Mapping Iso-Orientation Columns by Contrast Agent-Enhanced Functional Magnetic Resonance Imaging: Reproducibility, Specificity, and Evaluation by Optical Imaging of Intrinsic Signal

Abstract

Activation resembling ocular dominance or orientation columns has been mapped with high-resolution functional magnetic resonance imaging (fMRI). However, the neuronal interpretation of these functional maps is unclear because of the poor sensitivity of fMRI, unknown point spread function (PSF), and lack of comparison with independent techniques. Here we show that cerebral blood volume (CBV)-weighted fMRI with a blood plasma contrast agent (monocrystalline iron oxide nanoparticles), in combination with continuous temporally encoded stimulation, can map columnar neuronal activity in the cat primary visual cortex with high sensitivity, selectivity, and reproducibility. We examined hemodynamic response PSF by comparing these CBV-based signals with oxygen metabolism-based negative blood oxygenation level-dependent signals. A significant positive correlation exists between CBV-and metabolism-based iso-orientation maps, suggesting that the hemodynamic PSF is narrower than intercolumn distances. We also compared CBV-based fMRI with optical intrinsic signal (OIS) imaging, a technique that identifies sites of increased neuronal activity, to investigate neuronal correlation. Iso-orientation maps obtained by fMRI and OIS were well matched, indicating that areas of the highest orientation-selective CBV signals correspond to sites of increased neural activity. Using CBV-based fMRI, we successfully mapped orientation-selective functional architecture in the medial bank of the visual cortex, an area inaccessible to OIS imaging. Thus, we conclude that contrast agent-based fMRI, in combination with continuous temporally encoded stimulation, is a highly sensitive technique capable of mapping neural activity at the resolution of functional columns without depth limitation.

Columnar Specificity of Microvascular Oxygenation and Blood Flow Response in Primary Visual Cortex: Evaluation by Local Field Potential and Spiking Activity

“…Close inspection of the activated domains in Figure 1 reveals that the pixels within some big blood vessel regions failed to reach statistical threshold, suggesting that the statistical analysis is a robust method for rejecting potential spurious responses and leads to more conservative estimation of functionally specific activation regions. This finding is consistent with what we previously reported (Lu and Roe, 2008;Tanigawa et al, 2010) and also compatible with other fMRI data analysis (Fukuda et al, 2006). Thus, statistical analysis not only reduces the influence of large vascular fluctuations, but also provides quantitative assessment of activation maps.…”

“…However, a prevailing hypothesis is that the CBF response can exhibit spatial specificity at the columnar scale (Woolsey et al, 1996). Based on the notion that increased flow leads to increased cerebral blood volume (CBV), columnar specificity of blood volume responses have been demonstrated on rat barrel cortex and striate cortex of cats and monkeys with the intrinsic optical imaging (IOI) technique (Sheth et al, 2004;Vanzetta et al, 2004), as well as with contrast agent-enhanced CBV fMRI methods (Fukuda et al, 2006). Spatially specific regulation of CBF has been also observed in the vertical dimension of cortex in which laminarspecific regulation of CBF in deep cortical layers was independent of dilation of large surface vessels (Caesar et al, 2003;Fabricius et al, 1997;Tian et al, 2010).…”

Functional MRI Limitations and Aspirations

“…An ongoing issue with regard to the upper resolution of fMRI is whether or not fine delineation necessarily translates to accurate delineation (Kriegeskorte and Bandettini 2007a,b) -meaning that detailed activation maps may not be precisely registered with underlying function. This remains to be demonstrated using a gold standard, but compelling data suggesting fine and accurate delineation have been presented in an animal model in which optical imaging data were compared with hemodynamic changes as measured by fMRI (Fukuda et al 2006;Moon et al 2007a,b).…”

Lessons from fMRI about Mapping Cortical Columns

“…To achieve high sensitivity for orientation column mapping, we used CBV-weighted fMRI with iron oxide nanoparticles and the continuous stimulation paradigm. After fMRI data collection, OIS experiments were performed with the same stimulation paradigm on the same animal (Fukuda et al, 2006a).…”

“…Thus, it is critical to examine whether fMRI can pinpoint sub-millimeter functional sites. This outstanding issue motivates us to study reproducibility, specificity and confirmation of fMRI columnar maps (Fukuda et al, 2006a;Moon et al, 2007). To do this, we selected a well-established orientation column model in cats, which has been extensively investigated by single-unit recordings, 2-DG autoradiography and optical imaging of intrinsic (OIS) signals (Payne and Peters, 2002).…”