Mapping the modulating effect of transcutaneous auricular vagus nerve stimulation on voxel-based analyses in patients with first-episode major depressive disorder: a resting-state functional magnetic resonance imaging study.

INTRODUCTION: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. METHODS: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. RESULTS: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. CONCLUSION: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

Mapping the modulating effect of transcutaneous auricular vagus nerve stimulation on voxel-based analyses in patients with first-episode major depressive disorder: a resting-state functional magnetic resonance imaging study

Introduction: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. Methods: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. Results: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. Conclusion: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

Thrifty-Eating Behavior Phenotype at the Food Court - Programming Goes Beyond Food Preferences.

Introduction: Prenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS). Methods: Caregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data. Results: In the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients' intake differences between groups in both samples. Conclusions: Resting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

Estrogen, Cognitive Performance, and Functional Imaging Studies: What Are We Missing About Neuroprotection?

Menopause transition can be interpreted as a vulnerable state characterized by estrogen deficiency with detrimental systemic effects as the low-grade chronic inflammation that appears with aging and partly explains age-related disorders as cancer, diabetes mellitus and increased risk of cognitive impairment. Over the course of a lifetime, estrogen produces several beneficial effects in healthy neurological tissues as well as cardioprotective effects, and anti-inflammatory effects. However, clinical evidence on the efficacy of hormone treatment in menopausal women has failed to confirm the benefit reported in observational studies. Unambiguously, enhanced verbal memory is the most robust finding from longitudinal and cross-sectional studies, what merits consideration for future studies aiming to determine estrogen neuroprotective efficacy. Estrogen related brain activity and functional connectivity remain, however, unexplored. In this context, the resting state paradigm may provide valuable information about reproductive aging and hormonal treatment effects, and their relationship with brain imaging of functional connectivity may be key to understand and anticipate estrogen cognitive protective effects. To go in-depth into the molecular and cellular mechanisms underlying rapid-to-long lasting protective effects of estrogen, we will provide a comprehensive review of cognitive tasks used in animal studies to evaluate the effect of hormone treatment on cognitive performance and discuss about the tasks best suited to the demonstration of clinically significant differences in cognitive performance to be applied in human studies. Eventually, we will focus on studies evaluating the DMN activity and responsiveness to pharmacological stimulation in humans.

Development of the brain functional connectome follows puberty-dependent nonlinear trajectories.

Adolescence is a developmental period that dramatically impacts body and behavior, with pubertal hormones playing an important role not only in the morphological changes in the body but also in brain structure and function. Understanding brain development during adolescence has become a priority in neuroscience because it coincides with the onset of many psychiatric and behavioral disorders. However, little is known about how puberty influences the brain functional connectome. In this study, taking a longitudinal human sample of typically developing children and adolescents (of both sexes), we demonstrate that the development of the brain functional connectome better fits pubertal status than chronological age. In particular, centrality, segregation, efficiency, and integration of the brain functional connectome increase after the onset of the pubertal markers. We found that these effects are stronger in attention and task control networks. Lastly, after controlling for this effect, we showed that functional connectivity between these networks is related to better performance in cognitive flexibility. This study points out the importance of considering longitudinal nonlinear trends when exploring developmental trajectories, and emphasizes the impact of puberty on the functional organization of the brain in adolescence.

Resting State Brain Network Function in Elderly: The Formation of Social Ties.

BACKGROUND: The purpose of this study is to determine the relevance of the relationship between brain network and the social ties management. METHODS: Participants are based on 52 Korean seniors aged 65 and older who live in Ganghwa-gun, Incheon. We used a closed-triad index (CTI), which is the most basic unit of analysis in the study of group phenomena. This index is a social networking variable that has been shown to have a different implication depending on the subject's condition and role. After two questionnaire surveys were conducted at three years intervals, participants were classified into an increased group and a decreased group according to the change of CTI. Resting-state fMRI analysis were followed to investigate the difference of brain networks between groups. RESULTS: According to the analysis of the study, the whole participants who had increased in number of CTI has higher local efficiency than the group of the participants who had no effect or decreased in CTI. CONCLUSIONS: Our study suggests that social relationship, which is substantially related to brain network, is a major factor in successful aging. Lastly, since there is a restriction that the study cannot explain the causal aspect of the brain network and the triad-relationship, there is a need for further investigation.

