fMRI of peripheral visual field representation

Clinical Neurophysiology 118 (2007) 1303–1314 www.elsevier.com/locate/clinph

fMRI of peripheral visual field representation Linda Stenbacka *, Simo Vanni Brain Research Unit, Low Temperature Laboratory and Advanced Magnetic Imaging Centre, Helsinki University of Technology, P.O. Box 3000, 02015-TKK Espoo, Finland Accepted 28 January 2007 Available online 20 April 2007

Abstract Objective: Despite mapping tools for central visual field, delineation of peripheral visual field representations in the human cortex has remained a challenge. Access to large visual field and differentiation of retinotopic areas with robust mapping procedures and automated analysis are beneficial in basic research and could accelerate development of clinical applications. Methods: We constructed a simple optical near view system for wide visual field stimulation, and examined the topology of retinotopic areas. We used multifocal (mf) design, which enables analysis with general linear model and standard fMRI softwares and is easily automated. Results: Our stimulation method enabled individual mapping of visual field up to 50 of eccentricity and showed that retinotopic visual areas extended through posterior cerebrum. In addition, we located a separate peripheral upper visual field representation in parietooccipital (PO) sulcus. Conclusions: These functional results are in line with earlier histological data, and support recent findings on human V6, a retinotopic area in the medial PO sulcus with an apparent emphasis on peripheral visual field. Significance: Our projection system and mf-design together enable efficient and robust retinotopic mapping of wide visual field, which can at low cost be adapted to any clinical environment with visual back-projection system.  2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: V1; Retinotopy; fMRI; V6; Visual field periphery

1. Introduction Retinotopic mapping and identification of visual areas with fMRI have become standard procedures for basic research, but clinical applications have suffered from complex analysis requiring manual labour and from limited extent of visual field stimulation in the narrow magnet bore. Localisation of retinotopic visual areas could be valuable for example for preoperative evaluation, and quantitative mapping of retinotopic organization would give information about the integrity of retina and retinocortical pathways. Previously the retinotopic organization of visual areas in living human brain has been examined with both

*

Corresponding author. Tel.: +358 9 4516162; fax: +358 9 4512969. E-mail address: [email protected].fi (L. Stenbacka).

positron emission tomography (PET; Fox et al., 1987; Shipp et al., 1995), and functional magnetic resonance imaging (fMRI). Several forms of stimulus setting have been applied with fMRI, including block design (Schneider et al., 1993), Fourier based phase-encoded retinotopic mapping (Engel et al., 1994; Sereno et al., 1995; DeYoe et al., 1996; Warnking et al., 2002; Dougherty et al., 2003), and multifocal (mf) design (Vanni et al., 2005). Ideally the stimuli would subtend the whole visual field and the mapping procedure would require as little user interaction as possible. The narrow magnet bore restricts the size of the stimulus, and thus in the majority of previous fMRI studies the stimuli extended only to 10–15 eccentricity of visual field (Engel et al., 1997; Vanni et al., 2005). According to human magnification factor (Duncan and Boynton, 2003) 10 of eccentricity would correspond to approximately 50% and 15 to 60% of surface area of

1388-2457/$32.00  2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2007.01.023

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the primary visual cortex. However, some groups have managed to map also the more peripheral visual field representations. Tootell and co-workers (1995) stimulated visual field up to 45 of eccentricity. Their stimulus projection system comprised of a screen rostral to subjects’ jaws and the subjects viewed the stimuli via a mirror. Recently, Pitzalis and co-workers (2006) mapped visual field up to 55 eccentricity with phase-encoded stimulation. Their subjects viewed the stimulus projection screen directly from a very short distance (10–12 cm). This approach enabled mapping of peripheral visual fields and detection of a new retinotopic area in the posterior bank of the PO sulcus. However, given that emmetropic eyes have difficulties accommodating when objects are closer than 25 cm from the eyes, comfortable very short viewing distances should benefit from optical aids. In this study we developed a simple optical aid for wide visual field mapping in magnet bore, and showed the extent and retinotopic organization of wide visual field in single individuals. We applied multifocal fMRI (mffMRI, Vanni et al., 2005) design, where multiple local visual field responses are measured in parallel using orthogonal temporal sequences. Originally Sutter and co-workers introduced maximal length shift register (m-sequence) stimuli (Sutter, 2001). The timing of each region of the stimulus is independent from all other regions, and thus the correlation between the stimulus and the response pattern reflects directly the underlying neural system. Later, James (2003) presented a more flexible mf-design where pulses of pattern reversal resulted in clearly larger visually evoked potential amplitudes. MffMRI relies on multiple discrete local retinotopic BOLD responses, contrary to phase-encoded retinotopic mapping, where a travelling wave of activation along the cortex gives a continuum of phases in the response. MffMRI allows application of the standard general linear model based tools in data analysis and more straightforward localisation and quantification of the signal. Compared to block designs, mf-technique enables simultaneous stimulation of several locations, and therefore it requires considerably shorter measurement time. We suggest that our approach, with modified optical aids to fit local coil and stimulus display configuration, could be applicable in clinical practice. 2. Methods 2.1. Subjects and stimuli We studied altogether twelve healthy right-handed volunteers (22–40 years, 7 males and 5 females). All subjects participated in the first experiment and smaller subgroups were measured in four control experiments. Our aim was first to show with several subjects that medial occipital retinotopic areas can be mapped up to periphery with mf-stimuli and our projection system, and then to study the results obtained with different mf-stimuli both in 3-D brains and on segmented cortical surfaces. The study was approved

