Changes In Neural Connectivity Research Articles

Estrogen deficiency affects synchronized neural connectivity in the olfactory bulb-nucleus accumbens circuit: A local field potential study in ovariectomized mouse model

Estrogen plays a crucial role in regulating various brain functions, including cognitive, emotional, and social behaviors. Menopausal women face a decline in estrogen levels, which has been linked to several physical and mental health issues. However, the impact of estrogen on the olfactory bulb–nucleus accumbens (OB-NAc) circuit, which is essential for regulating emotions and cognitive behaviors, remains poorly understood. To test the hypothesis that estrogen deficiency affects signal processing, we recorded local field potentials (LFPs) using intracranial electrodes implanted in four-week-old ovariectomized (OVX) mice during an open-field test (OFT). The results showed a decrease in locomotor activity and increase in anxiety-like behaviors in OVX mice. Furthermore, we found a decrease in high-gamma power in the OB. We analyzed coherence and inter-region phase-amplitude coupling (ir-PAC) to explore the connectivity between the OB and NAc. We observed a decrease in low-gamma and high-gamma coherence in OVX mice. Additionally, we found that the direction of connectivity from the NAc to the OB was disrupted in OVX mice. In summary, our study provides evidence that estrogen deficiency is linked to synchronized neural connectivity changes in the OB–NAc circuit. These findings have implications for our understanding of the roles played by the OB–NAc neural circuit and estrogen in the regulation of general exploratory behavior and anxiety-like behavior.

De novo motor learning creates structure in neural activity that shapes adaptation

Animals can quickly adapt learned movements to external perturbations, and their existing motor repertoire likely influences their ease of adaptation. Long-term learning causes lasting changes in neural connectivity, which shapes the activity patterns that can be produced during adaptation. Here, we examined how a neural population’s existing activity patterns, acquired through de novo learning, affect subsequent adaptation by modeling motor cortical neural population dynamics with recurrent neural networks. We trained networks on different motor repertoires comprising varying numbers of movements, which they acquired following various learning experiences. Networks with multiple movements had more constrained and robust dynamics, which were associated with more defined neural ‘structure’—organization in the available population activity patterns. This structure facilitated adaptation, but only when the changes imposed by the perturbation were congruent with the organization of the inputs and the structure in neural activity acquired during de novo learning. These results highlight trade-offs in skill acquisition and demonstrate how different learning experiences can shape the geometrical properties of neural population activity and subsequent adaptation.

Structural equation modeling of treatment-related changes in neural connectivity for youth with PTSD

BackgroundPrevious studies suggest that improvement in symptoms of posttraumatic stress disorder (PTSD) is accompanied by changes in neural connectivity, however, few studies have investigated directional (effective) connectivity. The current study assesses treatment-related changes in effective connectivity in youth with PTSD undergoing Trauma-Focused Cognitive Behavioral Therapy (TF-CBT). MethodsFunctional MRI scans before and after 16 weeks of TF-CBT for 20 youth with PTSD, or the same time interval for 20 healthy controls (HC) were included in the analysis. Structural equation modeling was used to model group differences in directional connectivity at baseline, and changes in connectivity from pre- to post-treatment. ResultsAt baseline, the PTSD group, relative to the HC group, had significantly greater connectivity in the path from dorsal cingulate to anterior cingulate and from dorsal cingulate to posterior cingulate corticies. From pre- to post-treatment, connectivity in these paths decreased significantly in the PTSD group, as did connectivity from right hippocampus to left superior temporal gyrus. Connectivity from the left amygdala to the lateral orbital frontal cortex was significantly lower in PTSD vs HC at baseline, but did not change from pre- to post-treatment. ConclusionAlthough based on a small sample, these results converge with previous studies in suggesting a central role for the dorsal cingulate cortex in PTSD symptoms. The direction of this connectivity suggests that the dorsal cingulate is the source of modulation of anterior and posterior cingulate cortex during trauma-focused cognitive behavioral therapy.

