognitive performance. Without constraining our analyses to specific regions or networks, we employed whole-brain voxel-based weighted degree (WD), a measure of local FC strength, to be correlated with three commonly used neuropsychological assessments of language, executive function and memory retrieval in both positive and negative directions in 67 cognitively healthy elderly adults. We also divided voxel-based WD into short-ranged and long-ranged WDs to evaluate the influence of FC distance on the WD-cognition relationship, and performed three validation tests. Our results showed that for language and executive function tests, positive WD correlates were located in the frontal and temporal cortices, and negative WD correlates in the precuneus and occipital cortices; for memory retrieval, positive WD correlates were located in the inferior temporal cortices, and negative WD correlates in the anterior cingulate cortices and supplementary motor areas. An FC-distance-dependent effect was also observed, with the short-ranged WD correlates of language and executive function tests located in the medial brain regions and the long-ranged WD correlates in the lateral regions. Our findings suggest that inter-individual differences in FC at rest are predictive of cognitive ability in the elderly adults. Moreover, the distinct patterns of positive and negative WD correlates of cognitive performance recapitulate the dichotomy between task-activated and task-deactivated neural systems, implying that a competition between distinct neural systems on functional network topology may have cognitive relevance.

Measuring cerebrovascular reactivity with the use of vasodilatory stimuli, such as acetazolamide, is useful for chronic cerebrovascular steno-occlusive disease. The purpose of this study was to evaluate the effects of acetazolamide on the assessment of hemodynamic impairment and functional connectivity by using noninvasive resting-state blood oxygen level-dependent MR imaging. A 20-minute resting-state blood oxygen level-dependent MR imaging scan was acquired with infusion of acetazolamide starting at 5 minutes after scan initiation. A recently developed temporal-shift analysis technique was applied on blood oxygen level-dependent MR imaging data before and after acetazolamide infusion to identify regions with hemodynamic impairment, and the results were compared by using contrast agent-based DSC perfusion imaging as the reference standard. Functional connectivity was compared with and without correction on the signal by using information from temporal-shift analysis, before and after acetazolamide infusion. Visually, temporal-shift analysis of blood oxygen level-dependent MR imaging data identified regions with compromised hemodynamics as defined by DSC, though performance deteriorated in patients with bilateral disease. The Dice similarity coefficient between temporal-shift and DSC maps was higher before (0.487 ± 0.150 by using the superior sagittal sinus signal as a reference for temporal-shift analysis) compared with after acetazolamide administration (0.384 ± 0.107) (P = .006, repeated-measures ANOVA). Functional connectivity analysis with temporal-shift correction identified brain network nodes that were otherwise missed. The accuracy of functional connectivity assessment decreased after acetazolamide administration (P = .015 for default mode network, repeated-measures ANOVA). Temporal-shift analysis of blood oxygen level-dependent MR imaging can identify brain regions with hemodynamic compromise in relation to DSC among patients with chronic cerebrovascular disease. The use of acetazolamide reduces the accuracy of temporal-shift analysis and network connectivity evaluation.

To identify the neural correlates of cognitive improvement in mild Alzheimer's disease (AD) subjects following 12 weeks of donepezil treatment. Resting-state functional connectivity magnetic resonance imaging (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral, and functional assessments. After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement. R-fMRI may provide novel insights into the brain's responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.

Previous neuroimaging studies of vascular cognitive impairment, no dementia (VCIND), have reported functional alterations, but far less is known about the effects of cognitive training on functional connectivity (FC) of intrinsic connectivity networks (ICNs) and how they relate to intervention-related cognitive improvement. This study provides comprehensive research on the changes in intra- and inter-brain functional networks in patients with VCIND who received computerized cognitive training, with a focus on the underlying mechanisms and potential therapeutic strategies. We prospectively collected 60 patients with VCIND who were randomly divided into the training group (N = 30) receiving computerized cognitive training and the control group (N = 30) receiving fixed cognitive training. Functional MRI scans and cognitive assessments were performed at baseline, at the 7-week training, and at the 6-month follow-up. Utilizing templates for ICNs, the study employed a linear mixed model to compare intra- and inter-network FC changes between the two groups. Pearson correlation was applied to calculate the relationship between FC and cognitive function. We found significantly decreased intra-network FC within the default mode network (DMN) following computerized cognitive training at Month 6 (p = 0.034), suggesting a potential loss of functional specialization. Computerized training led to increased functional coupling between the DMN and sensorimotor network (SMN) (p = 0.01) and between the language network (LN) and executive control network (ECN) at Month 6 (p < 0.001), indicating compensatory network adaptations in patients with VCIND. Notably, the intra-LN exhibited enhanced functional specialization after computerized cognitive training (p = 0.049), with significant FC increases among LN regions, which correlated with improvements in neuropsychological measures (p < 0.05), emphasizing the targeted impact of computerized cognitive training on language abilities. This study provides insights into neuroplasticity and adaptive changes resulting from cognitive training in patients with VCIND, with implications for potential therapeutic strategies.