by the Ethics Committee of Hospital District of Helsinki and Uusimaa, and all subjects gave their written informed consent before participation in the study. Figs. 1 and 2 represent the stimuli and the stimulus projection system, respectively. The stimulus images were generated with Matlab (Mathworks Inc.), and their timing was controlled with Presentation (Neurobehavioral systems Inc.). We used pattern reversal visual stimulus with the contrast of the checks reversing at 8 Hz. The sizes of the black (4 cd/m2) and white (40 cd/m2) checks increased linearly with eccentricity. Mean luminance of the display was 22 cd/m2 and contrast of the pattern was 82%. The mffMRI used in this paper follows the protocol described earlier (Vanni et al., 2005), but with fewer and larger visual field regions. We constructed four different mf-stimuli and used them in separate sessions. Three stimuli were binocular and one was monocular. Fig. 1a visualizes one example frame of stimulus A. We used this stimulus for twelve subjects to measure the extent of the retinotopic visual areas in the occipital lobe. Five of these twelve subjects were recorded with monocular stimulus B (Fig. 1b). The borders of visual areas were mapped for six subjects using binocular stimulation of the cardinal meridians (stimulus C; Fig. 1c) and for two of these six subjects the design was extended in a separate session to include also the intermediate positions and to map the internal representation of the retinotopic visual areas (stimulus D; Fig. 1d). Stimulus projection system comprised a data projector with three micromirrors (VistaPro, Electrohome Ltd.) outside the magnet room. The data projector generated 3000 ANSI lumens. A customized objective with 350 mm focal length was covered by 0.6 log unit neutral density filter to reduce the excessive luminous flux. Images went through a RF-shield tube and were reflected by a surface mirror into the magnet bore. The coil-end of the projection system is shown schematically in Fig. 2a. A semi-transparent back projection screen was attached at the level of the subjects’ eyebrows inside the head coil, which was open at its rear side. The screen filled the space above the subjects’ foreheads inside the coil, and the upper border of the screen was curved along the interior of the coil. The subjects viewed the stimuli via an MRI-compatible surface mirror (Precision Glass & Optics Ltd.). Distance between the eyes and the screen via the mirror was approximately 8 cm. In binocular experiments the subjects were asked to fixate to a point at the centre of the screen. To enable fixation at short distance, subjects wore glasses with +10 diopter correction (plastic frames & lenses from KEOPS Ltd.). In addition, to diminish the need of convergence during binocular viewing, we applied Fresnel prisms onto both lenses (Subject 1 with the glasses is shown in Fig. 2b). In monocular experiment we covered the left eyes of the subjects with thick cotton badges. The fixation point was located either on the right border or on the left border of the screen and the subject viewed the stimulus in nasal (three subjects) or temporal (two subjects) visual field through the +10

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Fig. 1. Single frames from the four different mf-designs. Only upper visual field stimuli are displayed. The upper and lower fields were stimulated in separate runs. Images a, b, and d extended to approximately 58 and were divided radially into three sections: 1–12, 12–30, and 30–58. Due to physical constrains, subjects were able to see as far as the last row of checks horizontally (49), but in vertical direction only the two innermost regions were fully visible (40). (a) The stimulus A comprised twelve regions. Each hemifield contained a 45 polar wedge, starting 5 off from the horizontal meridian. (b) The stimulus B was monocular, and divided into five sections. The subjects were able to see as far as the outer border of the fourth stimulus region, approximately 53 of eccentricity. The sizes of the regions and the checks were the same in stimuli C and D. Stimulus C consisted of four 22 polar angle wedges at the horizontal and vertical meridians and divided in three sections radially, and stimulus D contained 27 regions in 9 polar sections and three radial sections.

