Contact

Patricia Pais

Address: Spemannstr. 41
72076 Tuebingen
Room number: 4.B.10
Phone: +49 7071 601 917
Fax: +49 7071 601 701
E-Mail: Patricia.Pais

 

Picture of Pais, Patricia

Patricia Pais

Position: PhD Student  Unit: Yu Scheffler

My current research focus is the multimodal characterization of coma in rats. I use electrophysiology, functional MRI, optogenetics and calcium imaging, together with behavioral assessment, to investigate the mechanisms of coma induction and recovery.

 

Development and characterization of the coma state in the rat brain.

 

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Zebrafish as a target for high Magnetic Fields.

 

Figure 1. Zebrafish larvae at 2 days post fertilization.

2015-2018: Study of the rat brain during the coma state.

Coma is an unconscious state characterized by behavioral unresponsiveness, lack of sleep-wake cycles and extremely low level of neuronal activity. The pathophysiology of coma and the mechanisms of recovery of consciousness remain only partially understood. A reliable coma model in small animals is an essential tool to study the brain function during induction and recovery of the comatose state, as well as for the search of potential targets for treatment.

 

Brainstem coma model in rats

We have recently developed a rat coma model based on focal damage to the brainstem/midbrain arousal nuclei by means of brainstem ischemia. The model allows tracking the neurological recovery of animals during the acute phase of coma progression, a period that is usually not accessible for sistematic study of the brain function in humans, and provides a platform to test treatment strategies aiming at promoting consciousness.

Our first results showed that this brainstem coma is associated with an initial respiratory depression lasting approximately one hour, a time during which only limb reflexes are observed, at most, followed by gradual recovery of neurological function. The neurological score (assessed with a newly developed Rat Coma Scale) correlates with the electrophysiological signals from cortex, which becomes isoelectric after coma induction and evolves into burst-suppression patterns with later emergence of slow waves. Resting state fMRI indicates a gradual increase of connectivity from the basal forebrain, basal ganglia and thalamus, as coma progresses, which may be associated with a certain participation of this network in the regaining of brain function.

We are currently investigating the mechanisms underlying coma induction and recovery with parallel cortical calcium/glutamate imaging and optogenetic stimulation of deep brain nuclei during fMRI studies in the comatose rat.

TRAINING IN SCIENCE

From July 2014: PhD student at Max Planck for Biological Cybernetics - Graduate School of Neuroscience Tuebingen.

2013-2014: M.Sc in BIOMEDICAL ENGINEERING (60 ECTS) at Madrid Technical University (Spain). Master Final Project: In vitro neuronal network growing under the influence of a pulsed magnetic field.

2009-2013: B.Sc in MEDICAL BIOLOGY (240 ECTS) at Alcalá University (Spain).

2012-2013: Training on Neuroscience (30 ECTS) at the Graduate School of Neuroscience, Tübingen University.

 

CERTIFICATES

October 2014: FELASA B for animal testing.

 

SCIENTIFIC EXPERIENCE

From July 2014: Max Planck Institute for Biological Cybernetics, Tübingen (Germany), for the development of my PhD Thesis in Neuroscience. Working with high magnetic field MRI in the rat brain combining optogenetics and other techniques. Working in developmental biology of Zebrafish under high magnetic fields.

November-July2014: Centre for Biomedical Technologies, Madrid (Spain). Dissection of the locust brain, neurons culture and magnetic fields-dependent neurite outgrowth evaluation.

August 2013: Orthopaedic Institute and Tissue Bank, Santiago de Compostela (Spain). Osteoblasts culture and treatment of sponge bone from multi organ donors.

February-July 2013: Analytical Chemistry department of Alcalá University. Six months working for developing a new diagnostic technique for Galactosemia in urine samples, using a microfluidic chip.

June-July2012: Immunology department of Alcalá University. Two months working on the analysis of white blood cells and autophagy experiments using flow cytometry.

 

SCIENTIFIC AWARDS

Spanish Society for Neuroscience - SENC 2017, Alicante (Spain).

Poster presentation award (title: "Experimental model for coma research").

European Society for Molecular Imaging - ESMI 2015, Tuebingen (Germany).

Poster presentation award (title: "High magnetic field induced otolith fusion in Zebrafish larvae").

