Purpose

To test the relationship between fT1ρ and BOLD signals in a clinical population.

Methods

39 participants with BD and 32 healthy controls underwent functional neuroimaging during alternating fT1ρ and BOLD runs of a flashing checkerboard paradigm. Diagnosis was confirmed by a clinician. Participants provided informed written consent in accordance with the University of Iowa Institutional Review Board.

Each run consisted of seven alternating fixation (black screen) and flashing checkerboard (4 Hz) blocks lasting 40s. Participants were asked to press a button in response to a red square presented every 4 seconds during the flashing checkerboard blocks (Figure 1).

MR imaging was performed on a 3T Siemens Magnetom Tim Trio with a 12-channel receiver head coil. High-resolution T1 (coronal 3D MP-RAGE; field-of-view=256mm3; matrix= 256×256×256; resolution=1.0mm3; TR=2530ms; TE=2.8ms; TI=909ms; flip angle=10°; BW=180Hz/px; and R=2 GRAPPA) and T2–weighted (sagittal 3D SPACE; field-of-view=260×228×176 mm3; matrix=256×230×176; resolution=1.0 mm3; TR=4000ms; TE=406ms; BW=592Hz/px; turbo factor=121; slice turbo factor=2; and R=2 GRAPPA) were acquired in order to register functional images to a common atlas space. Functional T1ρ (spin-echo-planar-imaging(SE-EPI) [1]; TR=4s; TSL=10,50ms; SL amplitude(γB1/2π)=213Hz, field-of-view=240×240mm2; matrix=64×64(single shot); slice thickness/gap=5.0/1.25mm; TR=2000 ms; TE=15ms; BW=1954Hz/px; partial Fourier=5/8; fat saturation; 140 measurements) and BOLD (T2*-weighted gradient-echo echo-planar-imaging(GRE-EPI); field-of-view=220×220mm2; matrix=64×64(single shot); 30 slices; slice thickness/gap=4.0/1.0mm; TR=2000ms; TE=30ms; BW=2004Hz/px; fat saturation; 140 measurements) time series were acquired in an axial-olique orientation with the most inferior slice positioned at the base of the frontal and occipital lobes.

BRAINS AutoWorkup [2] and Advanced Normalization Tools (ANTS) were used on T1 and T2-weighted anatomical images to generate transformation to a common atlas for functional image registration [3]. Functional voxels were masked to exclude non-brain tissue and areas with <95% coverage across participants. Images were transformed to the Montreal Neurological Imaging (MNI) atlas space [4] after analysis for publication.

Functional images were processed using Analysis of Functional NeuroImages (AFNI) [5]. Anatomical registration, skull-stripping, and spatial smoothing(5mmFWHM Gaussian) were performed. T1ρ signal was calculated by fitting the 10 ms and 50 ms spin-lock time images to a mono-exponential signal decay model [1]. Percent signal change for fT1ρ and BOLD were calculated using a general linear model that modeled the timing of the flashing checkerboard blocks, second-order baseline correction, and motion parameters.

Linear mixed effect regression was used to test whether the relationship between BOLD and fT1ρ was altered in BD. A null model that included group and fT1ρ as predictors for the BOLD signal and an experimental model that also included the Group x fT1ρ interaction were compared using a likelihood ratio test [6]. Voxels where these two models were significantly different and where there was a significant effect of the interaction are presented in Figure 2. 3dclustsim was used to determine a threshold (1.44 cm3) for cluster-based correction for multiple comparisons (α=0.05).

Results

The relationship between fT1ρ signal and BOLD signal was weaker in BD in left caudate, thalamus, occipital pole, and middle and superior temporal gyri; right lateral occipital cortex and inferior temporal gyrus; and bilateral visual cortex and cerebellum (Figure 2) and was stronger in left inferior and middle temporal gyri.

Conclusions

fT1ρ and BOLD were decoupled in BD, suggesting that distinct mechanisms underlie these signals. Changes in BOLD that occur following neuron activity [7-9] require astrocyte signalling[10, 11] and occurs 4-6 seconds after stimulation [9]. FT1ρ is sensitive to pH [12, 13] and is thought to increase following activity due to increases in acidic metabolic and signalling molecules[14].

There was a weaker relationship between fT1ρ and BOLD in BD in several brain regions, but a stronger relationship was observed in others. These regions have been implicated in BD by prior BOLD imaging studies [15-22], suggesting that our results are disease-related. However, our findings may also change the interpretation of prior studies, as BOLD differences in clinical populations may reflect decoupling between neuron activity and blood flow. Our findings suggest an altered relationship between metabolism and blood flow in BD and that a combined imaging approach may provide new information about disease.

Acknowledgements

No acknowledgement found.

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