Mirror Back-projection screen Head-coil Projector

Fig. 2. (a) The stimulus projection system. Different parts of the system are not in scale. Subjects lay on their back and viewed the stimulus via a mirror attached inside the head coil. The projection screen was above subjects’ foreheads, and the image was projected from the back of the magnet. (b) Subject wearing +10 diopter glasses with prisms and protection for light reflection, auditory protection, and measurement outfit.

diopter lens. The prisms were not necessary in the monocular stimulus system. The lenses and the prisms enlarged the stimuli and we detected this enlargement by measuring the refraction of light originating from a point source. We took the enlargement into account when we calculated the sizes of the stimuli. Refraction of light in the +10 diopter lenses increased the stimulus size by approximately 3% in the centre and 12% in the border of the stimuli. The prisms caused nonlinear aberration of light: Sizes of the stimuli in the nasal visual field remained same but the stimuli in the temporal visual field were enlarged and this enlargement increased towards the edge of the visual field. The measured enlargement in stimulus size in temporal visual field with lenses and prisms was approximately 10% in the centre, 30% at half radius and 60% in the border of the stimuli. The binocular stimulus setting resulted in altogether horizontal visual field of 49 radius but the nasal edge of the glasses occluded the peripheral nasal field of both eyes resulting in approximately 2/3 binocular and 1/3 monocular fields. The vertical dimension of the visual field was

approximately 40, but we achieved vertical visual field of 40 radius with stimulation of the upper and the lower visual fields in separate runs. The monocular system resulted in 53 of horizontal (either temporal or nasal) visual field and 40 radius vertical field (in two runs). In addition to mf-experiments, the retinotopic organizations of four subjects were determined also with standard phase-encoded retinotopic mapping (Sereno et al., 1995; Warnking et al., 2002) in order to compare the methods and to confirm the results obtained with the mf-stimuli. We used black-and-white checkerboard pattern stimuli, extending up to 15, with contrast reversing at 8 Hz. The stimuli were projected on a screen, attached behind the subjects’ head. The subjects viewed the stimuli via a mirror inside the head coil (viewing distance 35 cm) and fixated to a point in the centre of the visual field. Four sets of responses were acquired: two wedges, each with two rows of checks extending 45 of polar angle and with one p phase difference, rotated clockwise or counter-clockwise and a ring, containing two rings of checks, expanded or contracted. The radial phase (wedges) or the polar phase (rings) of the stimulus pattern varied in each frame to diminish adaptation to pattern. For both wedges and rings, the phases of activations spreading along the cortex to two opposite directions were first averaged and then assigned to 3-D models of the grey-white-matter border of the individual brains. 2.2. MR data acquisition We measured the data with a 3-tesla MRI scanner (Signa, General Electric) and a standard GE single-channel head coil and used a T2*-weighted gradient-echo echoplanar imaging (EPI) sequence for functional imaging. The measurement parameters of the mf-experiments were TR 2 s, TE 30 ms, flip angle 60, and FOV 190 · 190 mm2. Acquisition matrix 64 · 64 and 3 mm slice thickness resulted in isotropic 3 · 3 · 3 mm3 voxels. Twenty-seven

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slices in interleaved order were acquired approximately orthogonal to PO sulcus. To correct for the magnetic field inhomogeneities introduced by the head, shimming was performed for the entire brain. Two runs were acquired for both upper and lower visual fields. Each stimulus region was active exactly half of the time during one run in pseudorandom order according to a quadratic residue sequence, and one run consisted of 240 time points (8 min). The parameters for phase-encoded retinotopy measurements were TR 1.3 s, TE 40 ms, flip angle 90, acquisition matrix 64 · 64, FOV 200 · 200 mm2, slice thickness 4 mm, thus resulting in 3.1 · 3.1 · 4.0 mm3 voxels. We acquired 16 slices to cover the visual areas in the occipital lobe. The total duration of each run was 7 min 22 s for collection of altogether 354 functional volumes. We acquired low-resolution T1-weighted images with spoiled gradient echo sequence in the end of each measurement session for visualization, normalization, and intraindividual coregistration with the surface reconstruction. The parameters for the low-resolution images were 124 slices, slice thickness 1.5 mm, FOV 230 · 230 mm2, and acquisition and reconstruction matrices 128 · 128. In addition, we measured higher resolution T1-weighted images of six subjects for the segmentation of the cortical sheet between the grey and the white matter. The measurement parameters were: slice thickness 0.9 mm, FOV 230 · 230 mm2, and acquisition and reconstruction matrices 256 · 256, resulting in isotropic 0.9 · 0.9 · 0.9 mm3 voxels. 2.3. MR data analysis Mf-data were analyzed with SPM2 software (Friston, 2003) using modified functions for regression. We applied head motion and slice timing correction and extracted the first four time points from the analysis to allow the stabilization of the magnetization. For the pre-processed data, the general linear model was fitted with one regression component for each of the visual field regions, and the following model was convolved with a standard hemodynamic response function provided by SPM2. For the group analysis (stimulus A, 12 subjects), all data were normalized to a standard anatomical space by using a T1-weighted MNI template provided by SPM2. The data were recalculated to 3 · 3 · 3 mm3 voxels and the normalized EPI images were smoothed with an isotropic Gaussian kernel of 9 · 9 · 9 mm3. We performed random-effects analysis (Friston et al., 1999) with one sample t test (p < 0.0001, uncorrected, and cluster size threshold 10 voxels) and showed the results in a normalized anatomical image provided by SPM2. In addition to group analysis of stimulus A, all data were analysed in individual level both in 3-D and a subset of data on cortical surface. We performed 3-D analysis with SPM2 (smoothing 6 · 6 · 6 mm3 and pFWE < 0.05) and surface analysis with Brain a`la Carte (BALC) Matlab (Mathworks Ltd.) toolbox provided by INSERM unit 594/Universite` Joseph Fourier, Grenoble, France