Yu X , Chen X , Pais P and Jiang Y (March-23-2018) Abstract Talk: Extracellular glutamate and intracellular calcium recording with fiber optic and simultaneous fMRI, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Introduction Here, we expressed genetically encoded fluorescent reporter iGluSnFR1 for extracellular glutamate (Glu) sensing and genetically encoded calcium indicator GCaMP6f for calcium sensing in both neurons and astrocytes, and applied two channel fiber optic recording system in combination with blood oxygenation level-dependent signal (BOLD) fMRI. This platform offers us a more direct interpretation of neuronal transient with fMRI, thus, would expand our understanding of the signal propagation through the neuron-glia-vessel network couple to BOLD fMRI signals. Methods All images were acquired with a 14.1 T/26cm horizontal bore magnet (Magnex), interfaced to an AVANCE III console (Bruker) and equipped with a 12 cm gradient set, capable of providing 100 G/cm with a rise time of 150 us (Resonance Research). A transreceiver surface coil was used to acquire fMRI images. fMRI scans with block design were performed using 3D Echo planar imaging sequence: TR, 1.5 s, TE,11.5 ms, 1.92X1.92X1.92 cm3, FOV, 48X48X48 matrix, 400X400X400 um3 spatial resolution. The reporter iGluSnFR and GCaMP6f were expressed by AAV5 virus in the two hemisphere forepaw somatosensory cortex (FP-S1) with Syn or GFAP promoter. Fiber optic (200 mm) was inserted into the area which expressed the cortex for fluorescent signal recording. Results/Discussion Neuronal calcium and Glu signals with simultaneous fMRI from the FP-S1 of two hemispheres were acquired, respectively. Evoked neuronal calcium and Glu spikes were shown to follow each electrical pulses (Fig 1A), while the Glu spikes have earlier onset time and faster time to peak response in comparison with neuronal calcium. Also, amplitude of the evoked Glu spike increased proportionally to the amplitude of BOLD signals as the function of the stimulation intensity (Fig. 1B). The simultaneous fMRI BOLD maps and the time course of BOLD signal were shown (Fig. 1C). Similar to previous study2, the astrocytic calcium signal is an integrated unitary spike, which has slower onset than the Glu spikes(Fig. 2A). Interestingly, we also observed the baseline drop of the Glu signal during the stimulation, which shows earlier onset with extended longer tail than the astrocytic signal. Also noteworthy is that the BOLD signals detected from both hemispheres are similar to each other(Fig.2B). Conclusions Concurrent glutamate and calcium recording was established with the BOLD fMRI brain mapping in anesthetized rats. This platform would lead to a better understanding of neurovascular coupling through the neuro-glial-vascular network in the animal brain. Future study will further clarify the neurovascular coupling events in the neuro-glial-vascular network and specify the source for the Glu baseline drop of during stimulation.
html CiteID: JiangCPY2018

Yu X , Pais P , Stelzer J , Edlow B and Jiang Y (March-22-2018) Abstract Talk: BOLD fluctuations under 0.01 Hz detected in resting-state functional MRI, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Introduction Spectral analysis in resting-state fMRI (rs-fMRI) studies has mainly focused on the 0.01 to 0.1 Hz frequency range1-6. Frequencies under 0.01 Hz are typically regarded as artifacts from scanner instabilities or physiological noise7, and are routinely excluded from the rs-fMRI analysis. Here, we show robust ultra-slow rs-fMRI signal fluctuations of high regularity in the brain of rats under anesthesia, which seem to be independent from breathing-derived motion8 or cardiovascular oscillations9,10 and possibly indicate a peculiar brain state in the animals. Methods 12 to 15 minutes of rs-fMRI data were acquired from anesthetized rats (under isoflurane, a-chloralose, medetomidine or urethane) using a 3D-EPI sequence with the following parameters: TE, 12.5 ms; TR, 1s; matrix size, 48x48x32; resolution, 400x400x600 µm. All images were acquired with a 12 cm diameter 14.1 T/26 cm magnet interfaced to an Avance III console. Trans-receiver surface coils were used to acquire the whole brain fMRI. Animals were mechanically ventilated, and a low dose of the paralytic agent pancuronium was used to prevent motion artifacts. Frequency decomposition analysis and power estimation of the 0.005-0.012 Hz frequency band were performed to map the ulstra slow oscillations (USO) in the rat brain. Results/Discussion Here we show that frequencies below the classical 0.01 Hz limit can be detected, with high amplitude and rhythmic pattern, in the Blood-Oxygen Level Dependent (BOLD) fMRI signal of animals receiving anesthesia (Fig.1). When present, these slow waves occured predominantly in the hypothalamic area, as confirmed with bandpass power analysis (Fig.2). The features of the reported USO (brain region predominance and apparent absence of correlation with motion or physiological artifacts), suggest that these oscillations might have a neural origin instead of being derived from MR hardware noise. Importantly, infraslow oscillations in a similar range were detected by EEG in brain-injured patients, which appeared related to modulations in the cortical excitability and have been hypothesized to emerge from a deep brain source11. Conclusions Our observations suggest that frequency components in the ultra-slow range may contribute to brain function. Future work will aim to clarify the source of these oscillations with neuronal and astrocytic calcium imaging and the utilization of cholinergic modulators to study reversibility of these oscillations in the rat brain.
html CiteID: PaisJSEY2018

