Dennis J. Sorce

Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts

Postmortem demonstration of increased iron in the substantia nigra (SN) is a well‐appreciated finding in Parkinsons disease (PD). Iron facilitates generation of free radicals, which are thought to play a role in dopamine neuronal loss. To date, however, magnetic resonance imaging (MRI) has failed to show significant in vivo differences in SN iron levels in subjects with PD versus control subjects. This finding may be due to the limitations in tissue contrasts achievable with conventional T1‐ and T2‐weighted MRI sequences that have been used. With the recent development of novel rotating frame transverse (T2ρ) and longitudinal (T1ρ) relaxation MRI methods that appear to be sensitive to iron and neuronal loss, respectively, we embarked on a study of 8 individuals with PD (Hoehn & Yahr, Stage II) and 8 age‐matched control subjects. Using these techniques with a 4T MRI magnet, we assessed iron deposits and neuronal integrity in the SN. First, T2ρ MRI, which is reflective of iron‐related dynamic dephasing mechanisms (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities), demonstrated a statistically significant difference between the PD and control group, while routine T2 MRI did not. Second, T1ρ measurements, which appear to reflect upon neuronal count, indicated neuronal loss in the SN in PD. We show here that sub‐millimeter resolution T1ρ and T2ρ MRI relaxation methods can provide a noninvasive measure of iron content as well as evidence of neuronal loss in the midbrain of patients with PD.

Exchange-influenced T2ρ contrast in human brain images measured with adiabatic radio frequency pulses

Transverse relaxation in the rotating frame (T2ρ) is the dominant relaxation mechanism during an adiabatic Carr–Purcell (CP) spin‐echo pulse sequence when no delays are used between pulses in the CP train. The exchange‐induced and dipolar interaction contributions (T2ρ,ex and T2ρ,dd) depend on the modulation functions of the adiabatic pulses used. In this work adiabatic pulses having different modulation functions were utilized to generate T2ρ contrast in images of the human occipital lobe at magnetic field of 4 T. T2ρ time constants were measured using an adiabatic CP pulse sequence followed by an imaging readout. For these measurements, adiabatic full passage pulses of the hyperbolic secant HSn (n = 1 or 4) family having significantly different amplitude—and frequency—modulation functions were used with no time delays between pulses. A dynamic averaging (DA) mechanism (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities) alone was insufficient to fully describe differences in brain tissue water proton T2ρ time constants. Measurements of the apparent relaxation time constants (T  2† ) of brain tissue water as a function of the time between centers of pulses (τcp) at 4 and 7 T permitted separation of the DA contribution from that of dipolar relaxation. The methods presented assess T2ρ relaxation influenced by DA in tissue and provide a means to generate T2ρ contrast in MRI. Magn Reson Med 53:823–829, 2005.

MRI contrast from relaxation along a fictitious field (RAFF)

A new method to measure rotating frame relaxation and to create contrast for MRI is introduced. The technique exploits relaxation along a fictitious field (RAFF) generated by amplitude‐ and frequency‐modulated irradiation in a subadiabatic condition. Here, RAFF is demonstrated using a radiofrequency pulse based on sine and cosine amplitude and frequency modulations of equal amplitudes, which gives rise to a stationary fictitious magnetic field in a doubly rotating frame. According to dipolar relaxation theory, the RAFF relaxation time constant (TRAFF) was found to differ from laboratory frame relaxation times (T1 and T2) and rotating frame relaxation times (T1ρ and T2ρ). This prediction was supported by experimental results obtained from human brain in vivo and three different solutions. Results from relaxation mapping in human brain demonstrated the ability to create MRI contrast based on RAFF. The value of TRAFF was found to be insensitive to the initial orientation of the magnetization vector. In the RAFF method, the useful bandwidth did not decrease as the train length increased. Finally, as compared with an adiabatic pulse train of equal duration, RAFF required less radiofrequency power and therefore can be more readily used for rotating frame relaxation studies in humans. Magn Reson Med, 2010.

Relaxation dispersion in MRI induced by fictitious magnetic fields

A new method entitled Relaxation Along a Fictitious Field (RAFF) was recently introduced for investigating relaxations in rotating frames of rank ≥ 2. RAFF generates a fictitious field (E) by applying frequency-swept pulses with sine and cosine amplitude and frequency modulation operating in a sub-adiabatic regime. In the present work, MRI contrast is created by varying the orientation of E, i.e. the angle ε between E and the z″ axis of the second rotating frame. When ε > 45°, the amplitude of the fictitious field E generated during RAFF is significantly larger than the RF field amplitude used for transmitting the sine/cosine pulses. Relaxation during RAFF was investigated using an invariant-trajectory approach and the Bloch-McConnell formalism. Dipole-dipole interactions between identical (like) spins and anisochronous exchange (e.g., exchange between spins with different chemical shifts) in the fast exchange regime were considered. Experimental verifications were performed in vivo in human and mouse brain. Theoretical and experimental results demonstrated that changes in ε induced a dispersion of the relaxation rate constants. The fastest relaxation was achieved at ε ≈ 56°, where the averaged contributions from transverse components during the pulse are maximal and the contribution from longitudinal components are minimal. RAFF relaxation dispersion was compared with the relaxation dispersion achieved with off-resonance spin lock T(₁ρ) experiments. As compared with the off-resonance spin lock T(₁ρ) method, a slower rotating frame relaxation rate was observed with RAFF, which under certain experimental conditions is desirable.