(Warnking et al., 2002); for more information contact Michel Dojat. For the surface analysis, we created individual 3-D anatomical models of the grey and white matter border of the medial occipital cortices, including PO sulcus, and unfolded the 3-D models onto 2-D surfaces. We assigned statistical t-maps (unsmoothed data) to the surfaces and smoothed the t-values (SD 1.5 mm) along the cortical sheet. We calculated the cortical magnification factor of V1 for six subjects who were measured with stimuli A and C. According to Schwartz (1994), the relationship between the visual field coordinates and cortical surface locations can be described with a formula w = k*ln(z + a) where w is cortical location (complex number), a describes the foveal representation in cortex and k is a constant term. z describes the visual field location (complex number). z can be calculated with the formula z = f*exp(i*h) where f is eccentricity of the stimulus in degrees and h is polar angle of the stimulus in radians. The magnification factor M is the absolute value of the derivative of w; jw 0 j = jkj/jz + aj. a and k can be approximated with known corresponding points in visual field and cortical surface, a protocol previously used for example by Duncan and Boynton (2003). After assigning all functional data to individual surfaces, we first delineated the primary visual cortex and then defined the centres of the responses to the different regions of stimulus A. The surface responses were located to the weighted average 2-D position of t-values exceeding given threshold in the V1 clusters. The six V1 responses in each hemisphere with known stimulus eccentricity allowed the estimation of a and k. We first estimated a and k for each individual subject and then calculated the average of the individual values and the average magnification factor for the subjects. 3. Results 3.1. Stimulus system One approach to reach the peripheral visual field is to bring the stimulus very close to the subjects, but emmetropic subjects find difficult to accommodate closer than 25 cm. We solved this problem with +10 diopter lenses. In addition, in binocular viewing conditions we diminished the need to converge with Fresnel prisms, attached to lenses. With this system we were able to construct visual stimuli reaching about 100 diameter horizontally and 40 vertically, and we found the system reasonably comfortable to subjects and easy to use. However, location of the stimuli close to eyes and refraction of the light in the lenses and prisms made the control of stimulus size and eccentricity with the binocular stimulus challenging. In addition, visual acuity in periphery and the resolution of the display were modest (512 pixels in the 14 cm horizontal field of view). The low resolution of the stimulus and thus the lack of high spatial frequencies may diminish responses to central visual field stimulation.

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Low stimulus resolution has most likely only minor influence in the visual field periphery, where the cone and ganglion cell densities are reduced and receptive fields of the ganglion cells are larger (for a review, see Dacey, 1994). Despite careful control of external reflections of the stimuli, the Fresnel prisms, used in the binocular conditions, lowered the quality of the image and reflected minor part of the most peripheral stimulation to hemiretina ipsilateral to stimulation. These reflections were examined with light originating from a point source. The reflection of light in the prisms contaminated the ipsilateral visual field quadrant across the vertical meridian, but did not spread stimulation between the upper and the lower visual fields. In the following results section, we were careful to exclude any data, which may have been contaminated with reflections. No reflections were detected from the lenses without the prisms, and thus the monocular stimuli reaching up 53 of eccentricity comprised less local aberrations and no reflections to the ipsilateral visual field. 3.2. Mapping of retinotopic visual areas in the medial surface of the occipital lobe We were able to map the medial occipital visual areas up to periphery, and mf-stimuli enabled the analysis of the results not only in 2-D surface models but also directly in 3-D and in group level. The 3-D analysis is a great advantage in clinical practice because segmentation of cortical surface for the 2-D analysis requires a high-resolution T1 image and is laborious. Normalized individual 3-D data can also be used in group level statistical analysis to examine the results in population level. However, the individual variability in 3-D location of visual areas (Hasnain et al., 1998) interferes in the group analysis of retinotopic areas. Spatial smoothing enables the analysis across subjects but it impairs the separation of responses related to a particular stimulus in different visual field regions and the accuracy of the response localisation. 3.2.1. Upper and lower visual field representations in group analysis Group analysis (n = 12) of responses (p < 0.0001, uncorrected) to stimulus A showed that retinotopic areas in medial occipital lobe extended anteriorly to PO sulcus and close to tectum. Fig. 3 visualizes the results of group level analysis and Table 1 lists the Talairach coordinates of the local response maxima in the medial part of occipital lobe likely representing V1/V2 responses. Laterally, the retinotopic areas extended from the medial occipital lobe most likely corresponding to visual areas V1, V2 and V3 to lateral part of occipital lobe. Talairach coordinates of the lateral responses were x= 44, y = 73, z = 11 and x = 38, y = 73, z = 9 which are close to location of human area V5 (Zeki et al., 1991; Watson et al., 1993). Separate upper visual field representations were found in dorsal lateral cuneus (Talairach coordinates x = 27, y = 84, z = 18 and x = 30, y = 83, z = 24), possibly corresponding acti-

