Switches for multiple behavioral states and a viral-based approach to non-invasive whole-brain cargo delivery (Conference Presentation)

2017 ◽  
Author(s):  
Viviana Gradinaru
Keyword(s):  
Whole Brain ◽  
Non Invasive ◽  
Cargo Delivery ◽  
Behavioral States

scholarly journals Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

2021 ◽  
Author(s):  
Patrick Vagenknecht ◽  
Maiko Ono ◽  
Artur Luzgin ◽  
Bin Ji ◽  
Makoto Higuchi ◽  
...  
Keyword(s):  
High Resolution ◽  
Progressive Supranuclear Palsy ◽  
Brain Imaging ◽  
Ex Vivo ◽  
Multiphoton Microscopy ◽  
Corticobasal Degeneration ◽  
Alzheimers Disease ◽  
Whole Brain ◽  
Optoacoustic Tomography ◽  
Non Invasive

Aim: Abnormal tau accumulation plays an important role in tauopathy diseases such as Alzheimers disease and Frontotemporal dementia. There is a need for high-resolution imaging of tau deposits at the whole brain scale in animal models. Here, we demonstrate non-invasive whole brain imaging of tau-targeted PBB5 probe in P301L model of 4-repeat tau at 130 μm resolution using volumetric multi-spectral optoacoustic tomography (vMSOT). Methods: The binding properties of a panel of imaging probes to amyloid-β, 4-repeat K18 tau fibrils were assessed by using Thioflavin T assay and surface plasmon resonance assay. We identified the probe PBB5 suitable for vMSOT tau imaging. The imaging performance was first evaluated using postmortem human brain tissues from patients with Alzheimers disease, corticobasal degeneration and progressive supranuclear palsy. Concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and non-transgenic littermate mice. Ex vivo measurements on excised brains along with multiphoton microscopy and immunofluorescence staining of tissue sections were performed for validation. The spectrally-unmixed vMSOT data was registered with MRI atlas for volume-of-interest analysis. Results: PBB5 showed specific binding to recombinant K18 tau fibrils, AD brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brain. i.v. administration of PBB5 in P301L mice led to retention of the probe in tau-laden cortex and hippocampus in contrast to wild-type animals, as also confirmed by ex vivo vMSOT, epi-fluorescence and multiphoton microscopy results. Conclusion: vMSOT with PBB5 facilitates novel 3D whole brain imaging of tau in P301L animal model with high-resolution for future mechanistic studies and monitoring of putative treatments targeting tau.

scholarly journals 4009 Magneto-electric nanoparticles (MENs) cobalt ferrite-barrium titanate (CoFe2O4–BaTiO3) for non-invasive neuromodulation

2020 ◽  
Vol 4 (s1) ◽  
pp. 11-11
Author(s):  
Tyler Nguyen ◽  
Zoe Vriesman ◽  
Peter Andrews ◽  
Sehban Masood ◽  
M Stewart ◽  
...  
Keyword(s):  
Magnetic Field ◽  
Neuronal Activity ◽  
Calcium Imaging ◽  
Post Treatment ◽  
Calcium Signals ◽  
Whole Brain ◽  
Non Invasive ◽  
Cortical Regions

OBJECTIVES/GOALS: Our goal is to develop a non-invasive stimulation technique using magneto-electric nanoparticles (MENs) for inducing and enhancing neuronal activity with high spatial and temporal resolutions and minimal toxicity, which can potentially be used as a more effective approach to brain stimulation. METHODS/STUDY POPULATION: MENs compose of core-shell structures that are attracted to strong external magnetic field (~5000 Gauss) but produces electric currents with weaker magnetic field (~450 Gauss). MENs were IV treated into mice and drawn to the brain cortex with a strong magnetic field. We then stimulate MENs with a weaker magnetic field via electro magnet. With two photon calcium imaging, we investigated both the temporal and spatial effects of MENs on neuronal activity both in vivo and in vitro. We performed mesoscopic whole brain calcium imaging on awake animal to assess the MENs effects. Furthermore, we investigated the temporal profile of MENs in the vasculatures post-treatment and its toxicities to CNS. RESULTS/ANTICIPATED RESULTS: MENs were successfully localized to target cortical regions within 30 minutes of magnetic application. After wirelessly applying ~450 G magnetic field between 10-20 Hz, we observed a dramatic increase of calcium signals (i.e. neuronal excitability) both in vitro cultured neurons and in vivo treated animals. Whole brain imaging of awake mice showed a focal increase in calcium signals at the area where MENs localized and the signals spread to regions further away. We also found MENs stimulatory effects lasted up to 24 hours post treatment. MEN stimulation increases c-Fos expression but resulted in no inflammatory changes, up to one week, by assessing microglial or astrocytes activations. DISCUSSION/SIGNIFICANCE OF IMPACT: Our study shows, through controlling the applied magnetic field, MENs can be focally delivered to specific cortical regions with high efficacy and wirelessly activated neurons with high spatial and temporal resolution. This method shows promising potential to be a new non-invasive brain modulation approach disease studies and treatments.