Yu X , Pais P , Stelzer J , Edlow B, Jiang Y and Zou M (March-21-2018) Abstract Talk: Eigenvector centrality mapping and seed-based analysis of resting state fMRI during acute brainstem-coma recovery in the rat, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Introduction Despite the known association between brainstem lesions and coma, a circuit-based understanding of coma pathogenesis and mechanisms of recovery is lacking1. We recently developed a model of coma in the rat with focal injury to the brainstem, which allows investigating the neural mechanisms of coma emergence and recovery2. Resting state functional MRI (rs-fMRI) experiments along coma evolution in the rat provided evidence for an acute recovery mechanism by which subcortical arousal centers outside the brainstem reactivate the cerebral cortex. Methods rs-fMRI scans were acquired during the first 8 hours post-coma using a 3D EPI sequence (TE, 12.5 ms; TR, 1s; matrix size, 48x48x32; resolution, 400x400x600 µm; 925 TRs) on a 14.1 T/26 cm magnet interfaced to an Avance III console. Pre-processing was performed in AFNI3 and Lipsia4. For each rs-fMRI scan, a voxel-wise map of eigenvector values was computed (eigenvector centrality map), indicating the importance of the respective voxel within the network, followed by least squares fit regression of the eigenvector values over the temporal succession. This resulted in a certain slope, informative of the increase or decrease in connectivity at a given voxel of the brain (Fig.1). Additionally, seed-based analysis was performed by calculating the Pearson's correlation coefficient between regions. Results/Discussion The eigenvector centrality mapping-based whole brain functional connectivity analysis showed increases along the acute recovery from coma in thalamus, basal forebrain and basal ganglia (Fig.1). Additionally, seed-based analysis revealed higher correlations along the post-coma period between the central and reticular thalamus, striatum, globus pallidus and the nuclei in the basal forebrain (Fig.2). Interestingly, the time courses of these nuclei increased their correlation with those in cingulate and somatosensory cortex only after 4 hours post-coma (Fig.2). Concurrent electrophysiology and behavioral assessment in the rats demonstrated recovery of the neurological function during the period of study. This result provides evidence for the participation of the thalamic-basal forebrain-basal ganglia network in recovery of consciousness during acute recovery from coma, a time window that is not accessible in the clinical practice for systematic study of the human brain function. Conclusions The convergent results from whole brain and seed-based fMRI analysis of connectivity highly suggest a potential role for the basal forebrain-basal ganglia-thalamocortical network in the initial phase of restoration of consciousness after brainstem injury. This study further verifies the applicability of the rat brainstem coma model to investigate brain dynamics during the acute phase of coma.
html CiteID: PaisEJSZY2018

Merkle H , Schulz H , Singh A, Yu X and Pais Roldán P (June-3-2015) Abstract Talk: Sensing the high magnetic field: Fusion of otoliths in zebrafish larvae entails a hint , 23rd Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2015), Toronto, Canada23 (0695) .
Here we described the impact of the high magnetic field (MF) on zebrafish larvae aiming to identify potential biological MR sensors. 14T-MF exposures longer than 2 hours in zebrafish larvae led to fusion of 2 otoliths (CaCO3 crystals in the inner ear responsible for balance and hearing) and a subsequent aberrant balance behavior, a phenotype already described in genetic mutants. Identification of the cellular and molecular mechanisms underlying this MF-induced otolith-fusion may be tackled with a zebrafish mutagenesis approach and might contribute in an efficient way to search for MR sensors in biological models.
html CiteID: PaisRoldanSMSY2015

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Articles (1):

Pais-Roldán P, Singh AP, Schulz H and Yu X (April-2016) High magnetic field induced otolith fusion in the zebrafish larvae Scientific Reports 6(24151) 1-11.

Posters (4):

Pais P, Edlow B, Jiang Y, Zou M and Yu X (November-12-2017): A rat model of coma pathogenesis and recovery, 47th Annual Meeting of the Society for Neuroscience (Neuroscience 2017), Washington, DC, USA.
Chen Y, Pais-Roldán P, Chen X and Yu X (April-26-2017): Stepwise optogenetic activation of the rat thalamic nuclei with MRI-guided robotic arm (MgRA), 25th Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2017), Honolulu, HI, USA.
Pais Roldán P, Edlow B and Yu X (May-9-2016): Developing a Rat Model of Brainstem Coma: Initial MRI and MRA Investigations of Basilar Artery Occlusion, 24th Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2016), Singapore.
Pais Roldán P, Singh A, Merkle H, Schulz H and Yu X (March-19-2015): Magnetic field-induced otolith fusion of the zebrafish larvae, 10th Annual Meeting of the European Society for Molecular Imaging (EMIM 2015), Tübingen, Germany.

Talks (4):

Jiang Y, Chen X, Pais P and Yu X (March-23-2018) Abstract Talk: Extracellular glutamate and intracellular calcium recording with fiber optic and simultaneous fMRI, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Pais P, Jiang Y, Stelzer J, Edlow B and Yu X (March-22-2018) Abstract Talk: BOLD fluctuations under 0.01 Hz detected in resting-state functional MRI, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Pais P, Edlow B, Jiang Y, Stelzer J, Zou M and Yu X (March-21-2018) Abstract Talk: Eigenvector centrality mapping and seed-based analysis of resting state fMRI during acute brainstem-coma recovery in the rat, 13th Annual Meeting of the European Society for Molecular Imaging (EMIM 2018), San Sebastián, Spain.
Pais Roldán P, Singh A, Merkle H, Schulz H and Yu X (June-3-2015) Abstract Talk: Sensing the high magnetic field: Fusion of otoliths in zebrafish larvae entails a hint, 23rd Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2015), Toronto, Canada(0695).

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Last updated: Monday, 22.05.2017