Enhanced Thalamic Functional Connectivity with No fMRI Responses to Affected Forelimb Stimulation in Stroke-Recovered Rats

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http://journal.frontiersin.org/article/10.3389/fncir.2016.00113/full?

Woo H. Shim^1,2,3,4†, Ji-Yeon Suh^1,4†, Jeong K. Kim¹, Jaeseung Jeong^3* and Young R. Kim^4*

• ¹Department of Radiology, ASAN Medical Center, University of Ulsan College of Medicine, Ulsan, South Korea
• ²ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Ulsan, South Korea
• ³Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
• ⁴Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA

Neurological recovery after stroke has been extensively investigated to provide better understanding of neurobiological mechanism, therapy, and patient management. Recent advances in neuroimaging techniques, particularly functional MRI (fMRI), have widely contributed to unravel the relationship between the altered neural function and stroke-affected brain areas. As results of previous investigations, the plastic reorganization and/or gradual restoration of the hemodynamic fMRI responses to neural stimuli have been suggested as relevant mechanisms underlying the stroke recovery process. However, divergent study results and modality-dependent outcomes have clouded the proper interpretation of variable fMRI signals. Here, we performed both evoked and resting state fMRI (rs-fMRI) to clarify the link between the fMRI phenotypes and post-stroke functional recovery. The experiments were designed to examine the altered neural activity within the contra-lesional hemisphere and other undamaged brain regions using rat models with large unilateral stroke, which despite the severe injury, exhibited nearly full recovery at ∼6 months after stroke. Surprisingly, both blood oxygenation level-dependent and blood volume-weighted (CBVw) fMRI activities elicited by electrical stimulation of the stroke-affected forelimb were completely absent, failing to reveal the neural origin of the behavioral recovery. In contrast, the functional connectivity maps showed highly robust rs-fMRI activity concentrated in the contra-lesional ventromedial nucleus of thalamus (VM). The negative finding in the stimuli-induced fMRI study using the popular rat middle cerebral artery model denotes weak association between the fMRI hemodynamic responses and neurological improvement. The results strongly caution the indiscreet interpretation of stroke-affected fMRI signals and demonstrate rs-fMRI as a complementary tool for efficiently characterizing stroke recovery.

Introduction

Ischemic stroke impairs neurovascular and metabolic functions in the brain and causes neurologic disabilities. Although severely damaged neurons fail to regenerate at the cortical level, interestingly, lost or compromised sensorimotor functions often recover at later stages of stroke. One of the restorative mechanisms underlying such recovery has been linked with the brain plasticity, the brain’s ability to reconstruct neural pathways and synapses in response to the loss of function (Kalénine et al., 2010; Heiss and Kidwell, 2014; Furlan et al., 2015). Despite the high interest and recent efforts, it is as yet unclear whether (or how) the stroke-affected brain areas functionally reposition in unaffected regions and/or reform connections with other brain areas to compensate for the impaired functions.

For identifying brain regions associated with restorative processes, task/stimulus-induced functional MRI (fMRI) has been frequently used to visualize brain activities associated with the neurologic recovery (for review see references Macey et al., 2015; Tang et al., 2015). More recently, resting state fMRI (rs-fMRI) has also provided a platform to explore spatiotemporal changes in neural connection across a wide range of brain regions. In general, by exploiting the temporal correlation of blood oxygenation level-dependent (BOLD) fMRI signals, the rs-fMRI has become an important method to assess the in vivo neuro-network (Carter et al., 2012; Grefkes and Fink, 2014; Thiel and Vahdat, 2015). Previous rs-fMRI investigations have reported that post-stroke loss and recovery of functions were associated with deterioration and subsequent retrieval of functional connectivity in the neural system, especially the interhemispheric connectivity changes (van Meer et al., 2010, 2012; Park et al., 2011). Based on these findings, alterations in the functional fields identified by either evoked fMRI or neural connectivity have been linked with the post-stroke functional recovery.

Past fMRI observations have suggested that remaining brain tissue, particularly the augmented neural activity in the contra-laterally homologous regions likely accounts for the restored sensorimotor function after stroke (Carey et al., 2002; Calautti and Baron, 2003). Typically, the assumption of intact neurovascular coupling underpins the interpretation of altered fMRI signals (Dijkhuizen et al., 2001; Kim et al., 2005). However, this link was challenged by us using multi-faceted fMRI measurements, in which the BOLD/CBV response ratio was significantly smaller in the stroke rats compared to the normal controls (Kim et al., 2005, 2006). Moreover, unclear relationship between fMRI and neurological recovery (i.e., complete absence of fMRI responses corresponding to the behavioral recovery) and questionable baseline physiology (e.g., choice of anesthesia) confounded the clear understanding of previous study results. (Weber et al., 2008; van Meer et al., 2010, 2012) The current study was designed to compare the functional fields and signal amplitudes acquired from both evoked fMRI and rs-fMRI in the stroke rat models exhibiting nearly full neurological recovery. Only using rats with large unilateral lesion encompassing most of the sensory and parts of the motor areas, the study focused on the role of sensorimotor activities in the contra-lesional hemisphere.

We hypothesized that in the chronic phase of stroke recovery, reinforced neural connections among the remaining intact brain regions are utilized more than the simple functional replacement and/or expansion of evoked activation toward the contra-lesional hemisphere. A well-established fMRI protocol with electrical stimulation of the rat forelimb was used to define the active sensorimotor brain regions (Dijkhuizen et al., 2003; Kim et al., 2005) while the BOLD rs-fMRI was used to investigate the functional connectivity networks. Noting that the proper brain function requires not only localized activation but also the integration of neural activities across multiple brain regions, the current study may elucidate the relationship between the different fMRI approaches to improve our understanding of the post-stroke recovery process and offer clues to the underlying neurobiological mechanisms.

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