ANTECEDENTES: El propósito de este estudio fue determinar la relevancia de la relación entre la red cerebral y el manejo de los lazos sociales. MÉTODO: los participantes son 52 adultos mayores coreanos de 65 años o más que viven en Ganghwa-gun, Incheon. Utilizamos un índice de tríada cerrada (CTI), que es la unidad de análisis más básica en el estudio de los fenómenos grupales. Este índice es una variable de red social que ha demostrado tener una implicación diferente dependiendo de la condición y el rol del sujeto. Después de realizar dos encuestas por cuestionario a intervalos de tres años, los participantes se clasificaron en un grupo aumentado y un grupo disminuido de acuerdo con el cambio de CTI. Se siguió el análisis de fMRI en estado de reposo para investigar la diferencia de las redes cerebrales entre los grupos. RESULTADOS: Según el análisis del estudio, todos los participantes que habían aumentado en número de CTI tienen una mayor eficiencia local que el grupo de participantes que no tuvieron ningún efecto o disminuyeron en CTI. CONCLUSIONES: Nuestro estudio sugiere que la relación social que está sustancialmente relacionada con la red cerebral es un factor importante en el envejecimiento exitoso. Por último, dado que existe una restricción de que el estudio no puede explicar el aspecto causal de la red cerebral y la relación tríada, existe la necesidad de una mayor investigación.

Topological Data Analysis Reveals Robust Alterations in the Whole-Brain and Frontal Lobe Functional Connectomes in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by difficulty to control the own behavior. Neuroimaging studies have related ADHD with the interplay of fronto-parietal attention systems with the default mode network (DMN; Castellanos and Aoki, 2016). However, some results have been inconsistent, potentially due to methodological differences in the analytical strategies when defining the brain functional network, i.e., the functional connectivity threshold and/or the brain parcellation scheme. Here, we make use of topological data analysis (TDA) to explore the brain connectome as a function of the filtration value (i.e., the connectivity threshold), instead of using a static connectivity threshold. Specifically, we characterized the transition from all nodes being isolated to being connected into a single component as a function of the filtration value. We explored the utility of such a method to identify differences between 81 children with ADHD (45 male, age: 7.26-17.61 years old) and 96 typically developing children (TDC; 59 male, age: 7.17-17.96 years old), using a public dataset of resting state (rs)fMRI in human subjects. Results were highly congruent when using four different brain segmentations (atlases), and exhibited significant differences for the brain topology of children with ADHD, both at the whole-brain network and the functional subnetwork levels, particularly involving the frontal lobe and the DMN. Therefore, this is a solid approach that complements connectomics-related methods and may contribute to identify the neurophysio-pathology of ADHD.

Alterations in knee sensorimotor brain functional connectivity contributes to ACL injury in male high-school football players: a prospective neuroimaging analysis.

