Selected Topics Relating to Functional MRI Study of the Brain.

The authors selected some interesting current topics among many in the field of functional MRI (fMRI) of the brain. The selection was based on authours' immediate interests in exploring these aspects further; the topics are presented and discussed along with their perspectives. If progress can be made in these areas, it would be very advantageous to the field of brain research. The topics are (I) Detectable MRI signals in response to functional activity of the brain, including the current status of neurocurrent MRI; (II) Vascular-dependent and vascular-independent MRI signals, leading to the distinction of functional and structural MRI; (III) Functional specificity and functional connectivity of local sites, including differences between task-fMRI and resting state fMRI; (IV) Functional networks: an example of application to assessing the vocational aptitude test by fMRI; (V) Neural oscillation relevant to the formation of fMRI signals and of networks; (VI) Upgrading fMRI to "information-content-reflecting" fMRI, discussed as one of the prospects of near-future fMRI.

Exploring early human brain development with structural and physiological neuroimaging.

Early brain development, from the embryonic period to infancy, is characterized by rapid structural and functional changes. These changes can be studied using structural and physiological neuroimaging methods. In order to optimally acquire and accurately interpret this data, concepts from adult neuroimaging cannot be directly transferred. Instead, one must have a basic understanding of fetal and neonatal structural and physiological brain development, and the important modulators of this process. Here, we first review the major developmental milestones of transient cerebral structures and structural connectivity (axonal connectivity) followed by a summary of the contributions from ex vivo and in vivo MRI. Next, we discuss the basic biology of neuronal circuitry development (synaptic connectivity, i.e. ensemble of direct chemical and electrical connections between neurons), physiology of neurovascular coupling, baseline metabolic needs of the fetus and the infant, and functional connectivity (defined as statistical dependence of low-frequency spontaneous fluctuations seen with functional magnetic resonance imaging (fMRI)). The complementary roles of magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS) are discussed. We include a section on modulators of brain development where we focus on the placenta and emerging placental MRI approaches. In each section we discuss key technical limitations of the imaging modalities and some of the limitations arising due to the biology of the system. Although neuroimaging approaches have contributed significantly to our understanding of early brain development, there is much yet to be done and a dire need for technical innovations and scientific discoveries to realize the future potential of early fetal and infant interventions to avert long term disease.

Altered resting-state cerebral blood flow and functional connectivity of striatum in bipolar disorder and major depressive disorder.

BACKGROUND: Clinically distinguishing bipolar disorder (BD) from major depressive disorder (MDD) during depressive states is difficult. Neuroimaging findings suggested that patients with BD and those with MDD differed with respect to the gray matter volumes of their subcortical structures, especially in their striatum. However, whether these disorders have different effects on functionally striatal neuronal activity and connectivity is unclear. METHODS: Arterial spin labeling and resting-state functional MRI was performed on 25 currently depressive patients with BD, 25 depressive patients with MDD, and 34 healthy controls (HCs). The functional properties of striatal neuronal activity (cerebral blood flow, CBF) and its functional connectivity (FC) were analyzed, and the results from the three groups were compared. The result of the multiple comparisons was corrected on the basis of the Gaussian Random Field theory. RESULTS: The patients with BD and those with MDD both had higher CBF values than the HCs in the right caudate and right putamen. The hyper-metabolism of right striatum in BD patients was associated with increased average duration per depressive episode. The two disorders showed commonly increased FC between the striatum and dorsolateral prefrontal cortex, whereas the altered FC of the striatum with precuneus/cuneus was observed only in patients with BD. CONCLUSIONS: Patients with BD and those with MDD had a common deficit in their prefrontal-limbic-striatal circuits. The altered striato-precuneus FC can be considered as a marker for the differentiation of patients with BD from those with MDD.

Resting state fMRI reveals the altered synchronization of BOLD signals in essential tremor.

