Lead Research Scientist Charles Liao
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Investigation of Cortical Neurovascular Functions and Therapy for Hyperacute Ischemia

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.

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.

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.

Preventing Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of several commonly used chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and it is noteworthy that no effective treatment has been established so far. In this study, we assess the effect of hypothermia in preventing CIPN in healthy subjects and then, cancer subjects undergoing adjuvant paclitaxel chemotherapy. This study may contribute to alleviating dose-limitation due to CIPN and increase the likelihood of success of chemotherapy.

1. Imaging of temperature dependent hemodynamics in the rat sciatic nerve by functional photoacoustic microscopy. L. D. Liao, J. Orellana, Y. H. Liu, Y. R. Lin, A. Vipin, N. V. Thakor, K. Shen, and E. Wilder-Smith, Biomedical engineering online, vol. 12, pp. 120-32, Nov 2013.

The mechanisms of the peripheral nerve damage induced by paclitaxel are unclear, but are directly dose related. We have demonstrated the influence of hypothermia in reducing nerve blood flow in rats. This study underlies the hypothesis that limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves.
Additionally, future work will be directed towards gaining in-depth knowledge of the neuroprotective mechanisms promoted by hypothermia. We will develop an animal model of paclitaxel-induced peripheral neuropathy and probe the blood perfusion and nerve conduction changes with hypothermia, using the multimodal imaging system and mass spectrometric analysis. Since CIPN is a major dose-limiting side-effect of chemotherapy, this proposed technique will indeed improve the lifestyle of cancer patients.

2. Hypothermia for Preventing Chemotherapy-Induced Neuropathy - A Pilot Study on Safety and Tolerability in Healthy Controls. A.Bandla, R.Sundar, L. D. Liao, S.Tan, S.Lee, N. V. Thakor, and E. Wilder-Smith, Acta oncologica 2015 submitted

We hypothesize that limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects. Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use achieved tolerable temperature to investigate hypothermia in preventing CIPN in breast-cancer patients receiving adjuvant weekly paclitaxel. This pilot study may contribute to alleviating dose-limitation due to CIPN and increase the likelihood of success of chemotherapy.