OBJECTIVE: This study's purpose was to utilize a prospective dataset to examine differences in functional brain connectivity in male high school athletes who suffered an anterior cruciate ligament (ACL) injury relative to their non-injured peers. METHODS: Sixty-two male high school football players were evaluated using functional magnetic resonance imaging prior to their competitive season to evaluate resting-state functional brain connectivity. Three athletes later experienced an ACL injury and were matched to 12 teammates who did not go on to sustain an ACL injury (controls) based on school, age, height, weight, and year in school. Twenty-five knee-motor regions of interest (ROIs) were created to identify differences in connectivity between the two groups. Between-subject F and t tests were used to identify significant ROI differences using a false discovery rate correction for multiple comparisons. RESULTS: There was significantly less connectivity between the left secondary somatosensory cortex and the left supplementary motor area (p = 0.025), right pre-motor cortex (p = 0.026), right supplementary motor area (p = 0.026), left primary somatosensory cortex (superior division; p = 0.026), left primary somatosensory cortex (inferior division; p = 0.026), and left primary motor cortex (p = 0.048) for the ACL-injured compared to the control subjects. No other ROI-to-ROI comparisons were significantly different between the groups (all p > 0.05). CONCLUSION: Our preliminary data indicate a potential sensorimotor disruption for male football players who go on to experience an ACL injury. Future studies with larger sample sizes and complementary measures of neuromuscular control are needed to support these findings.

A systematic review of brain functional connectivity patterns involved in episodic and semantic memory.

The study of functional connectivity and declarative memory has lately been focused on finding biomarkers of neuropsychological diseases. However, little is known about its patterns in healthy brains. Thus, in this systematic review we analyze and integrate the findings of 81 publications regarding functional connectivity (measured by fMRI during both task and resting-state) and semantic and episodic memory in healthy adults. Moreover, we discriminate and analyze the main areas and links found in specific memory phases (encoding, storage or retrieval) based on several criteria, such as time length, depth of processing, rewarding value of the information, vividness and amount or kind of details retrieved. There is a certain degree of overlap between the networks of episodic and semantic memory and between the encoding and retrieval stages. Although several differences are pointed out during the article, this calls to attention the need for further empirical studies that actively compare both types of memory, particularly using other baseline conditions apart from the traditional resting state. Indeed, the active involvement of the default mode network in both declarative memory and resting condition suggests the possibility that during rest there is an on-going memory processing. We find support for the 'attention to memory' hypothesis, the memory differentiation model and the appropriate transfer hypothesis, but some evidence is inconsistent with the traditional hub-and-spoke model.

Altered Functional Brain Network Integration, Segregation, and Modularity in Infants Born Very Preterm at Term-Equivalent Age.

OBJECTIVES: To determine the functional network organization of the brain in infants born very preterm at term-equivalent age and to relate network alterations to known clinical risk factors for poor neurologic outcomes in prematurity. STUDY DESIGN: Resting-state functional magnetic resonance imaging data from 66 infants born very preterm (gestational age <32 weeks and birth weight <1500 g) and 66 healthy neonates born at full term, acquired as part of a prospective, cross-sectional study, were compared at term age using graph theory. Features of resting-state networks, including integration, segregation, and modularity, were derived from correlated hemodynamic activity arising from 93 cortical and subcortical regions of interest and compared between groups. RESULTS: Despite preserved small-world topology and modular organization, resting-state networks of infants born very preterm at term-equivalent age were less segregated and less integrated than those of infants born full term. Chronic respiratory illness (ie, bronchopulmonary dysplasia and the length of oxygen support) was associated with decreased global efficiency and increased path lengths (P < .05). In both cohorts, 4 functional modules with similar composition were observed (parietal/temporal, frontal, subcortical/limbic, and occipital). The density of connections in 3 of the 4 modules was decreased in the very preterm network (P < .01); however, in the occipital/visual cortex module, connectivity was increased in infants born very preterm relative to control infants (P < .0001). CONCLUSIONS: Early exposure to the ex utero environment is associated with altered resting-state network functional organization in infants born very preterm at term-equivalent age, likely reflecting disrupted brain maturational processes.

Abnormal Cortico-Cerebellar Functional Connectivity in Autism Spectrum Disorder.

