Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Mishra, Asht M.; Xiang, Biao; Sanganahalli, Basavaraju G.; Waxman, Stephen G.; Shatillo, Olena; Gröhn, Olli; Hyder, Fahmeed; Pitkänen, Asla; Blumenfeld, Hal

doi:10.1371/journal.pone.0095280

Cited by 55 publications

(39 citation statements)

References 38 publications

(50 reference statements)

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“…Functional connectivity measures provide insights into information processing including memory [49]. Our results show that TBI reduced intra- and cortical-hippocampal functional connectivity in regions implicated in memory processing, in agreement with previous studies [50,51]). Interestingly, 7,8-DHF, exercise and their combination were able to normalize functional connectivity, in agreement with previous findings that physical activity supports functional network reorganization [52] and BDNF has been implicated in regulation of connectivity of brain networks [53].…”

Section: Discussionsupporting

confidence: 91%

7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery

Krishna

Agrawal

Zhuang³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Metabolic dysfunction accompanying traumatic brain injury (TBI) severely impairs the ability of injured neurons to comply with functional demands. This limits the success of rehabilitative strategies by compromising brain plasticity and function, and highlights the need for early interventions to promote energy homeostasis. We sought to examine whether the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) normalizes brain energy deficits and restablishes more normal patterns of functional connectivity, while enhancing the effects of exercise during post-TBI period. Moderate fluid percussion injury (FPI) was performed and 7,8-DHF (5 mg/kg, i.p.) was administered in animals subjected to FPI that either had access to voluntary wheel running for 7 days after injury or were sedentary. Compared to sham-injured controls, TBI resulted in reduced hippocampal activation of the BDNF receptor TrkB and associated CREB, reduced levels of plasticity markers GAP-43 and Syn I, as well as impaired memory as indicated by the Barnes maze task. While 7,8-DHF treatment and exercise individually mitigated TBI-induced effects, administration of 7,8-DHF concurrently with exercise facilitated memory performance and augmented levels of markers of cell energy metabolism viz., PGC-1α, COII and AMPK. In parallel to these findings, resting-state functional MRI (fMRI) acquired at 2 weeks after injury showed that 7,8-DHF with exercise enhanced hippocampal functional connectivity, and suggests 7,8-DHF and exercise to promote increases in functional connectivity. Together, these findings indicate that post-injury 7,8-DHF treatment promotes enhanced levels of cell metabolism, synaptic plasticity in combination with exercise increases in brain circuit function that facilitates greater physical rehabilitation after TBI.

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Section: Discussionsupporting

confidence: 91%

7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery

Krishna

Agrawal

Zhuang³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Altered functional connectivity has also been shown after TBI, clinically (Nakamura et al, 2009; Kasahara et al, 2010, 2011; Mayer et al, 2011; Stevens et al, 2012; Pandit et al, 2013; Zhou et al, 2013; Han et al, 2014; Hillary et al, 2014) but with few studies in experimental models (Holschneider et al, 2013; Mishra et al, 2014) and no rsfMRI studies in the well-known controlled cortical impact (CCI) injury model of TBI where we have shown some degree of structural reorganization (Harris et al, 2009a) as well as functional reorganization (Harris et al, 2013a,b) that generally coincides with spontaneous recovery in this model.…”

Section: Introductionmentioning

confidence: 99%

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

Harris

Verley

Gutman

et al. 2016

Experimental Neurology

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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 esp...

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“…[16][17][18] These structural findings have also been confirmed by functional magnetic resonance imaging (MRI) and resting state MRI and magnetoencephalography (MEG) that implicates DAI with subsequent circuit disruption and disorders of brain connectivity following mTBI. [19][20][21][22] In addition to these structural changes in axonal connectivity, axonal stretch and ionic imbalances after injury likely induce additional changes not immediately obvious in structural studies. 15 In fact, recent studies have begun to posit that mTBIs can involve primary electrophysiological change related to an …”

Section: Introductionmentioning

confidence: 99%

Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury

Hånell

Greer

Jacobs

2015

Journal of Neurotrauma

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Mild traumatic brain injury (mTBI) can produce long lasting cognitive dysfunction. There is typically no cell death and only diffuse structural injury after mTBI. Thus, functional changes in intact neurons may contribute to symptoms. We have previously shown altered intrinsic properties of axotomized and intact neurons within 2 d after a central fluid percussion injury in mice expressing yellow fluorescent protein (YFP) that allow identification of axonal state prior to recording. Here, whole-cell patch clamp recordings were used to examine synaptic properties of YFP(+) layer V pyramidal neurons. An increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was recorded from axotomized neurons at 1 d and intact neurons at 2 d after injury, likely reflecting an increased number of afferents. This also was reflected in the increased amplitude of the EPSC evoked by local extracellular stimulation for all neurons from injured cortex and increased likelihood of producing an action potential for intact cells. Field potentials recorded in superficial layers after online deep layer stimulation contained a single negative peak in controls but multiple negative peaks in injured tissue. The amplitude of this evoked negativity was significantly larger than controls over a series of stimulus intensities at both the 1 d and 2 d survival times. Interictal-like spikes never occurred in the field potential recordings from controls but were observed in 20-80% of stimulus presentations in injured cortex. Together, these results suggest an overall increase in network excitability and the production of particularly powerful (intact) neurons that have both increased intrinsic and synaptic excitability.

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Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Cited by 55 publications

References 38 publications

7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery

7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery

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

Increased Network Excitability Due to Altered Synaptic Inputs to Neocortical Layer V Intact and Axotomized Pyramidal Neurons after Mild Traumatic Brain Injury

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