Patrick Poulet

Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging.

Diffusion tensor magnetic resonance imaging (DT‐MRI) was applied for in vivo quantification of myelin loss and regeneration. A transgenic mouse line (Oligo‐TTK) expressing a truncated form of the herpes simplex virus 1 thymidine kinase gene (hsv1‐tk) in oligodendrocytes was studied along with two induced phenotypes of myelin pathology. Myelin loss and axonal abnormalities differentially affect values of DT‐MRI parameters in the brain of transgenic mice. Changes in the anisotropy of the white matter were assessed by calculating and mapping the radial (D⊥) and axial (D∥) water diffusion to axonal tracts and fractional anisotropy (FA). A significant increase in D⊥ attributed to the lack of myelin was observed in all selected brain white matter tracts in dysmyelinated mice. Lower D∥ values were consistent with the histological observation of axonal modifications, including reduced axonal caliber and overexpression of neurofilaments and III β‐tubulin. We show clearly that myelination and axonal changes play a role in the degree of diffusion anisotropy, because FA was significantly decreased in dysmyelinated brain. Importantly, myelin reparation during brain postnatal development induced a decrease in the magnitude of D⊥ and an increase in FA compared with the same brain before recovery. The progressive increase in D∥ values was attributed to the gain in normal axonal morphology. This regeneration was confirmed by the detection of enlarged oligodendrocyte population, newly formed myelin sheaths around additional axons, and a gradual increase in axonal caliber.

Recovery from Chronic Demyelination by Thyroid Hormone Therapy: Myelinogenesis Induction and Assessment by Diffusion Tensor Magnetic Resonance Imaging

The failure of the remyelination processes in multiple sclerosis contributes to the formation of chronic demyelinated plaques that lead to severe neurological deficits. Long-term cuprizone treatment of C57BL/6 mice resulted in pronounced white matter pathology characterized by oligodendrocyte depletion, irreversible demyelination and persistent functional deficits after cuprizone withdrawal. The use of a combination of in vivo diffusion tensor magnetic resonance imaging (DT-MRI) and histological analyses allowed for an accurate longitudinal assessment of demyelination. Injection of triiodothyronine (T3) hormone over a 3 week interval after cuprizone withdrawal progressively restored the normal DT-MRI phenotype accompanied by an improvement of clinical signs and remyelination. The effects of T3 were not restricted to the later stages of remyelination but increased the expression of sonic hedgehog and the numbers of Olig2+ and PSA-NCAM+ precursors and proliferative cells. Our findings establish a role for T3 as an inducer of oligodendrocyte progenitor cells in adult mouse brain following chronic demyelination.

Astrocytic hypertrophy in dysmyelination influences the diffusion anisotropy of white matter

The effect of a proteolipid protein (PLP) mutation on the developing white matter anisotropy was examined by diffusion tensor magnetic resonance imaging (DT‐MRI) in a noninvasive study of a mouse model of Pelizaeus‐Merzbacher disease (PMD). The jimpy PLP mutation in mice produces an irreversible dysmyelination in jimpy males, whereas heterozygous females exhibit a transient hypomyelination, as assessed by a longitudinal study of the same mice during development. Modifications of the different individual DT‐MRI parameters were highlighted by specific changes in tissue structures caused by the mutation that includes the hypomyelination, axonal abnormalities, and recovery. Astrocytic hypertrophy is a striking cellular event in dysmyelinated jimpy brain, where most axons or bundles of fibers are entirely wrapped by astrocyte cytoplasmic processes, so its influences on DT‐MRI parameters in dysmyelination were examined for the first time. DT‐MRI data of the jimpy brain were compared with those obtained from dysmyelination of (oligo‐TTK) transgenic mice, induced by oligodendrocyte killing, which have a mild astrocyte hypertrophy (Jalabi et al., 2005 ), and from recovering jimpy females, which have reduced astrocyte hypertrophy. The unique morphological feature of astrocytes in jimpy males coupled with an increase in the water channel protein aquaporin 4 (AQP4) was found to facilitate the directional water diffusion in the white matter. In addition to the major changes of DT‐MRI parameters in the two dysmyelinated mice caused by the myelin loss and axonal modifications, the amplified magnitude of radial and axial diffusions in jimpy males was attributed principally to the strongly pronounced astrocyte hypertrophy.

Detection of cortical activation with time-resolved diffuse optical methods.

Simulations based on diffusion theory that use a finite-element method and rely on an magnetic resonance imaging head model suggest that time-resolved diffuse optical techniques could provide information about the depth at which variations in perfusion take place and improve the detection of cortical activation. Experimental investigations were performed with sequentially driven picosecond laser diodes and an eight-channel time-correlated single-photon-counting detection system. The experimental results obtained for activation in the motor cortex, and for the Valsalva maneuver, confirm our assumptions and are in good agreement with the simulated data.

Simultaneous mapping of absorption and scattering coefficients from a three-dimensional model of time-resolved optical tomography.

