Synopsis
The
hemodynamic response is nonlinear in response to short duration stimuli, and
this nonlinearity varies across cortex. To study the nonlinearities in
subcortical vs. cortical structures, we performed high-resolution fMRI at 7
Tesla to characterize responses to short visual stimuli in superior colliculus
(SC), lateral geniculate nucleus (LGN) and primary visual cortex (V1). Response nonlinearity was increased in SC, and response timecourses were consistently narrower in LGN than in
V1. We conclude that analysis of subcortical activations using fMRI will
require flexible models of the hemodynamic response, and suggest future studies
to identify the neural and vascular factors contributing to these
nonlinearities.Introduction
Classic
models of the hemodynamic response treat it as a linear system, an assumption
that works well for long stimuli that are spaced far apart in time [1].
However, short stimuli and short interstimulus intervals (ISIs) elicit
nonlinear responses: short stimuli cause proportionally larger fMRI responses [2,3],
and short ISIs cause a reduction and broadening of the fMRI response [4,5,6]. This
nonlinearity can vary substantially across cortical regions [7]. Improvements
to high-resolution imaging techniques have led to an increased number of
studies focusing on deep brain structures, and animal studies have shown that BOLD
responses are different in subcortical structures as well [8,9]. We aimed to
determine how hemodynamic nonlinearities vary in human thalamus and brainstem. We
focused on the visual system, varying stimulus duration and ISI to compare the
resulting nonlinearities in subcortical vs. cortical structures.
Methods
Four subjects gave informed consent and
were scanned on a 7T Siemens scanner with a custom-built 32-channel head coil
array. Each session began with a 0.75 mm isotropic multi-echo MPRAGE [10].
Functional runs acquired 38 oblique slices, positioned to capture the superior
colliculus (SC), lateral geniculate nucleus (LGN), and calcarine sulcus
(primary visual cortex, V1). Functional scans consisted of a single-shot
gradient echo SMS-EPI at 1.1 mm isotropic resolution (R=4 acceleration with
FLEET-ACS [11], MultiBand factor=2, matrix=174x174, blipped CAIPI shift=FOV/2, TR=1.11
s, TE=26 ms, echo spacing=0.79 ms, flip angle=70°). Each functional run lasted 260 seconds.
During stimulus presentation a simple fixation task was continuously
administered to minimize eye movement. The first two runs presented a radial
checkerboard flickering at 12 Hz for 16 seconds, followed by a blank gray
screen for 16 seconds. These runs were averaged together and used to localize
the visually driven voxels in the SC, LGN, and V1. SC and LGN ROIs were
hand-drawn using the functional maps as guides; the V1 ROI was defined using
the V1 labeling generated by Freesurfer, and thresholding the z-statistic map
from the localizer runs above z=4. The following runs presented checkerboard
stimuli lasting either 0.167, 0.5, 1, 2, or 4 seconds. Half the runs used a
long ISI (17–19 s), and half the runs used a short ISI (2–3 s). The trial response to each stimulus type was
deconvolved in MATLAB using a finite impulse response (FIR) basis set to model the
mean timeseries in each ROI, and the impulse
response was modeled in FSL using the linear optimal basis set (FLOBS).
The first two functional localizer runs were used to identify
visually driven voxels in SC, LGN, and V1 (Fig. 1). The trial response in each
ROI was then identified across all remaining runs using FIR basis functions (Fig.
2a-c). Stimulus duration induced a nonlinear trial response in V1, as
previously identified [1,2,3], with shorter duration stimuli eliciting larger
amplitude responses than expected (2d,g). The nonlinearity was similar in LGN
(2e,h), but substantially larger in SC (2f,i), in which the trial response to a
167 ms stimulus was almost as large as the response to a 1 s. stimulus.