Essential tremor (ET) is one of the most common movement disorders in humans. Nevertheless, there remain several controversies surrounding ET, such as whether it is a disorder of abnormal neuronal oscillations within the tremor network. In this work, the resting-state fMRI data were collected from 17 ET patients and 17 age- and gender-matched healthy controls. First, using FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) the abnormal synchronization of fMRI signals in ET patients were investigated. Then, global functional connectivity intensity (gFCI) and density (gFCD) were analyzed in the regions exhibiting significant FOCA differences. Compared with healthy controls, patients with ET showed the increased FOCA values found in the bilateral cuneus, the left lingual gyrus, the left paracentral lobule, the right middle temporal gyrus, the bilateral precentral gyrus, the right postcentral gyrus, the pallidum and putamen. Decreased FOCA values in ET patients were located in the frontal gyrus, the bilateral anterior cingulate and the medial dorsal nucleus of right thalamus. In ET patients, significant changes in gFCI and gFCD were located in the cuneus, the middle temporal gyrus and the middle frontal gyrus. Changes in gFCI were also found in the medial frontal gyrus and thalamus in addition to changes in gFCD in the precentral gyrus. Our results provided further evidence that ET might present with abnormal spontaneous activity in the tremor network, including motor-related cotex, basal ganglia and thalamus, as well as distributed non-motor areas. This work also demonstrated that FOCA and functional connectivity have the potential to provide important insight into the pathophysiological mechanism of ET.

Abstinence to chronic methamphetamine switches connectivity between striatal, hippocampal and sensorimotor regions and increases cerebral blood volume response.

Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei - regions known to be important in mediating reinstatement of drug-taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal - striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels.

Recruitment of prefrontal-striatal circuit in response to skilled motor challenge.

A variety of physical fitness regimens have been shown to improve cognition, including executive function, yet our understanding of which parameters of motor training are important in optimizing outcomes remains limited. We used functional brain mapping to compare the ability of two motor challenges to acutely recruit the prefrontal-striatal circuit. The two motor tasks - walking in a complex running wheel with irregularly spaced rungs or walking in a running wheel with a smooth internal surface - differed only in the extent of skill required for their execution. Cerebral perfusion was mapped in rats by intravenous injection of [C]-iodoantipyrine during walking in either a motorized complex wheel or in a simple wheel. Regional cerebral blood flow (rCBF) was quantified by whole-brain autoradiography and analyzed in three-dimensional reconstructed brains by statistical parametric mapping and seed-based functional connectivity. Skilled or simple walking compared with rest, increased rCBF in regions of the motor circuit, somatosensory and visual cortex, as well as the hippocampus. Significantly greater rCBF increases were noted during skilled walking than for simple walking. Skilled walking, unlike simple walking or the resting condition, was associated with a significant positive functional connectivity in the prefrontal-striatal circuit (prelimbic cortex-dorsomedial striatum) and greater negative functional connectivity in the prefrontal-hippocampal circuit. Our findings suggest that the level of skill of a motor training task determines the extent of functional recruitment of the prefrontal-corticostriatal circuit, with implications for a new approach in neurorehabilitation that uses circuit-specific neuroplasticity to improve motor and cognitive functions.

Challenges in measuring individual differences in functional connectivity using fMRI: The case of healthy aging.

Many studies report individual differences in functional connectivity, such as those related to age. However, estimates of connectivity from fMRI are confounded by other factors, such as vascular health, head motion and changes in the location of functional regions. Here, we investigate the impact of these confounds, and pre-processing strategies that can mitigate them, using data from the Cambridge Centre for Ageing & Neuroscience (www.cam-can.com). This dataset contained two sessions of resting-state fMRI from 214 adults aged 18-88. Functional connectivity between all regions was strongly related to vascular health, most likely reflecting respiratory and cardiac signals. These variations in mean connectivity limit the validity of between-participant comparisons of connectivity estimates, and were best mitigated by regression of mean connectivity over participants. We also showed that high-pass filtering, instead of band-pass filtering, produced stronger and more reliable age-effects. Head motion was correlated with gray-matter volume in selected brain regions, and with various cognitive measures, suggesting that it has a biological (trait) component, and warning against regressing out motion over participants. Finally, we showed that the location of functional regions was more variable in older adults, which was alleviated by smoothing the data, or using a multivariate measure of connectivity. These results demonstrate that analysis choices have a dramatic impact on connectivity differences between individuals, ultimately affecting the associations found between connectivity and cognition. It is important that fMRI connectivity studies address these issues, and we suggest a number of ways to optimize analysis choices. Hum Brain Mapp 38:4125-4156, 2017. © 2017 Wiley Periodicals, Inc.

Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.

Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-ß (Aß) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aß) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aß based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional strategies.

Effects of Long-Duration Administration of 1% Isoflurane on Resting Cerebral Blood Flow and Default Mode Network in Macaque Monkeys.

Isoflurane is an inhalational anesthetic that is widely used in medical procedures or biomedical research. The duration of anesthesia administration varies from minutes to hours. It is known that isoflurane has dose-dependent effects on brain functionality and physiology, and long-duration anesthesia administration could cause neurocognitive decline in animals and humans. However, the duration effect of isoflurane on the brain physiology and functionality still remains poorly understood. In the present study, cerebral blood flow (CBF) and functional connectivity of adult rhesus monkeys (maintained with 1% isoflurane for 4 h) were examined by using magnetic resonance imaging. The results demonstrate that long-duration isoflurane exposure could result in CBF reduction in most brain areas and functional connectivity decrease in the dominant default-mode network. This study reveals the anesthetic duration effects in the central nervous system of anesthetized subjects and suggests that such duration effects should be considered in examining the brain function of anesthetized animals or humans with contemporary neuroimaging approaches.

Longitudinal Evidence for Dissociation of Anterior and Posterior MTL Resting-State Connectivity in Aging: Links to Perfusion and Memory.

Neuroimaging studies of spontaneous signal fluctuations as measured by resting-state functional magnetic resonance imaging have revealed age-related alterations in the functional architecture of brain networks. One such network is located in the medial temporal lobe (MTL), showing structural and functional variations along the anterior-posterior axis. Past cross-sectional studies of MTL functional connectivity (FC) have yielded discrepant findings, likely reflecting the fact that specific MTL subregions are differentially affected in aging. Here, using longitudinal resting-state data from 198 participants, we investigated 5-year changes in FC of the anterior and posterior MTL. We found an opposite pattern, such that the degree of FC within the anterior MTL declined after age 60, whereas elevated FC within the posterior MTL was observed along with attenuated posterior MTL-cortical connectivity. A significant negative change-change relation was observed between episodic-memory decline and elevated FC in the posterior MTL. Additional analyses revealed age-related cerebral blood flow (CBF) increases in posterior MTL at the follow-up session, along with a positive relation of elevated FC and CBF, suggesting that elevated FC is a metabolically demanding alteration. Collectively, our findings indicate that elevated FC in posterior MTL along with increased local perfusion is a sign of brain aging that underlie episodic-memory decline.

A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice.

APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.

Connectivity Profiles Reveal a Transition Subarea in the Parahippocampal Region That Integrates the Anterior Temporal-Posterior Medial Systems.