Contrasting brain patterns of writing-related DTI parameters, fMRI connectivity, and DTI-fMRI connectivity correlations in children with and without dysgraphia or dyslexia.

Objective: In this study, we used resting-state fMRI data to map differences in functional connectivity between a comprehensive set of 8 distinct cortical and subcortical brain regions in healthy controls and Internet addicts. We also investigated the relationship between resting state connectivity strength and the level of psychopathology (ex. score of internet addiction scale and score of Barratt impulsiveness scale).BRBR Background: There is a lot of evidence of relationship between Internet addiction and impaired inhibitory control. Clinical evidence suggests that Internet addicts have a high level of impulsivity as measured by behavioral task of response inhibition and a self report questionnaire.BRBR Method: 15 Internet addicts and 15 demographically similar non-addicts participated in the current resting-state fMRI experiment. For the connectivity analysis, regions of interests (ROIs) were defined based on the previous studies of addictions. Functional connectivity assessment for each subject was obtained by correlating time-series across the ROIs, resulting in 8x8 matrixs for each subject. Within-group, functional connectivity patterns were observed by entering the z maps of the ROIs of each subject into second-level one sample t test. Two sample t test was also performed to examine between group differences.BRBR Results: Between group, the analysis revealed that the connectivity in between the orbito frontal cortex and inferior parietal cortex, between orbito frontal cortex and putamen, between the orbito frontal cortex and anterior cingulate cortex, between the insula and anterior cingulate cortex, and between amydgala and insula was significantly stronger in control group than in the Internet addicts, while the connectivity in between the orbito frontal cortex and insula showed stronger negative correlation in the Internet addicts relative to control group (p < 0.001, uncorrected). No significant relationship between functional connectivity strength and current degree of Internet addiction and degree of impulsitivy was seen.BRBR Conclusion: This study found that Internet addicts had declined connectivity strength in the orbitofrontal cortex (OFC) and other regions (e.g., ACC, IPC, and insula) during resting-state. It may reflect deficits in the OFC function to process information from different area in the corticostriatal reward network. BRBR Application: The results might help to develop theoretical modeling of Internet addiction for Internet addiction discrimination.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between 'pressure-only' and 'pressure+cold' stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. KEY POINTS: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

The conventional approach to investigating functional connectivity in the block-designed study usually concatenates task blocks or employs residuals of task activation. While providing many insights into brain functions, the block design adds more manipulation in functional network analysis that may reduce the purity of the blood oxygenation level-dependent signal. Recent studies utilized one single long run for task trials of the same condition, the so-called continuous design, to investigate functional connectivity based on task functional magnetic resonance imaging. Continuous brain activities associated with the single-task condition can be directly utilized for task-related functional connectivity assessment, which has been examined for working memory, sensory, motor, and semantic task experiments in previous research. But it remains unclear how the block and continuous design influence the assessment of task-related functional connectivity networks. This study aimed to disentangle the separable effects of block/continuous design and working memory load on task-related functional connectivity networks, by using repeated-measures analysis of variance. Across 50 young healthy adults, behavioral results of accuracy and reaction time showed a significant main effect of design as well as interaction between design and load. Imaging results revealed that the cingulo-opercular, fronto-parietal, and default model networks were associated with not only task activation, but significant main effects of design and load as well as their interaction on intra- and inter-network functional connectivity and global network topology. Moreover, a significant behavior-brain association was identified for the continuous design. This work has extended the evidence that continuous design can be used to study task-related functional connectivity and subtle brain-behavioral relationships.