The cerebral cortex and the cerebellum are spatially remote areas that are connected by complex circuits that link both primary and associative areas. Previous studies have revealed abnormalities in autism spectrum disorder (ASD); however, it is not clear whether cortico-cerebellar connectivity is differentially manifested in the disorder. To explore this issue, we investigated differences in intrinsic cortico-cerebellar functional connectivity between individuals with typical development (TD) and those with ASD. To this end, we used functional magnetic resonance imaging (fMRI) of 708 subjects under a resting state protocol provided by the ABIDE I Consortium. We found that people with ASD had diminished functional connectivity between the cerebellum and the following cortical regions: (i) right fusiform gyrus, (ii) right postcentral gyrus, (iii) right superior temporal gyrus, (iv) right middle temporal gyrus, and (v) left middle temporal gyrus. All of these regions are involved in many cognitive systems that contribute to commonly affected functions in ASD. For right fusiform gyrus, right superior temporal gyrus, and left middle temporal gyrus, we reproduced the results in an independent cohort composed of 585 subjects of the ABIDE II Consortium. Our results points toward a consistent atypical cortico-cerebellar connectivity in ASD.

Functional Evidence for Memory Stabilization in Sensorimotor Adaptation: A 24-h Resting-State fMRI Study.

Adaptation learning is crucial to maintain precise motor control in face of environmental perturbations. Although much progress has been made in understanding the psychophysics and neurophysiology of sensorimotor adaptation (SA), the time course of memory consolidation remains elusive. The lack of a reproducible gradient of memory resistance using protocols of retrograde interference has even led to the proposal that memories produced through SA do not consolidate. Here, we pursued an alternative approach using resting-state fMRI to track changes in functional connectivity (FC) induced by learning. Given that consolidation leads to long-term memory, we hypothesized that a change in FC that predicted long-term memory but not short-term memory would provide indirect evidence for memory stabilization. Six scans were acquired before, 15 min, 1, 3, 5.5, and 24 h after training on a center-out task under veridical or distorted visual feedback. The experimental group showed an increment in FC of a network including motor, premotor, posterior parietal cortex, cerebellum, and putamen that peaked at 5.5 h. Crucially, the strengthening of this network correlated positively with long-term retention but negatively with short-term retention. Our work provides evidence, suggesting that adaptation memories stabilize within a 6-h window, and points to different mechanisms subserving short- and long-term memory.

Local dimension-reduced dynamical spatio-temporal models for resting state network estimation.

To overcome the limitations of independent component analysis (ICA), today's most popular analysis tool for investigating whole-brain spatial activation in resting state functional magnetic resonance imaging (fMRI), we present a new class of local dimension-reduced dynamical spatio-temporal model which dispenses the independence assumptions that severely limit deeper connectivity descriptions between spatial components. The new method combines novel concepts of group sparsity with contiguity-constrained clusterization to produce physiologically consistent regions of interest in illustrative fMRI data whose causal interactions may then be easily estimated, something impossible under the usual ICA assumptions.

Effect of scanner acoustic background noise on strict resting-state fMRI

Functional MRI (fMRI) resting-state experiments are aimed at identifying brain networks that support basal brain function. Although most investigators consider a ‘resting-state' fMRI experiment with no specific external stimulation, subjects are unavoidably under heavy acoustic noise produced by the equipment. In the present study, we evaluated the influence of auditory input on the resting-state networks (RSNs). Twenty-two healthy subjects were scanned using two similar echo-planar imaging sequences in the same 3T MRI scanner: a default pulse sequence and a reduced “silent” pulse sequence. Experimental sessions consisted of two consecutive 7-min runs with noise conditions (default or silent) counterbalanced across subjects. A self-organizing group independent component analysis was applied to fMRI data in order to recognize the RSNs. The insula, left middle frontal gyrus and right precentral and left inferior parietal lobules showed significant differences in the voxel-wise comparison between RSNs depending on noise condition. In the presence of low-level noise, these areas Granger-cause oscillations in RSNs with cognitive implications (dorsal attention and entorhinal), while during high noise acquisition, these connectivities are reduced or inverted. Applying low noise MR acquisitions in research may allow the detection of subtle differences of the RSNs, with implications in experimental planning for resting-state studies, data analysis, and ergonomic factors.