scholarly journals Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

2021 ◽  
Author(s):  
Patrick Vagenknecht ◽  
Artur Luzgin ◽  
Maiko Ono ◽  
BIN JI ◽  
Makoto Higuchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Resolution ◽  
Tissue Homogenate ◽  
Fluorescence Signal ◽  
Post Mortem ◽  
Whole Brain ◽  
Optoacoustic Tomography ◽  
Non Invasive ◽  
The Brain

Abstract Background Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer’s disease and Frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models are highly desired. Herein, we approach this challenge by non-invasively imaging the brain of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 µm spatial resolution using tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). Results PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer’s disease brain tissue homogenate by competitive binding against [11C]PBB3, and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and non-transgenic littermate mice. A dose dependent optoacoustic and fluorescence signal intensity was observed in the mouse brains with i.v. administration of different concentrations of PBB5. i.v. administration of PBB5 in P301L mice showed higher retention in tau-laden cortex and hippocampus compared to wild-type, confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, immunofluorescence staining using AT-8 antibody for phosphorylated tau. Conclusions We demonstrated non-invasive 3D whole-brain imaging of tau in P301L mice with a vMSOT system using PBB5 at a previously unachieved ~ 115 µm spatial resolution. This platform provides new tool to study tau spreading and clearance in tauopathy mouse model, foreseeable in monitoring of tau targeting putative therapeutics.

scholarly journals Simultaneous Measurement of Cerebral Blood Flow and Arterial Transit Time for Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1298-1298 ◽  
Author(s):  
Qin Qin ◽  
Wenbo Li ◽  
Dexiang Liu ◽  
John J Strouse
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Transit Time ◽  
Gray Matter ◽  
Whole Brain ◽  
Non Invasive ◽  
3D Acquisition ◽  
The Mean ◽  
Arterial Transit Time ◽  
Large Vessels

Abstract Introduction Studies of patients with ischemic stroke and silent cerebral infarcts from sickle cell anemia (SCA) have revealed abnormalities of both large and small vessels. Cerebral blood flow (CBF), a measure of the microvascular perfusion of the brain, has been recognized as a potentially sensitive and specific indicator of early cerebrovascular impairment in both children and adults with SCA. Arterial spin labeling (ASL) MRI is a non-invasive technique to acquire perfusion-weighted signal. This is typically at a single post-labeling delay (PLD) and provides only CBF measurement. The addition of multiple PLDs also permits the measurement of arterial transit time (ATT), the transit time from the labeled plane to the imaging voxels. ATT is prolonged with stenosis and/or occlusion of large vessels. In order to allow detection of both small and large vessel disease simultaneously for SCA, we employed a 4D whole-brain ASL protocol to measure CBF and ATT concurrently. Methods Experiments were performed on a 3T Philips Achieva scanner using a 32-channel head coil for reception. Seven healthy volunteers (age 36 ± 8 yrs; 3M / 4F) and 5 SCA patients with no history of stroke, recent transfusion, or renal impairment (21 ± 3 yrs; 3M / 2F) were enrolled after informed consent. The clinical laboratory performed complete blood counts on venous blood obtained the same day. The Pseudo continuous ASL (PCASL) sequence was implemented with 1000ms labeling duration and 12 PLDs (from 500 ms to 2700 ms in 200 ms intervals). A 3D acquisition scheme was employed with a field of view of 240 x 240 x 140 mm3 and acquisition resolution = 6.7 x 7.4 x 7 mm3. Total scan time was about 5 min. Fitting was performed per voxel using nonlinear-least-squares algorithm (Matlab) and maps of CBF and ATT were extracted concurrently. For each subject, five ROIs in the gray matter (frontal lobe, temporal lobe, parietal lobe, occipital lobe, and cerebellum) were manually drawn bilaterally from the corresponding anatomical image. Results Figure 1 display representative CBF and ATT maps of a participant with SCA estimated from the multi-delay PCASL scans. CBF maps (Figure 1a) were found to be uniform within the gray matter. White matter has lower CBF than gray matter and shows a longer transit time as expected. ATT maps (Figure 1b) reflected the heterogeneity between different brain regions. ATT values were about 200-400 ms shorter in the temporal lobe and medial frontal lobe, compared to the parietal/occipital lobes and cerebellum. Averaged CBF values from the five ROIs of all the subjects were calculated. For the control group (Hb = 14.1 ± 1.5 g/dL) and SCA group (Hb = 9.1 ± 2.1 g/dL), the mean CBF values were 49 ± 15 mL/100g/min vs 102 ± 23 mL/100g/min, and the mean ATT values were 1662 ± 317 ms vs 1245 ± 171 ms, respectively. Linear regression identified significant correlations between mean CBF and hemoglobin: CBF = - 9.8 Hb + 189 (r = -0.94; p < 0.001) and ATT = 81.2 Hb + 511 (r = 0.76; p = 0.004) (Figure 2). Discussion We have successfully implemented a fast and non-invasive MRI technique to measure two perfusion metrics (CBF and ATT) with a whole-brain coverage on SCA patients. It was well established only using other perfusion imaging modalities that CBF, among subjects with normal hemodynamic regulation and without neurovascular impairment, is inversely correlated with hemoglobin concentration. Conversely, a linear correlation between ATT and Hb is expected as a result of adaptive vasodilatation and lower blood viscosity. Our study's cross-subject validation of this relationship using the multi-delay PCASL method with 3D acquisition shows the potential of this technique to accurately define blood flow from both small and large vessels. This may be useful to identify people with SCA at increased risk of brain injury from silent cerebral infarct and stroke. Figure 1 Representative CBF (a) and ATT (b) maps acquired with 3D whole-brain coverage in axial, coronal and sagittal planes. Figure 1. Representative CBF (a) and ATT (b) maps acquired with 3D whole-brain coverage in axial, coronal and sagittal planes. Figure 2 Linear relationship between Hb and (a) CBF; (b) ATT. Figure 2. Linear relationship between Hb and (a) CBF; (b) ATT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Whole brain mapping of somatosensory responses in awake marmosets investigated with ultra-high field fMRI