Traditional anatomical studies of the parahippocampal region (PHR) defined the lateral portion into two subregions, the perirhinal (PRC) and parahippocampal (PHC) cortices. Based on this organization, several models suggested that the PRC and the PHC play different roles in memory through connections with different memory-related brain networks. To identify the key components of the human PHR, we used a well accepted connection-based parcellation method on two independent datasets. Our parcellation divided the PRC and PHC into three subregions, specifically, the rostral PRC, caudal PRC (PRCc), and PHC. The connectivity profile for each subregion showed that the rostral PRC was connected to the anterior temporal (AT) system and the PHC was connected to the posterior medial (PM) system. The transition area (PRCc) integrated the AT-PM systems. These results suggest that the lateral PHR not only contains functionally segregated subregions, but also contains a functionally integrated subregion. SIGNIFICANCE STATEMENT: We redefined the cartography of the human parahippocampal region (PHR) and identified a transition subarea based on distinct anatomical and functional connectivity profiles. This well defined anatomical organization of the PHR is necessary for expanding our understanding and studying the functional relevance of its subregions in recognition memory. We found that the transition subregion [caudal perirhinal cortex (PRCc)] is a functionally integrated subregion that integrates the anterior temporal (AT)-posterior medial (PM) systems. In addition, we found that the core components of the AT and PM systems connect with the PHR in the rostral PRC and parahippocampal cortex (PHC), respectively, rather than connecting with the traditional, larger, and thus less concise PRC and PHC areas. This may lead to new insights into the human memory system and related neurodegenerative diseases.

Two Anatomically and Computationally Distinct Learning Signals Predict Changes to Stimulus-Outcome Associations in Hippocampus.

Complex cognitive processes require sophisticated local processing but also interactions between distant brain regions. It is therefore critical to be able to study distant interactions between local computations and the neural representations they act on. Here we report two anatomically and computationally distinct learning signals in lateral orbitofrontal cortex (lOFC) and the dopaminergic ventral midbrain (VM) that predict trial-by-trial changes to a basic internal model in hippocampus. To measure local computations during learning and their interaction with neural representations, we coupled computational fMRI with trial-by-trial fMRI suppression. We find that suppression in a medial temporal lobe network changes trial-by-trial in proportion to stimulus-outcome associations. During interleaved choice trials, we identify learning signals that relate to outcome type in lOFC and to reward value in VM. These intervening choice feedback signals predicted the subsequent change to hippocampal suppression, suggesting a convergence of signals that update the flexible representation of stimulus-outcome associations.

Extrinsic and Intrinsic Brain Network Connectivity Maintains Cognition across the Lifespan Despite Accelerated Decay of Regional Brain Activation.

The maintenance of wellbeing across the lifespan depends on the preservation of cognitive function. We propose that successful cognitive aging is determined by interactions both within and between large-scale functional brain networks. Such connectivity can be estimated from task-free functional magnetic resonance imaging (fMRI), also known as resting-state fMRI (rs-fMRI). However, common correlational methods are confounded by age-related changes in the neurovascular signaling. To estimate network interactions at the neuronal rather than vascular level, we used generative models that specified both the neural interactions and a flexible neurovascular forward model. The networks' parameters were optimized to explain the spectral dynamics of rs-fMRI data in 602 healthy human adults from population-based cohorts who were approximately uniformly distributed between 18 and 88 years (www.cam-can.com). We assessed directed connectivity within and between three key large-scale networks: the salience network, dorsal attention network, and default mode network. We found that age influences connectivity both within and between these networks, over and above the effects on neurovascular coupling. Canonical correlation analysis revealed that the relationship between network connectivity and cognitive function was age-dependent: cognitive performance relied on neural dynamics more strongly in older adults. These effects were driven partly by reduced stability of neural activity within all networks, as expressed by an accelerated decay of neural information. Our findings suggest that the balance of excitatory connectivity between networks, and the stability of intrinsic neural representations within networks, changes with age. The cognitive function of older adults becomes increasingly dependent on these factors. SIGNIFICANCE STATEMENT: Maintaining cognitive function is critical to successful aging. To study the neural basis of cognitive function across the lifespan, we studied a large population-based cohort (n = 602, 18-88 years), separating neural connectivity from vascular components of fMRI signals. Cognitive ability was influenced by the strength of connection within and between functional brain networks, and this positive relationship increased with age. In older adults, there was more rapid decay of intrinsic neuronal activity in multiple regions of the brain networks, which related to cognitive performance. Our data demonstrate increased reliance on network flexibility to maintain cognitive function, in the presence of more rapid decay of neural activity. These insights will facilitate the development of new strategies to maintain cognitive ability.