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vation in the area V3A (Tootell et al., 1997), and in medial cuneus. The separate upper visual field representation in dorsal lateral cuneus emerged mainly from the most central stimuli, whereas the most peripheral stimuli activated the region in the medial cuneus, separate from the lateral cluster. Corresponding to upper visual field responses in dorsomedial occipital lobe, moderate lower visual field responses were found, in addition to robust dorsal responses, in the ventral surface of occipital lobe. This is in accordance with earlier imaging data (Wandell et al., 2005). 3.2.2. Upper and lower visual field representations in individual analysis We examined the results of stimulus A at individual level to localise the responses more precisely in 3-D and in relation to retinotopic areas in 2-D. The analysis of individual data showed that the peripheral stimulation evoked both V1 and extrastriate responses (pFWE < 0.05), which extended to anterior calcarine sulcus, lingual gyrus and PO sulcus with some individual variability. In addition, we found similar separate upper and lower visual field representations as with the group analysis. Fig. 4 visualizes the results of stimulus A for Subjects 2 and 3, overlaid on their anatomical MRIs, and Fig. 5 shows corresponding results on their 2-D surface models. Note that in 3-D the division of labour between the ventral and dorsal visual fields, indicating approximately the calcarine sulcus and thus typical V1 position, is relatively dorsal in S2 and relatively ventral in S3. Without functional localiser these subjects would be prone to errors when interpreting their V1 position. Responses to the monocular stimuli (B) confirmed the results of the binocular session (A, above). Fig. 6 visualizes the stimulus B responses of Subject 1 both in 3-D and on cortical surface. 3.2.3. Delineation of retinotopic areas on cortical surface Identification of individual retinotopic areas on cortical surface with stimuli A or B is not straightforward (Figs. 5 and 6), because they did not comprise stimulus in the cardinal meridians, which are represented at the borders of retinotopic areas (Sereno et al., 1995). We used stimuli C and D to identify the retinotopic areas and to map their internal representations on cortical surface. Fig. 7 visualizes the responses to stimuli C and D on right occipital lobes of Subjects 1 and 3. While the 16-wedge stimulus (stimulus D) comprised all regions of stimulus C, the two gave different results in extrastriate areas for the same visual field regions. Whereas meridians (stimulus C) activated robustly all levels of retinotopic areas, the full stimulus (D) did not activate V3, VP, V3A, and V4v systematically (Fig. 7). Because our multifocal design is based on general linear model and assumes linear additivity of the component responses, a missing signal in the more crowded mf-design suggests that the responses to neighbouring visual field regions in the higher areas fail to sum linearly. In design C, the horizontal meridian stimulation in central part of the visual field failed to activate dorsal V2/V3

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Fig. 3. Group results to stimulus A in three different parasagittal sections. Numbers in the upper right corners of the images indicate distances of the sections in millimetres from the midline. The black rectangles indicate upper visual field representation in the medial cuneus.

borders in four of six subjects (Fig. 7). Only the most peripheral horizontal meridian stimulation activated the dorsal V2/V3 borders in all six subjects. Interpreted most parsimoniously, the central part of the horizontal meridian in these subjects seems to be represented together with the upper visual field in the ventral V2 and VP. 3.2.4. Magnification factor for V1 We calculated the cortical magnification factor for V1 with the formula M = jkj/jz + aj for six subjects whose

responses to stimulus A were analysed on cortical surface. Estimated values for k and a were approximately k = 16.8813 and a = 0.5242 (the average for both hemispheres of six subjects). The relationship between the visual field position and the inverse of the magnification factor is often described as 1/M = jz + aj/jkj, z represents visual field location. Thus, assuming that magnification factor depends only on the eccentricity of the stimulus, in our calculations 1/M = 0.0592E + 0.0310, where E is visual field eccentricity.

Table 1 Talairach coordinates and t-values of the local signal maxima in the medial part of the occipital lobe Contralateral visual field location

Lower Upper Lower Upper Lower Upper

1–12 1–12 12–30 12–30 30–49 30–49

Group level results for stimulus A.

Right hemisphere

Left hemisphere

x

y

z

t-value

x

y

z

t-value

12 12 9 12 15 15

84 78 80 67 66 52

10 7 26 3 20 3

9.46 13.46 12.20 22.65 11.20 13.46

6 9 12 12 18 21

84 79 89 67 69 58

4 6 24 3 15 6

13.75 8.65 6.56 19.92 7.33 11.70

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Fig. 4. Individual results to stimulus A for Subjects 2 and 3 in three parasagittal sections of left hemispheres. Numbers in the upper right corners of the images indicate distances of the sections in millimetres from the midline. Note the major individual variability in the absolute positions of the responses.