2020 ◽  
Author(s):  
Justine C. Cléry ◽  
Yuki Hori ◽  
David J. Schaeffer ◽  
Joseph S. Gati ◽  
J. Andrew Pruszynski ◽  
...  
Keyword(s):  
Brain Mapping ◽  
Tactile Stimulation ◽  
New World ◽  
Body Representation ◽  
Functional Magnetic Resonance ◽  
Resonance Imaging ◽  
Whole Brain ◽  
Non Invasive ◽  
The Face ◽  
Somatosensory Responses

AbstractThe common marmoset (Callithrix jacchus) is a small-bodied New World primate that is becoming an important model to study brain functions. Despite several studies exploring the somatosensory system of marmosets, all results have come from anesthetized animals using invasive techniques and post-mortem analyses. Here we demonstrate the feasibility for getting high-quality and reproduceable sensorimotor mapping in awake marmosets with functional magnetic resonance imaging (fMRI). We acquired fMRI sequences in four animals while they received tactile stimulation (via air-puffs), delivered to the face, arm or leg. We found that the body representation progressed medially from the leg to the face in areas 3a, 3b, 1/2, and from caudal to rostral sites in areas S2 and PV. SI and SII exhibited a body representation in their functional connectivity pattern within the posterior and midcingulate and the thalamus. Interestingly, we also found a somatotopic body representation in two subcortical areas: the thalamus and, for the first time, in the putamen. These maps have similar organizations as those previously found in Old World macaque monkeys and humans, suggesting that these subcortical somatotopic organizations were already established before Old and New World primates diverged. Our results show the first whole brain mapping of somatosensory responses acquired in a non-invasive way in awake marmosets.Significant statementHere we used somatosensory stimulation combined with functional magnetic resonance imaging to map whole brain activation in awake marmosets. We used light tactile stimulation, consisting of air-puffs, delivered on the face, arm or leg. We found a topographic body representation in primary (SI) and secondary (SII) somatosensory regions, thalamus and putamen. We also revealed the existence of a body representation organization within the thalamus and the cingulate cortex by computing functional connectivity maps from seeds defined in SI/SII for face, arm and leg using resting-state fMRI data. This non-invasive approach will be essential for chronic studies by guiding invasive recording and manipulation techniques.

scholarly journals Multiscale brain modelling

2005 ◽  
Vol 360 (1457) ◽  
pp. 1043-1050 ◽  
Author(s):  
P. A Robinson ◽  
C. J Rennie ◽  
D. L Rowe ◽  
S. C O'Connor ◽  
E Gordon
Keyword(s):  
Electrical Activity ◽  
Brain Function ◽  
Large Scale ◽  
Multiple Scales ◽  
Brain Anatomy ◽  
Brain Electrical Activity ◽  
Whole Brain ◽  
Non Invasive ◽  
Spatio Temporal ◽  
Evoked Response Potentials

A central difficulty of brain modelling is to span the range of spatio-temporal scales from synapses to the whole brain. This paper overviews results from a recent model of the generation of brain electrical activity that incorporates both basic microscopic neurophysiology and large-scale brain anatomy to predict brain electrical activity at scales from a few tenths of a millimetre to the whole brain. This model incorporates synaptic and dendritic dynamics, nonlinearity of the firing response, axonal propagation and corticocortical and corticothalamic pathways. Its relatively few parameters measure quantities such as synaptic strengths, corticothalamic delays, synaptic and dendritic time constants, and axonal ranges, and are all constrained by independent physiological measurements. It reproduces quantitative forms of electroencephalograms seen in various states of arousal, evoked response potentials, coherence functions, seizure dynamics and other phenomena. Fitting model predictions to experimental data enables underlying physiological parameters to be inferred, giving a new non-invasive window into brain function that complements slower, but finer-resolution, techniques such as fMRI. Because the parameters measure physiological quantities relating to multiple scales, and probe deep structures such as the thalamus, this will permit the testing of a range of hypotheses about vigilance, cognition, drug action and brain function. In addition, referencing to a standardized database of subjects adds strength and specificity to characterizations obtained.

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