Diagnosis of Autism Spectrum Disorders Using Temporally Distinct Resting-State Functional Connectivity Networks.

INTRODUCTION: Resting-state functional magnetic resonance imaging (R-fMRI) is dynamic in nature as neural activities constantly change over the time and are dominated by repeating brief activations and deactivations involving many brain regions. Each region participates in multiple brain functions and is part of various functionally distinct but spatially overlapping networks. Functional connectivity computed as correlations over the entire time series always overlooks interregion interactions that often occur repeatedly and dynamically in time, limiting its application to disease diagnosis. AIMS: We develop a novel framework that uses short-time activation patterns of brain connectivity to better detect subtle disease-induced disruptions of brain connectivity. A clustering algorithm is first used to temporally decompose R-fMRI time series into distinct clusters with similar spatial distribution of neural activity based on the assumption that functionally distinct networks should be largely temporally distinct as brain states do not simultaneously coexist in general. A Pearson correlation-based functional connectivity network is then constructed for each cluster to allow for better exploration of spatiotemporal dynamics of individual neural activity. To reduce significant intersubject variability and to remove possible spurious connections, we use a group-constrained sparse regression model to construct a backbone sparse network for each cluster and use it to weight the corresponding Pearson correlation network. RESULTS: The proposed method outperforms the conventional static, temporally dependent fully connected correlation-based networks by at least 7% on a publicly available autism dataset. We were able to reproduce similar results using data from other centers. CONCLUSIONS: By combining the advantages of temporal independence and group-constrained sparse regression, our method improves autism diagnosis.

Effects of Early and Late Bilingualism on Resting-State Functional Connectivity.

Of current interest is how variations in early language experience shape patterns of functional connectivity in the human brain. In the present study, we compared simultaneous (two languages from birth) and sequential (second language learned after age 5 years) bilinguals using a seed-based resting-state MRI approach. We focused on the inferior frontal gyrus (IFG) as our ROI, as recent studies have demonstrated both neurofunctional and neurostructural changes related to age of second language acquisition in bilinguals in this cortical area. Stronger functional connectivity was observed for simultaneous bilinguals between the left and right IFG, as well as between the inferior frontal gyrus and brain areas involved in language control, including the dorsolateral prefrontal cortex, inferior parietal lobule, and cerebellum. Functional connectivity between the left IFG and the right IFG and right inferior parietal lobule was also significantly correlated with age of acquisition for sequential bilinguals; the earlier the second language was acquired, the stronger was the functional connectivity. In addition, greater functional connectivity between homologous regions of the inferior frontal gyrus was associated with reduced neural activation in the left IFG during speech production. The increased connectivity at rest and reduced neural activation during task performance suggests enhanced neural efficiency in this important brain area involved in both speech production and domain-general cognitive processing. Together, our findings highlight how the brain's intrinsic functional patterns are influenced by the developmental timeline in which second language acquisition occurs. SIGNIFICANCE STATEMENT: Of current interest is how early life experience leaves its footprint on brain structure and function. In this regard, bilingualism provides an optimal way to determine the effects of the timing of language learning because a second language can be learned from birth or later in life. We used resting-state fMRI to look at simultaneous and sequential bilinguals who differed only in age of acquisition, and found stronger connectivity between language and cognitive control regions in bilinguals who learned their two languages simultaneously, a pattern that was associated with more efficient brain activation during speech. Our findings highlight how functional connections in the brain differ depending upon when learning takes place.

Disconnection and hyper-connectivity underlie reorganization after TBI: A rodent functional connectomic analysis.