Using
FSL's linear optimal basis set, we estimated the hemodynamic response in each
region, and obtained physiologically plausible HRFs for the V1 and LGN ROIs
(Fig. 3a,b). The hemodynamic impulse response in V1 was consistently narrower
for brief stimuli, and was consistently broader in V1 than in LGN (Fig. 3c;
FWHM=5.15 s in V1; 4.52 s in LGN). Comparing runs with short ISIs and long ISIs
revealed an additional impact of ISI length on the FWHM of the hemodynamic
impulse response, with narrower HRFs occurring in the short ISI condition (Fig.
4; Long ISI condition, LGN 4.56 s, V1=5.32 s; Short ISI condition, LGN=4.34 s,
V1=5.23 s).
Discussion
We
found that the nonlinearity of the fMRI response increases in brainstem
components of the visual pathway, compared to cortical structures. In addition,
hemodynamic impulse responses in LGN were narrower than in V1, indicating that
the temporal dynamics of the response as well as the linearity of its magnitude
may be altered. Further narrowing of the impulse response
occurred in both structures in experiments using short ISIs, and in response to
stimuli of short duration. Both neural and vascular components could contribute
to these differences, as saccade-related neural activity can contribute to response nonlinearity, and future studies could combine
electrophysiological recordings with functional imaging to dissociate these
factors. Narrower hemodynamic response functions lead to increased fast
temporal dynamics in the fMRI signal [12]; these results therefore suggest that
fast temporal dynamics could be detected in subcortical structures when
employing rapid event-related study designs.
Acknowledgements
This
work was funded by the Athinoula A. Martinos Center for Biomedical Imaging, NIH
K01-EB011498 and R01-EB019437
to J.R.P., a fellowship from the Harvard Society of Fellows to L.D.L., and NIH NIBIB
P41-EB015896 and NCRR shared resource instrumentation grants S10-RR023401, S10-RR023403
and S10-RR020948.References
1. Boynton, G. M., Engel, S. A., Glover,
G. H. & Heeger, D. J. Linear systems analysis of functional magnetic
resonance imaging in human V1. The Journal of Neuroscience 16,
4207–4221 (1996).
2. Vazquez, A. L. & Noll, D. C.
Nonlinear aspects of the BOLD response in functional MRI. Neuroimage 7,
108–118 (1998).
3. Glover, G. H. Deconvolution of impulse
response in event-related BOLD fMRI. Neuroimage 9, 416–429
(1999).
4. Friston, K. J., Josephs, O., Rees, G.
& Turner, R. Nonlinear event-related responses in fMRI. Magn. Reson.
Med. 39, 41–52 (1998).
5. Huettel, S. A. & McCarthy, G.
Evidence for a refractory period in the hemodynamic response to visual stimuli
as measured by MRI. Neuroimage 11, 547–553 (2000).
6. de Zwart, J. A. et al.
Hemodynamic nonlinearities affect BOLD fMRI response timing and amplitude. Neuroimage
47, 1649–1658 (2009).
7. Birn, R. M., Saad, Z. S. &
Bandettini, P. A. Spatial Heterogeneity of the Nonlinear Dynamics in the FMRI
BOLD Response. Neuroimage 14, 817–826 (2001).
8. Lau, C. et al. BOLD responses
in the superior colliculus and lateral geniculate nucleus of the rat viewing an
apparent motion stimulus. Neuroimage 58, 878–884 (2011).
9. Devonshire, I. M. et al.
Neurovascular coupling is brain region-dependent. Neuroimage 59,
1997–2006 (2012).
10. van der Kouwe, A. J. W., Benner, T.,
Salat, D. H., & Fischl, B. (2008). Brain morphometry with multiecho MPRAGE.
NeuroImage, 40(2), 559–69.
11. Polimeni, J. R., Bhat, H., Witzel,
T., Benner, T., Feiweier, T., Inati, S. J., Renvall, V., Heberlein, K., &
Wald, L. L. (2015). Reducing sensitivity losses due to respiration and motion
in accelerated Echo Planar Imaging by reordering the autocalibration data
acquisition. Magnetic Resonance in Medicine, earlyview. In press.
12. Chen, J. E. & Glover, G. H. BOLD
fractional contribution to resting-state functional connectivity above 0.1Hz. Neuroimage
107, 207–218 (2015).