A Newton-Raphson inversion algorithm has been extended for simultaneous absorption and scattering reconstruction of fully three-dimensional (3D) diffuse optical tomographic imaging from time-resolved measurements. The proposed algorithm is derived from the efficient computation of the Jacobian matrix of the forward model and uses either the algebraic reconstruction technique or truncated singular-value decomposition as the linear inversion tool. Its validation was examined with numerically simulated data from 3-D finite-element discretization models of tissuelike phantoms, with several combinations of geometric and optical properties, as well as two commonly used source-detector configurations. Our results show that the fully 3-D image reconstruction of an object can be achieved with reasonable quality when volumetric light propagation in tissues is considered, and temporal information from the measurements can be effectively employed. Also, we investigated the conditions under which 3-D issues could be approximately addressed with two-dimensional reconstruction algorithms and further demonstrated that these conditions are seldom predictable or attainable in practice. Thus the application of 3-D algorithms to realistic situations is necessary.

Simultaneous fluorescence yield and lifetime tomography from time-resolved transmittances of small-animal-sized phantom

There has been recently a considerable interest in simultaneously reconstructing yield and lifetime distributions of fluorescent imaging agents inside a bulky tissue, since combined monitoring of these two parameters provides a potential means of in vivo interrogating quantitative and environmental information of specific molecules, as well as accessing interactions among them. It is widely accepted that an advantageous way of accomplishing the task in the context of small-animal imaging is to use a time-domain (TD) modality. In this paper, we present a full three-dimensional, featured-data algorithm for TD diffuse fluorescence tomography, which inverts the Laplace-transformed TD coupled photon diffusion equations and employs a pair of real-domain transform-factors to effectively separate the fluorescent yield and lifetime parameters. By use of a specifically designed 16x16 channel time-correlated single photon counting system and a normalized Born formulation for the inversion, the proposed scheme in a transmission mode is experimentally validated to achieve simultaneous reconstruction of the fluorescent yield and lifetime distributions with reasonable accuracy.

Photoacoustic detection of triplet state and singlet oxygen in highly absorbing samples

Abstract— A photoacoustic (PA) effect theory taking into account two heat sources corresponding to the radiationless relaxation processes of two states of different lifetimes and to the heat diffusion across the sample is herewith presented. Results obtained demonstrate that the amplitude and the phase of the PA signal depend on the samples thermal properties, on its optical absorption coefficient, on the lifetime of the long‐lived excited state, and on the ratio of the two heat sources. This ratio can be expressed as a function of the product of the energy of the excited state times the quantum yield of its production. Simulations of PA amplitude and phase variations vs light modulation frequency exhibit new features of the PA signal: phase inversion and fast decrease of the amplitude. Experimental verifications were carried out on solutions and gels. Fitting of the amplitude and phase variations allow us to measure the lifetime and conversion yield of the intermediate state which can be a triplet state or singlet oxygen, O2(1Δg). The addition of an acceptor, specific to O2(1Δg), induces changes in the amplitude of the PA signal which can be used to study the production and deactivation of this excited form of oxygen. This work demonstrates the usefullness of PA in the detection of metastable excited states such as the triplet state and singlet oxygen and in their quantitative analysis.

Time-resolved absorption and hemoglobin concentration difference maps: a method to retrieve depth-related information on cerebral hemodynamics.

Time-resolved diffuse optical methods have been applied to detect hemodynamic changes induced by cerebral activity. We describe a near infrared spectroscopic (NIRS) reconstruction free method which allows retrieving depth-related information on absorption variations. Variations in the absorption coefficient of tissues have been computed over the duration of the whole experiment, but also over each temporal step of the time-resolved optical signal, using the microscopic Beer-Lambert law.Finite element simulations show that time-resolved computation of the absorption difference as a function of the propagation time of detected photons is sensitive to the depth profile of optical absorption variations. Differences in deoxyhemoglobin and oxyhemoglobin concentrations can also be calculated from multi-wavelength measurements. Experimental validations of the simulated results have been obtained for resin phantoms. They confirm that time-resolved computation of the absorption differences exhibited completely different behaviours, depending on whether these variations occurred deeply or superficially. The hemodynamic response to a short finger tapping stimulus was measured over the motor cortex and compared to experiments involving Valsalva manoeuvres. Functional maps were also calculated for the hemodynamic response induced by finger tapping movements.

Improvement of absorption and scattering discrimination by selection of sensitive points on temporal profile in diffuse optical tomography

We present a new method allowing the reconstruction of 3D time-domain diffuse optical tomography images, based on the time-dependent diffusion equation and an iterative algorithm (ART) using specific points on the temporal profiles. The first advantage of our method versus the full time-resolved scheme consists in considerably reducing the inverse problem resolution time. Secondly, in the presence of scattering heterogeneities, our method provides images of better quality comparatively to classical methods using full-time data or the first moments of the profiles.

Streak camera: a multidetector for diffuse optical tomography.

We describe an experimental setup for time-resolved diffuse optical tomography that uses a seven-channel light guide to transmit scattered light to a streak camera. This setup permits the simultaneous measurement of the time profiles of photons reemitted at different boundary sites of the objects studied. The instrument, its main specifications, and detector-specific data analysis before image reconstruction are described. The instrumentation was tested with phantoms simulating biological tissue, and the absorption and reduced scattering images that were obtained are discussed.