Plastic neural network with transmission delays promotes equivalence between function and structure

The brain is formed by cortical regions that are associated with different cognitive functions. Neurons within the same region are more likely to connect than neurons in distinct regions, making the brain network to have characteristics of a network of subnetworks. The values of synaptic delays between neurons of different subnetworks are greater than those of the same subnetworks. This difference in communication time between neurons has consequences on the firing patterns observed in the brain, which is directly related to changes in neural connectivity, known as synaptic plasticity. In this work, we build a plastic network of Hodgkin–Huxley neurons in which the connectivity modifications follow a spike-time dependent rule. We define an internal-delay among neurons communicating within the same subnetwork, an external-delay for neurons belonging to distinct subnetworks, and study how these communicating delays affect the entire network dynamics. We observe that the neuronal network exhibits a specific connectivity configuration for each synchronised pattern. Our results show how synaptic delays and plasticity work together to promote the formation of structural coupling among the neuronal subnetworks. We conclude that plastic neuronal networks are able to promote equivalence between function and structure meaning that topology emerges from behaviour and behaviour emerges from topology, creating a complex dynamical process where topology adapts to conform with the plastic rules and firing patterns reflect the changes on the synaptic weights.

Cerebral Neural Changes in Venous–Arterial Extracorporeal Membrane Oxygenation Survivors

Extracorporeal membrane oxygenation (ECMO) is used as temporary cardiorespiratory support in patients with critical ailments, but very little is known about the functional cerebral changes in ECMO survivors. Degree centrality (DC), a graph-based assessment of network organization, was performed to explore the neural connectivity changes in ECMO survivors compared to controls and their correlation with cognitive and neurological measures. This exploratory observational study was conducted from August 2020 to May 2022. ECMO survivors and controls underwent functional magnetic resonance imaging (fMRI) of the brain. We performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity with other voxels. DC was measured by the fMRI graph method and comparisons between the two groups were performed. All participants underwent neuropsychological assessment (Montreal Cognitive Assessment, MoCA). Blood serum neuron-specific enolase and the Glasgow Coma Scale (GCS) were assessed in ECMO survivors. DC values in the right insula and right precuneus gyrus were lower in ECMO survivors and higher in the right medial superior frontal gyrus compared to controls (all p < 0.001). Decreased connectivity in the right insular and right precuneus gyrus correlated with total MoCA scores, delayed recollection, and calculation (all p < 0.05). Increased serum NSE levels, GCS score, and GCS-motor response correlated with decreased connectivity in the right insular and right precuneus gyrus and increased connectivity in the right medial superior frontal gyrus (all p < 0.05). We showed that both functional impairment and adaptation were observed in survivors of ECMO, suggesting that neural connectivity changes may provide insights into the mechanisms that may potentially link ECMO survivors to neurological and cognitive disorders.

Irritability in early to middle childhood: Cross-sectional and longitudinal associations with resting state amygdala and ventral striatum connectivity

BackgroundIrritability is a common symptom that may affect children’s brain development. This study aims to (1) characterize age-dependent and age-independent neural correlates of irritability in a sample of 4–8 year old children, and (2) examine early irritability as a predictor of change in brain connectivity over time. MethodsTypically developing children, ages 4–8 years, with varying levels of irritability were included. Resting state fMRI and parent-rated irritability (via Child Behavior Checklist; CBCL) were collected at up to three time points, resulting in a cross-sectional sample at baseline (N = 176, M = 6.27, SD = 1.49), and two subsamples consisting of children who were either 4 or 6 years old at baseline that were followed longitudinally for two additional timepoints, one- and two-years post-baseline. That is, a “younger” cohort (age 4 at baseline, n = 34, M age = 4.44, SD = 0.25) and an “older” cohort (age 6 at baseline, n = 29, M age = 6.50, SD = 0.30). Across our exploratory analyses, we examined how irritability related to seed-based intrinsic connectivity via whole-brain connectivity ANCOVAs using the left and right amygdala, and left and right ventral striatum as seed regions. ResultsCross-sectionally, higher levels of irritability were associated with greater amygdala connectivity with the posterior cingulate, controlling for child age. No age-dependent effects were observed in the cross-sectional analyses. Longitudinal analyses in the younger cohort revealed that early higher vs. lower levels of irritability, controlling for later irritability, were associated with decreases in amygdala and ventral striatum connectivity with multiple frontal and parietal regions over time. There were no significant findings in the older cohort. ConclusionsFindings suggest that irritability is related to altered neural connectivity during rest regardless of age in early to middle childhood and that early childhood irritability may be linked to altered changes in neural connectivity over time. Understanding how childhood irritability interacts with neural processes can inform pathophysiological models of pediatric irritability and the development of targeted mechanistic interventions.