3.3. Comparison of multifocal and phase-encoded mapping The horizontal and vertical meridian positions were comparable between the multifocal (stimulus C) and phase-encoded mapping (Fig. 7). In addition, in both subjects measured with the mf-stimulus covering the full polar cycle with 16 wedges (stimulus D), the two methods resulted in similar response distribution in V1 (Fig. 7, two columns on the right). Note that whereas the phaseencoded display interpolates the phases (colours) of neighbouring active voxels thus assuming smooth transient in visual field representation, our visualization of the mfresults avoids this assumption and bluntly shows the strongest cluster assigned on the surface separately and partly on top of weaker t-values from the other clusters. This results in patchy activation and areas with no activation above threshold. The more central responses to the phase-encoded stimuli are most likely due to better stimulus resolution with the standard projection system (23 pixels/degree) compared to the near-view system in the mf-mapping (4.4 pixels/ degree), resulting in stronger BOLD signal and larger activation with the given threshold. In addition, the responses to the phase-encoded stimuli reached further anterior, corresponding to more peripheral representation, than the responses to the central mf-stimulus of approximately same size.

3.4. Separate peripheral upper visual field representation in the dorsal parieto-occipital sulcus The group analysis showed separate upper visual field representations in the medial posterior bank of parietooccipital sulcus (Fig. 3, black rectangles). Talairach coordinates of the local response maxima were x = 12, y = 77, z = 37 and x = 18, y = 77, z = 34. Only the most peripheral stimuli activated these regions. In 3-D, these clusters were situated laterally from the peripheral lower visual field representation. In the individual data, nine of twelve subjects had separate upper visual field responses (pFWE < 0.05) bilaterally in the posterior bank of PO sulcus. The average of local maxima of nine individual subjects after normalization of the data was x = 12 ± 6, y = 74 ± 7, z = 30 ± 8, t-value = 11.39 ± 5.88 and x = 12 ± 6, y = 71 ± 5, z = 28 ± 5, t-value = 9.73 ± 4.43. Five of six subjects whose data were analysed on cortical surface had separate upper visual field clusters in PO sulcus (Fig. 5). These clusters were located anterior (along the surface) to peripheral V2d and V3 in the posterior bank of parieto-occipital sulci and they were partially overlapping with the most peripheral horizontal meridian responses. These upper field representations in PO sulcus are clearly separate from V3A responses (in 3D distance between the clusters was 21 mm), the latter mainly emerging for the most foveal regions in our design

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Fig. 5. Responses of Subjects 2 and 3 to stimulus A, assigned on their left medial occipital surfaces. The black lines are the borders between the retinotopic areas. The borders are estimated according to meridian representation obtained with stimulus C. The darker background visualizes the location of the parieto-occipital (PO) and calcarine (CA) sulci.

(Fig. 5). In addition, three of five subjects measured with monocular stimulus B showed separate upper visual field clusters in dorsal PO sulcus (one example subject shown in Fig. 6). 4. Discussion We developed a simple optical method that enables stimulation of the peripheral visual field in the narrow

magnet bore, and we used this stimulus system to map the retinotopic areas in the medial occipital lobe. Our results are in line with previous maps of occipital visual areas (Tootell et al., 1996; Van Essen, 2003; Orban et al., 2004), but extend to larger eccentricities. In accordance with the histological data (Rademacher et al., 1993; Amunts et al., 2000), our results show that the most peripheral representation in the retinotopic areas extends in depth through the cerebrum and the deepest activations

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Fig. 6. Results obtained with monocular stimulus of Subject 1. (a) Responses to upper and lower visual field stimuli in three parasagittal sections. (b) The responses to four upper and four lower stimulus regions on cortical surface. Black lines represent the borders between the retinotopic areas according to meridian representations (stimulus C).

Fig. 7. Phase-encoded maps (stimulus eccentricity up to 15) and the results of mf-stimulation for stimuli C and D for (threshold at t = 6 for all data). The borders between the retinotopic visual areas are drawn along the horizontal and vertical meridians or estimated between the responses (dashed line). Visual field regions corresponding to cortical responses are colour-coded in the hemicircles on the left of each graph. For the mf-stimuli, the colour on the surface reflects only the strongest response for each node with no interpolation. In the phase-encoded design the algorithm smoothes the local responses between active nodes for visualization.