MRI contrasts in high rank rotating frames

MRI relaxation measurements are performed in the presence of a fictitious magnetic field in the recently described technique known as RAFF (Relaxation Along a Fictitious Field). This method operates in the 2nd rotating frame (rank n = 2) by using a nonadiabatic sweep of the radiofrequency effective field to generate the fictitious magnetic field. In the present study, the RAFF method is extended for generating MRI contrasts in rotating frames of ranks 1 ≤ n ≤ 5. The developed method is entitled RAFF in rotating frame of rank n (RAFFn).

Glioma cell density in a rat gene therapy model gauged by water relaxation rate along a fictitious magnetic field.

Longitudinal and transverse rotating‐frame relaxation time constants, T1ρ and T2ρ, have previously been successfully applied to detect gene therapy responses and acute stroke in animal models. Those experiments were performed with continuous‐wave irradiation or with frequency‐modulated pulses operating in an adiabatic regime. The technique called Relaxation Along a Fictitious Field (RAFF) is a recent extension of frequency‐modulated rotating‐frame relaxation methods. In RAFF, spin locking takes place along a fictitious magnetic field, and the decay rate is a function of both T1ρ and T2ρ processes. In this work, the time constant characterizing water relaxation with RAFF (TRAFF) was evaluated for its utility as a marker of response to gene therapy in a rat glioma model. To investigate the sensitivity to early treatment response, we measured several rotating‐frame and free‐precession relaxation time constants and the water apparent diffusion coefficients, and these were compared with histological cell counts in 8 days of treated and control groups of animals. TRAFF was the only parameter exhibiting significant association with cell density in three different tumor regions (border, intermediate, and core tissues). These results indicate that TRAFF may provide a marker to identify tumors responding to treatment. Magn Reson Med, 2011.

Detection of neuronal loss using T1ρ MRI assessment of 1H2O spin dynamics in the aphakia mouse

The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) is well characterized in Parkinsons disease (PD). Recent developments in magnetic resonance imaging (MRI) techniques have provided the opportunity to evaluate for changes in cellular density. Longitudinal relaxation measurements in the rotating frame (T(1rho)) provide a unique magnetic resonance imaging contrast in vivo. Due to the specificity of T(1rho) to water-protein interactions, the T(1rho) MRI method has strong potential to be used as a non-invasive method for quantification of neuronal density in the brain. Recently introduced adiabatic T(1rho) magnetic resonance imaging mapping methods provide a tool to assess molecular motional regimes with high sensitivity due to utilization of an effective magnetic field sweep during adiabatic pulses. In this work, to investigate the sensitivity of T(1rho) to alterations in neuronal density, adiabatic T(1rho) MRI measurements were employed in vivo on Pitx3-homeobox gene-deficient aphakia mice in which the deficit of DA neurons in the SNc is well established. The theoretical analysis of T(1rho) maps in the different areas of the brain of aphakia mouse suggested variation of the (1)H(2)O rotational correlation times, tau(c). This suggests tau(c) to be a sensitive indicator for neuronal loss during neurological disorders. The results manifest significant dependencies of the T(1rho) relaxations on the cell densities in the SNc, suggesting T(1rho) MRI method as a candidate for detection of neuronal loss in neurological disorders.

Exchange-induced relaxation in the presence of a fictitious field

In the present study we derive a solution for two site fast exchange-induced relaxation in the presence of a fictitious magnetic field as generated by amplitude and frequency modulated RF pulses. This solution provides a means to analyze data obtained from relaxation experiments with the method called RAFFn (Relaxation Along a Fictitious Field of rank n), in which a fictitious field is created in a coordinate frame undergoing multi-fold rotation about n axes (rank n). The RAFF2 technique is relevant to MRI relaxation methods that provide good contrast enhancement for tumor detection. The relaxation equations for n=2 are derived for the fast exchange regime using density matrix formalism. The method of derivation can be further extended to obtain solutions for n>2.

RAFFn relaxation rate functions

In the present study we derive expressions for relaxation rate functions due to dipolar interactions between identical spins in the rotating frames of rank greater than or equal to 3. The rotating frames are produced due to fictitious magnetic field as generated by amplitude and frequency modulated radiofrequency (RF) pulses operating in non-adiabatic regime. This solution provides a means for description of the relaxations during method entitled Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn), in which a fictitious field is created in a coordinate frame undergoing multi-fold rotation about n axes (i.e., rank n). We validate the proposed model by comparison with the accepted trigonometric relations for relaxation rates between tilted frames. The agreement between the proposed model for RAFF3 and the trigonometric model is excellent.