Investigation of Cortical Neurovascular Functions and Therapy for Hyperacute Ischemia

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Our lab focuses on investigating the cerebral neurovascular function changes affected by hyperacute ischemic stroke, as well as the progressive changes of the affected cortical regions (i.e., ischemic core and penumbra). Using the developed novel combination of electrocorticography (ECoG) recordings and functional photoacoustic microscopy (fPAM) imaging (i.e., ECoG-fPAM) we investigate cortical functions after photothrombotic ischemia (PTI) in a rat ischemia model. The cortical functions are assessed over a chosen ischemic region via somatosensory-evoked potential (SSEP), resting-state ECoG signals (i.e., alpha-to-delta (ADR) ratio) and evoked hemodynamic responses (i.e., cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2)). Histological assessment method (2, 3, 5-triphenyl-tetrazolium chloride (TTC) staining) is also used to assess the infarct volume induced by ischemia. In addition, the neuroprotective effect of sensory stimulation as a non-invasive therapeutic intervention for hyperacute ischemia is evaluated in the affected animals.

1. Rescue of cortical neurovascular functions during the hyperacute phase of ischemia by peripheral sensory stimulation. L. Liao, Y. H. Liu, H. Y. Lai, A. Bandla, Y. Y. Shih, Y. Y. Chen, and N. V. Thakor, Neurobiology of disease, vol. 75C, pp. 53-63, Jan 5 2015.

We established a hybrid, dual-modality system, including six-channel ECoG-fPAM system, to image brain functional responses to peripheral sensory stimulation during the hyperacute phase of PTI. The potential therapeutic effects of peripheral sensory stimulation during the hyperacute phase of stroke were investigated in the present study utilizing a rat model of photothrombotic ischemia (PTI). The results indicated that 80 ± 4.2% of neurovascular function was preserved when stimulation was delivered within 2.5 h.

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2. Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model. L.-D. Liao, A. Bandla, J. M. Ling, Y.-H. Liu, and N. Thakor, Neurophotonics, vol. 1, Jun 2014.

We assessed the outcomes of bilateral peripheral sensory stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally using the developed ECoG-fPAM system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to hyperacute, focal stroke. Our results confirmed the neuroprotective effect of bilateral peripheral sensory stimulation in improving cerebral perfusion and restoring cortical neurovascular response into the region of penumbra.

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3. Investigation of therapeutic time window of rtPA thrombolysis in a rat PTI model

Improving outcomes in thrombolytic therapy is reliant on the understanding of the dynamic neurovascular functions during hyperacute ischemia, however, it is still not well-understood. Here, we investigate the neurovascular functions during hyperacute, focal ischemia in a small-animal photothrombotic ischemia (PTI) model following recombinant tissue plasminogen activator (rtPA) thrombolysis. We employ a custom-designed electrocorticogram (ECoG) - functional photoacoustic microscopy (fPAM) imaging system (i.e., ECoG-fPAM) for probing the hyperacute ischemic neurovascular functions. Our study demonstrated for the first time the simultaneous changes in neural activity (somatosensory-evoked potential (SSEP) and resting state (RS) ECoG calculated as inter-hemispheric coherence, alpha-delta ratio (ADR) and pairwise derived brain symmetry index (pdBSI)) and the cerebral hemodynamics (cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2)) at different rtPA infusion onset times. Interestingly, very early (< 1 h) and late (> 4 h) administration of rtPA post-PTI, resulted in deteriorated neurovascular functions owing to reactive hyperemic injury and reperfusion injury, respectively. Further, the presence of a therapeutic time window, in the initial 1 to 3 hours post-PTI, is affirmed by the significant recovery of neurovascular functions. This experimental model and corresponding data will serve as a benchmark to explore neurovascular mechanisms and to study potential interventions for bettering rtPA treatment outcomes.

4. Transcranial direct current stimulation (tDCS) in combination with peripheral sensory stimulation for ischemia therapy
We hypothesize that cathodal-transcranial direct current stimulation with peripheral sensory stimulation can help recovery during the hyperacute phase of ischemia. Using our ECoG-fPAM system, changes of neural activities (e.g., evoked potential and alpha-to-delta ratio) and vascular responses (e.g., cerebral blood volume and hemoglobin oxygen saturation) can be acquired for evaluating the effects of the proposed treatment. This study opens a new window for the treatment of hyperacute phase stroke, which is highly likely to be translated to clinical application in the near future.

5. Stem cell-based therapies for ischemic stroke

Imaging techniques have driven much advancement in medical sciences by facilitating the understanding of relationship between structure and function through the visualization of fundamental biological processes. Although computed tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques have been used to monitor the homing of MSCs to lesions and study the cell dynamics, advances have been limited by poor spatial resolution, long scanning time or unfavourable risk-benefit or cost-benefit ratios. Consequently, with the limited sensitivity and specificity inherent to current methods, multi-modal imaging offers the opportunity to simultaneously capture visual information over many spatial scales at high resolution and signal-to-noise ratio (SNR) to render fast and efficient acquisition of anatomical and molecular information to give the spatial localization and functional characteristics of diseases. In this study, we pioneer two optical imaging modalities of fluorescence and photoacoustic (PA) imaging into one versatile minimally-invasive molecular imaging platform utilizing a single particle as imaging probes. This innovation allows us to simultaneously investigate stem cell homing and corresponding hemodynamic changes in ischemic area in an in vivo stroke model for the first time. In addition, this platform will transform the way we evaluate the effectiveness of stem cell therapy, by using the results of the spatial-temporal evolution of 3D penumbra and its real time homing map.

Principal Investigator

LunDeLiao

Dr. Charles Lun-De Liao

Visiting Senior Research Scientist

lsill@nus.edu.sg