Abstract 15082: Altered Functional Brain Circuitry in Fetuses With Complex Congenital Heart Disease

Recent reports describing regional alterations involving critical hubs of the developing brain have emerged in neonates with complex CHD prior to surgery. However, the extent to which postnatal brain connectivity disturbances reflect a prenatal onset of aberrant functional circuitry development is unknown. Here, we investigated whether neural connectivity changes are present in fetuses with CHD before birth. We acquired 176 resting state scans from 156 pregnant women who were prospectively enrolled. We analyzed 76 scans from 61 CHD fetuses (mean±sd:33.4±3.1 gestational weeks, GW); which included transposition of the great arteries, n=22; hypoplastic left heart syndrome, n=20; other CHD, n=34) and 103 scans from 95 healthy controls (33.8±3.3 GW). First, we defined 98 anatomic regions ( nodes ) using a fetal atlas. Next, for each fetus, we computed connectivity – the pairwise Fisher- z transformed Pearson correlation, ( z(r) ) – across all 98 nodes. Only the strongest 4% of connections, or 190 edges , were included. Next, we grouped nodes into 16 clusters, or modules , based on a node’s connectivity to other nodes. We then compared (1) the number of connections within ( w-edges ) and between ( b-edges ) modules, and (2) the strength of connectivity within ( w-strength ) and between ( b-strength ) modules. We expected 12/190 w-edges and 177/190 b-edges but observed 55 and 54 w-edges in healthy (H) and CHD fetuses, respectively, 4.5x greater than the expected. Thus, in both cohorts, the normalized w-edges were significantly greater than the normalized b-edges ( p &lt; 0.001); there were no significant between-group differences. However, w-strength (H,1.16±0.26; CHD, 1.14±0.31) and b-strength (H, 1.05±0.19; CHD, 1.04±0.26) were significantly reduced in CHD ( p &lt;0.001). In both, w-strength was greater than b-strength (p&lt;0.001). For the first time, we demonstrated that CHD functional networks follow normative trajectories where within-module connectivity predominates, both in strength and number, in-utero. Fetal CHD connectivity strength, however, was weaker compared to controls suggesting that altered functional brain circuitry in CHD has its origins in-utero. Further studies are needed to assess the surveillance and prognostic potential of these findings.

Neural Dysconnectivity in the Hippocampus Correlates With White Matter Lesions and Cognitive Measures in Patients With Coronary Artery Disease.

PurposeRecent neuroimaging reports have shown the microstructural changes in coronary artery disease (CAD) and its correlation with cognitive dysfunction while little is known about the functional characteristics of CAD. We hypothesize that functional characteristics may give clues to underlying pathology in CAD and its link with cognitive dysfunction. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the neural connectivity changes in CAD patients compared with healthy controls and their correlation with cognitive measures.MethodsThirty CAD patients and 36 healthy controls were included in our study. All participants underwent functional magnetic resonance imaging (fMRI) of the brain. We performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity with other voxels. DC was measured by the fMRI graph method and comparisons between the two groups were done. All participants underwent neuropsychological assessment (Montreal Cognitive Assessment, MoCA and Mini-Mental State Examination, MMSE).ResultsOur data analysis included 30 CAD patients (59.90 ± 7.53 years) and 36 HCs (61.61 ± 6.19 years). CAD patients showed a greater prevalence of white matter lesions using the Fazekas score than healthy controls (P < 0.001). Importantly, CAD patients showed significantly lower (P < 0.001) MoCA and MMSE scores compared with healthy controls. CAD patients showed significantly decreased DC value (P < 0.001) in the right hippocampus (hippocampus_R), right lingual gyrus (lingual_R), and significantly increased DC value (P < 0.001) in the left middle frontal gyrus (Frontal_Mid_L) when compared with healthy controls respectively. DC value in the hippocampus_R significantly correlated (P < 0.00) with MMSE and MoCA scores in CAD patients. Fazekas scores in CAD patients showed a significant correlation (P < 0.001) with the DC value in the hippocampus_R.ConclusionThese findings suggest that reduced cerebral neural connectivity in CAD may contribute to their cognitive impairment and white matter microstructural damage.

Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0–10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

A novel approach to understanding Parkinsonian cognitive decline using minimum spanning trees, edge cutting, and magnetoencephalography

Graph theory-based approaches are efficient tools for detecting clustering and group-wise differences in high-dimensional data across a wide range of fields, such as gene expression analysis and neural connectivity. Here, we examine data from a cross-sectional, resting-state magnetoencephalography study of 89 Parkinson’s disease patients, and use minimum-spanning tree (MST) methods to relate severity of Parkinsonian cognitive impairment to neural connectivity changes. In particular, we implement the two-sample multivariate-runs test of Friedman and Rafsky (Ann Stat 7(4):697–717, 1979) and find it to be a powerful paradigm for distinguishing highly significant deviations from the null distribution in high-dimensional data. We also generalize this test for use with greater than two classes, and show its ability to localize significance to particular sub-classes. We observe multiple indications of altered connectivity in Parkinsonian dementia that may be of future use in diagnosis and prediction.

Genetic variation in endocannabinoid signaling is associated with differential network-level functional connectivity in youth.

The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04±0.62years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values=[<0.001, <0.001]) and lesser (95% CI for p values=[0.006, <0.001]) in A-allele carriers relative to non-carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A-allele carriers, such that non-carriers with connectivity more similar to A-allele carriers (i.e., greater connectivity) had lower anxiety symptoms (β=-0.041, p=0.030). These findings provide novel evidence of network-level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype-associated neural differences may emerge at a younger age than genotype-associated differences in anxiety.

Spatial cell type composition in normal and Alzheimers human brains is revealed using integrated mouse and human single cell RNA sequencing

Single-cell RNA sequencing (scRNA-seq) resolves heterogenous cell populations in tissues and helps to reveal single-cell level function and dynamics. In neuroscience, the rarity of brain tissue is the bottleneck for such study. Evidence shows that, mouse and human share similar cell type gene markers. We hypothesized that the scRNA-seq data of mouse brain tissue can be used to complete human data to infer cell type composition in human samples. Here, we supplement cell type information of human scRNA-seq data, with mouse. The resulted data were used to infer the spatial cellular composition of 3702 human brain samples from Allen Human Brain Atlas. We then mapped the cell types back to corresponding brain regions. Most cell types were localized to the correct regions. We also compare the mapping results to those derived from neuronal nuclei locations. They were consistent after accounting for changes in neural connectivity between regions. Furthermore, we applied this approach on Alzheimer’s brain data and successfully captured cell pattern changes in AD brains. We believe this integrative approach can solve the sample rarity issue in the neuroscience.

Neural Connectivity Changes Facilitated by Familiar Auditory Sensory Training in Disordered Consciousness: A TBI Pilot Study.

For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI.Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov).

Estimating the Heritability of Developmental Change in Neural Connectivity, and Its Association With Changing Symptoms of Attention-Deficit/Hyperactivity Disorder

BackgroundTwin studies show that age-related change in symptoms of attention-deficit/hyperactivity disorder (ADHD) is heritable. However, we do not know the heritability of the development of the neural substrates underlying the disorder. Here, we estimated the heritability of developmental change in white matter tracts and the brain’s intrinsic functional connectivity using longitudinal data. We further determined associations with change in ADHD symptoms. MethodsThe study reports on 288 children, which included 127 siblings, 19 cousins, and 142 singletons; 150 (52%) had a diagnosis of ADHD (determined by clinician interview with parent); 188 were male. All had two clinical assessments (overall baseline mean age: 9.4 ± 2.4 years; follow-up: 12.5 ± 2.6 years). Diffusion tensor imaging estimated microstructural properties of white matter tracts on 252 participants. Resting-state functional magnetic resonance imaging estimated intrinsic connectivity within and between major brain networks on 226 participants. Total additive genetic heritability (h2) of the annual rate of change in these neural phenotypes was calculated using SOLAR (Sequential Oligogenic Linkage Analysis Routines). ResultsSignificant heritability was found for the rates of change of 6 white matter tract microstructural properties and for change in the connectivity between the ventral attention network and both the cognitive control and dorsal attention networks. Change in hyperactivity-impulsivity was associated with heritable change in white matter tracts metrics and change in the connectivity between the ventral attention and cognitive networks. ConclusionsThe relatively small number of heritable, ADHD-associated developmental neural phenotypes can serve as phenotypes for future gene discovery and understanding.

Age-related decline in visual working memory: The effect of nontarget objects during a delayed estimation task.