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on the lower bank of the calcarine fissure are next to tectum. From our stimuli, the stimulus C (cardinal meridian stimulus) is the best for delineation of retinotopic areas, perhaps with somewhat broader wedges because the central representation was missing in the dorsal V2/V3 border, and stimulus D (full stimulus) is the best for mapping the integrity of the retinocortical pathway. We found that Fresnel prisms, which were used to help by the convergence in binocular conditions, cause non-linear aberrations of the stimuli and we suggest implementation of prism lenses instead of Fresnel prisms. Future development should increase resolution, which can be achieved e.g. by longer focal length of the projector objective. We found strong responses in visual field periphery, and we were able to map the occipital retinotopic areas up to approximately 40 of eccentricity in vertical direction and ±49 of eccentricity in horizontal direction with binocular stimuli. The monocular stimulus enabled mapping up to 53. According to cortical magnification factor (Duncan and Boynton, 2003), visual field of 50 radius corresponds to about 90% of the surface area of the primary visual cortex (calculated from the larger temporal field extending up to 90). Stimulation from centre to far periphery enables almost complete delineation of the retinotopic areas. Previous fMRI and PET studies have found responses around parieto-occipital sulcus related to for example visual motion (Dupont et al., 1994; Kleinschmidt et al., 2002), blinks (Bristow et al., 2005), and eye movements (Anderson et al., 1994; Law et al., 1998), but only the knowledge of the peripheral visual field representation enables the identification of the parieto-occipital responses in relation to the known retinotopic visual areas. MffMRI proved to be fast and reliable method for retinotopic mapping in peripheral visual field representations of V1, and it also enables delineation of extrastriate areas when a subset of visual field regions were stimulated. The mf-stimulus covering the full polar cycle (stimulus D) resulted in weak responses in extrastriate areas compared to stimulus covering only the horizontal and the vertical meridians (stimulus C). In principle with an orthogonal design, where the timing of each stimulus area is linearly independent from the other areas, such difference should not emerge. However, nonlinear interactions between visual field representations (Press et al., 2001; Vanni et al., 2004), such as saturation of a neural response when more than one neighbouring regions are stimulated in parallel, can result in weaker responses than expected. Large receptive fields, as in the extrastriate areas, could predispose to nonlinear interactions related to parallel stimulation (Kastner et al., 2001; Williams et al., 2003). The results obtained with the mf-mapping were in line with the phase-encoded data, but the phase-encoded stimulus resulted in greater activation in the representations of the central visual field, most likely because of the better resolution of the phase-encoded stimulus. The relatively poor spatial resolution of our near view system affects more

responses of neurons with small receptive fields in the central vision. However, previously the mf-method with a stimulus resolution similar to our phase-encoded design has been shown to activate also the central visual field representation (Vanni et al., 2005). In addition to differences in the central representation, the phase-encoded stimulus activated more peripheral representations than the mf-stimulus of same size. A focal cortical response, and thus a BOLD signal, may spread several millimetres probably through lateral connections (Parkes et al., 2005; Tolias et al., 2005). However, due to suppressive interactions between the regions, parallel stimulation of neighbouring areas in mf-design can reduce the apparent spread of the response. Analysis of linear cortical magnification factor in V1 showed following inverse relationship between the magnification factor M and the visual field eccentricity E; 1/ M = 0.0592E + 0.0310. This result is in line with earlier studies based on more central stimuli. Previously the estimations of the relationship between cortical magnification factor in V1 and eccentricity have resulted in M = 20.05(E + 0.08)1.26 (Sereno et al., 1995) and 1/M = 0.059E + 0.073 (Gru¨sser, 1995). Engel and co-workers (1997) found an exponential function E = exp(0.063(d + 36.54)) which describes the relationship between the eccentricity of the stimulus (E) and the distance from the representation of the 10 of eccentricity on cortical surface (d). It can be reduced into M = 15.87/E (Popovic and Sjo¨strand, 2001) or 1/M = E/15.87. Later, Duncan and Boynton (2003) described the relationship 1/M = 0.065E + 0.054. The upper and lower visual field representations were asymmetrical at the level of V2 and V3/VP (see Fig. 7). This could be also reflected into 3-D group and individual data in Figs. 3 and 4 where some ventral clusters are found after stimulating the lower visual field. As suggested earlier from a different set of data (Vanni et al., 2004), this discrepancy could be due to asymmetric division of the visual field representation, the division of labour between dorsal and ventral V2/V3 taking place few polar degrees below horizontal meridian. This would be difficult to detect with phase-encoded mapping, because visual field sign is not affected by the absolute position of the border. In addition, a quantitative model is required to estimate the absolute visual field position from phase-encoded data (Dougherty et al., 2003), and such analysis is uncommon. This result must, however, be verified with better resolution of the stimulus in the more central part of the visual field. We found a separate upper visual field representation in medial cuneus and localised this upper visual field representation in the posterior bank of parieto-occipital sulcus, anterior to dorsal V2 and V3 along the cortical surface. Previous magnetoencephalography studies have found early visually evoked potentials in medial cuneus (Tzelepi et al., 2001; Vanni et al., 2001), and a lesion close to this region has been shown to result in motion blindness (Blanke et al., 2003) and in selective impairment in detec-