While past neuroimaging methods have contributed greatly to our understanding of brain function after traumatic brain injury (TBI), resting state functional MRI (rsfMRI) connectivity methods have more recently provided a far more unbiased approach with which to monitor brain circuitry compared to task-based approaches. However, current knowledge on the physiologic underpinnings of the correlated blood oxygen level dependent signal, and how changes in functional connectivity relate to reorganizational processes that occur following injury is limited. The degree and extent of this relationship remain to be determined in order that rsfMRI methods can be fully adapted for determining the optimal timing and type of rehabilitative interventions that can be used post-TBI to achieve the best outcome. Very few rsfMRI studies exist after experimental TBI and therefore we chose to acquire rsfMRI data before and at 7, 14 and 28 days after experimental TBI using a well-known, clinically-relevant, unilateral controlled cortical impact injury (CCI) adult rat model of TBI. This model was chosen since it has widespread axonal injury, a well-defined time-course of reorganization including spine, dendrite, axonal and cortical map changes, as well as spontaneous recovery of sensorimotor function by 28 d post-injury from which to interpret alterations in functional connectivity. Data were co-registered to a parcellated rat template to generate adjacency matrices for network analysis by graph theory. Making no assumptions about direction of change, we used two-tailed statistical analysis over multiple brain regions in a data-driven approach to access global and regional changes in network topology in order to assess brain connectivity in an unbiased way. Our main hypothesis was that deficits in functional connectivity would become apparent in regions known to be structurally altered or deficient in axonal connectivity in this model. The data show the loss of functional connectivity predicted by the structural deficits, not only within the primary sensorimotor injury site and pericontused regions, but the normally connected homotopic cortex, as well as subcortical regions, all of which persisted chronically. Especially novel in this study is the unanticipated finding of widespread increases in connection strength that dwarf both the degree and extent of the functional disconnections, and which persist chronically in some sensorimotor and subcortically connected regions. Exploratory global network analysis showed changes in network parameters indicative of possible acutely increased random connectivity and temporary reductions in modularity that were matched by local increases in connectedness and increased efficiency among more weakly connected regions. The global network parameters: shortest path-length, clustering coefficient and modularity that were most affected by trauma also scaled with the severity of injury, so that the corresponding regional measures were correlated to the injury severity most notably at 7 and 14 days and especially within, but not limited to, the contralateral cortex. These changes in functional network parameters are discussed in relation to the known time-course of physiologic and anatomic data that underlie structural and functional reorganization in this experiment model of TBI.

Distinctive Resting State Network Disruptions Among Alzheimer's Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients.

BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.

Dual-task-related neural connectivity changes in patients with Parkinson' disease.

BACKGROUND AND OBJECTIVES: Dual-task (DT) gait impairment in people with Parkinson's disease (PD) and specifically in those with freezing of gait (FOG), reflects attentional dependency of movement. This study aimed to elucidate resting-state brain connectivity alterations related to DT gait abnormalities in PD with and without FOG. METHODS: PD patients (n=73) and healthy age-matched controls (n=20) underwent DT gait analysis and resting-state functional Magnetic Resonance Imaging (rs-MRI) while 'off' medication. Patients were classified as freezer (n=13) or non-freezer (n=60). Functional connectivity (FC) alterations between PD and controls and between patient subgroups were assessed in regions of interest (ROIs) within the fronto-parietal and motor network. RESULTS: PD had longer stance times, shorter swing times and more step length asymmetry during DT gait and needed more time and steps during DT turning compared to controls. Additionally, freezers showed similar impairments and longer double support times compared to non-freezers during DT gait. PD demonstrated hyper-connectivity between the inferior parietal lobule and premotor cortex (PMC) and between the cerebellum and the PMC and M1. FOG-specific hypo-connectivity within the striatum and between the caudate and superior temporal lobe and hyper-connectivity between the dorsal putamen and precuneus was correlated with worse DT performance. CONCLUSION: PD showed FC alterations in DT-related networks, which were not correlated to DT performance. However, FOG-specific FC alterations in DT-related regions involving the precuneus and striatum were correlated to worse DT performance, suggesting that the balance between cognitive and motor networks is altered.