Visual working memory (VWM) is an essential aspect of cognitive functioning that becomes compromised in older adults. A canonical probe of VWM is the change detection task in which participants compare a visually presented stimulus with items being maintained in VWM. Older adults show a decreased ability to detect changes between a stimulus and the contents of VWM compared with younger adults. Previously, we used a dynamic neural field (DNF) model to explore changes in neural connectivity that can explain this pattern of decline in performance. These simulations suggest that older adults have cortical interactions that are more diffuse compared to younger adults. In the current article, we examined the precision of representations in VWM using the delayed-estimation task. Participants are first presented with a memory array. After a delay, a location is cued, and participants click on a color wheel to indicate which color was at that location. The model predicted that older adults should show increased guessing rates and decreased precision (defined as the variability of color responses around the target location) relative to younger adults. The model also predicted that presenting the nontarget items during test should improve the precision of responses for older adults but not for younger adults. Results from two experiments supported these predictions of the model. These findings further advance an emerging theory of the neurocognitive decline of VWM and illustrate how older adults' VWM representations are influenced by the context in which information is being recalled. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Intervention-induced changes in neural connectivity during motor preparation may affect cortical activity at motor execution

Effective interventions have demonstrated the ability to improve motor function by reengaging ipsilesional resources, which appears to be critical and feasible for hand function recovery even in individuals with severe chronic stroke. However, previous studies focus on changes in brain activity related to motor execution. How changes in motor preparation may facilitate these changes at motor execution is still unclear. To address this question, 8 individuals with severe chronic hemiparetic stroke participated in a device-assisted intervention for seven weeks. We then quantified changes in both coupling between regions during motor preparation and changes in topographical cortical activity at motor execution for both hand opening in isolation and together with the shoulder using high-density EEG. We hypothesized that intervention-induced changes in cortico-cortico interactions during motor preparation would lead to changes in activity at motor execution specifically towards an increased reliance on the ipsilesional hemisphere. In agreement with this hypothesis, we found that, following the intervention, individuals displayed a reduction in coupling from ipsilesional M1 to contralesional M1 within gamma frequencies during motor preparation for hand opening. This was followed by a reduction in activity in the contralesional primary sensorimotor cortex during motor execution. Similarly, during lifting and opening, a shift to negative coupling within ipsilesional M1 from gamma to beta frequencies was accompanied by an increase in ipsilesional primary sensorimotor cortex activity following the intervention. Together, these results show that intervention-induced changes in coupling within or between motor regions during motor preparation may affect cortical activity at execution.

A proof-of-concept study comparing tinnitus and neural connectivity changes following multisensory perceptual training with and without a low-dose of fluoxetine

Background. This proof-of-concept study investigated a method of multisensory perceptual training for tinnitus, and whether a short, low-dose administration of fluoxetine enhanced training effects and changed neural connectivity. Methods. A double-blind, randomized placebo controlled design with 20 participants (17 male, 3 female, mean age = 57.1 years) involved 30 min daily computer-based, multisensory training (matching visual, auditory and tactile stimuli to perception of tinnitus) for 20 days, and random allocation to take 20 mg fluoxetine or placebo daily. Behavioral measures of tinnitus and correlations between pairs of a priori regions of interest (ROIs), obtained using resting-state functional magnetic resonance imaging (rs-fMRI), were performed before and after the training. Results. Significant changes in ratings of tinnitus loudness, annoyance, and problem were observed with training. No statistically significant changes in Tinnitus Functional Index, Tinnitus Handicap Inventory or Depression Anxiety Stress Scales were found with training. Fluoxetine did not alter any of the behavioural outcomes of training compared to placebo. Significant changes in connectivity between ROIs were identified with training; sensory and attention neural network ROI changes correlated with significant tinnitus rating changes. Rs-fMRI results suggested that the direction of functional connectivity changes between auditory and non-auditory networks, with training and fluoxetine, were opposite to the direction of those changes with multisensory training and placebo. Conclusions. Improvements in tinnitus measures were correlated with changes in sensory and attention networks. The results provide preliminary evidence for changes in rs-fMRI accompanying a multisensory training method in persons with tinnitus.

Quantifying Altered Neural Connectivity of the Stretch Reflex in Chronic Hemiparetic Stroke.

Post-stroke flexion synergy limits arm/hand function and is also linked to hyperactive stretch reflexes or spasticity. It is implicated in the increased role of indirect motor pathways following damage to direct corticospinal projections. We hypothesized that this maladaptive neuroplasticity also affects stretch reflexes. Specifically, multi-synaptic interactions in indirect motor pathways may increase nonlinear neural connectivity and time lag between stretch and reflex muscle response. Continuous position perturbations were applied to the elbow joint when eleven participants with stroke generated two levels of shoulder abduction (SABD) torques with their paretic arm to induce synergy-related spasticity. Likewise, the perturbations were applied to eleven control subjects while performing SABD and elbow flexion levels matching the synergy torques in stroke. We quantified linear and non-linear connectivity and the corresponding time lags between perturbations and muscle activity. Enhanced nonlinear connectivity with a prolonged time lag was found in stroke as compared to controls. Non-linear connectivity and time lag also increased with the expression of the flexion synergy, as induced by greater SABD load levels, in stroke. This study provides new evidence of changes in neural connectivity and long-latency time lag in the stretch reflex response post-stroke. The results suggest the contribution of indirect motor pathways to synergy-related spasticity.

Abstract 121: Visualization and Quantification of Post-Stroke Neural Connectivity in Mice Using Serial Two-Photon Tomography

Background: It is a challenge to characterize post-stroke changes in neural connectivity at microscopic scale across the entire rodent brain. Serial two-photon tomography (STPT) is an advanced laser-scanning microscopy technique which collects serial fluorescence images across the brain and reconstructs 3D datasets. We examined changes in motor connectivity after cortical infarcts in mice, using retrograde viral tract tracing, STPT imaging, automated registration workflow, and machine learning algorithms. Methods: Young male C57/B6 mice received a photothrombotic motor cortex (M1) stroke (n=3) or sham surgery (n=3). 15 days later, a retrograde pseudorabies trans-synaptic virus encoding fluorescent protein was injected into the left forelimb flexor muscles to label motor system projections. Mice were sacrificed 3 weeks post-stroke. STPT images were analyzed using supervised machine learning (pixel-wise random forest via the “ilastik” software package) and datasets were mapped to the Allen Mouse Brain Atlas for region-specific visualization and quantification of fluorescent signals. Results: Machine learning algorithms successfully identified neuronal cell bodies, neuronal processes, and ischemic tissue throughout the brain. The fluorescent signal of cells and neuronal processes was higher in the right M1 and SS of uninjured mice than the left M1 and SS. After stroke, this signal was diminished in the right M1 and SS. Labeled neurons were also reduced in the left M1 suggesting the presence of secondary transcortical connections. Conclusions: STPT generates whole brain datasets that when analyzed with ML algorithms show early alterations in post-stroke neural connectivity in the corticospinal tract. Further studies utilizing monosynaptic and conditional viral tracers will better assess the full spectrum of connectivity changes during post-stroke functional recovery.

Diffusion Tensor Imaging Connectomics Reveals Preoperative Neural Connectivity Changes in Children with Postsurgical Posterior Fossa Syndrome.

Posterior fossa syndrome (PFS), characterized by loss of language and other neurological impairments within the immediate postoperative period, occurs in approximately 25% of children who undergo surgical resection of posterior fossa tumors. Diffusion tensor imaging connectomics offer promise for elucidation of pathway-level disruption in neural connectivity of patients with this disorder. We aim to determine differences in pre- and postoperative connectomics between children with PFS and children with mild or no language deficit after surgery. Pre- and postoperative diffusion tensor imaging connectomics were applied and compared among patients with PFS, mild deficits, and intact language. A total of 35 patients were included in the study. Twenty-three patients with preoperative data and 24 patients with postoperative data were included in the analysis. Mean ages: PFS-8.5 years, mild-3.1 years, intact language-9.4 years (P = .02). Diagnoses included medulloblastoma (44.1%), pilocytic astrocytoma (28.6%), ependymoma (8.6%), other (11.4%), and unknown (8.6%). Five (21.7%) patients had PFS, 4 (17.4%) had mild deficits, and 14 (60.9%) had intact language. The assortativity coefficient was significantly higher in patients with PFS when compared to patients with mild deficits (P = .023). In the connectometry analyses, decreased connectivity was found involving the corpus callosum, right corticothalamic pathway, and right corticostriatal pathway in patients with PFS when compared to patients with intact language. Our findings revealed significant differences in preoperative neural connectivity involving the corticothalamic and other pathways among children who did, versus who did not, develop PFS postoperatively. Diffusion tensor imaging connectomics offers a unique opportunity to study the effect of the posterior fossa tumors on cerebello-cerebral networks and provide new insights into the mechanism of the structural plasticity/reorganization after surgery.