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tion of frequency-doubling stimuli (Castelo-Branco et al., 2006). Pitzalis and co-workers (2006) showed that posterior bank of PO sulcus contains a retinotopic area with both upper and lower visual field representations (Talairach coordinates of the area were x = 11, y = 72, z = 46). On the basis of location, position in respect to the other extrastriate areas, and retinotopic organization they proposed that this new area in PO sulcus is a human homologue of monkey V6. In accordance with previous research (Jousma¨ki et al., 1996; Portin et al., 1998; Pitzalis et al., 2006), we suggest that the human V6 is located in the dorsal posterior bank of the PO sulcus. The lower visual field representation of putative V6 in our data is difficult to separate from the most peripheral part of the V2d and V3 responses, and thus the upper visual field representation in this location serves as the indicator of human V6. The positions of V6 varied between subjects (standard deviations of the V6 coordinates were 5–8 mm). This variation is in line with previous results of intersubject variability of V6 (Pitzalis et al., 2006) and other retinotopic areas (Hasnain et al., 1998). In contrast to location of V6 in dorsal PO region, human V6 has been positioned also in more ventral part of PO sulcus according to visual (Dechent and Frahm, 2003; Stiers et al., 2006) and visuomotor (de Jong et al., 2001) responses. However, our results suggest that the more ventral part of PO sulcus may contain peripheral V1 responses, as the retinotopic mapping with wide stimuli reveals peripheral visual field representations of areas V1 and V2 to extend into ventral PO sulcus (see Table 1 and Figs. 3 and 4). In monkeys, V6 is retinotopically organized with contralateral representation. Its cells have large receptive fields extending up to 80, with relatively less emphasis on the central vision (Galletti et al., 1999). Our results are in line with these findings; the V6 response emerges for the most peripheral stimulus, from approximately 30 to 50 of eccentricity. The location of our V6 and even more ventral part of PO sulcus has earlier been associated with putative V6A (de Jong et al., 2001; Dechent and Frahm, 2003). In monkeys V6A is located dorsal to V6 at the anterior bank of the PO sulcus, it has no clear retinotopic organization and it contains also visually unresponsive neurons (Galletti et al., 1996). The human homologue of V6A has also been placed to superior parietal lobule (Simon et al., 2002) and to occipito-parietal junction (Prado et al., 2005) next to our V6. However, due to lack of retinotopy in V6A we were not able to delineate human V6A with our purely visual retinotopic stimuli as expected. We showed a new method to stimulate the wide visual field in magnet bore, and we were able to map the representation of the visual field periphery. Our stimulation method was simple and effective. Reflection and dispersion of the peripheral light in the Fresnel prisms could be measured with a point light source and such reflections were excluded in the monocular system were the prisms were not imple-

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mented. In the future we plan to develop the optical properties of the system and try to build a more versatile setup enabling higher resolution stimulation in different types of head coils. Development of the mf-design by including differing stimulus parameters in neighbouring visual field regions should enable reduction of surround suppression, and thus more complete set of responses not only from the striate, but also from the extrastriate, areas. With these developments, visual fMRI could become a clinical tool not only for probing the retinocortical pathway and preoperative mapping of the V1, but also for quantitative parametric studies of striate and extrastriate visual cortical functions. Acknowledgments We thank Marita Kattelus, Linda Henriksson and Antti Tarkiainen for technical support, Vesa Viljanen (KEOPS Ltd.) and Tero Seta¨la¨ for help with optics, INSERM unit 594/Universite` Joseph Fourier, Grenoble, France, for providing Brain a´ la Carte toolbox. In addition, we want to thank Claudio Galletti, Patrizia Fattori and Jaakko Eskelinen for valuable discussions, and Andrew James and Linda Henriksson for helping to design multifocal fMRI approach. This study has been supported by the Academy of Finland Grant No. 105628 and National Programme for Centres of Excellence (2006–2011), and by the Sigrid Juse´lius Foundation. References Amunts K, Malikovic A, Mohlberg H, Schormann T, Zilles K. Brodmann’s areas 17 and 18 brought into stereotaxic space – where and how variable? NeuroImage 2000;11:66–84. Anderson TJ, Jenkins IH, Brooks DJ, Hawken MB, Frackowiak RSJ, Kennard C. Cortical control of saccades and fixation in man, a PET study. Brain 1994;117:1073–84. Blanke O, Landis T, Mermoud C, Spinelli L, Safran AB. Directionselective motion blindness after unilateral posterior brain damage. Eur J Neurosci 2003;18:709–22. Bristow D, Frith C, Rees G. Two distinct neural effects of blinking on human visual processing. NeuroImage 2005;27:136–45. Castelo-Branco M, Mendes M, Silva MF, Janua´rio C, Machado E, Pinto A, et al. Specific retinotopically based magnocellular impairment in a patient with medial visual dorsal stream damage. Neuropsychologia 2006;44:238–53. Dacey DM. Physiology, morphology and spatial densities of identified ganglion cell types in primate retina. Higher-order processing in the visual system Ciba Foundation Symposium 1994; 184: 12–34. de Jong BM, van der Graaf FHCE, Paans AMJ. Brain activation related to the representations of external space and body scheme in visuomotor control. NeuroImage 2001;14:1128–35. Dechent P, Frahm J. Characterization of the human visual V6 complex by functional magnetic resonance imaging. Eur J Neurosci 2003;17:2201–11. DeYoe EA, Carman GJ, Bandettini P, Glickman S, Wieser J, Cox R, et al. Mapping striate and extrastriate visual areas in human cerebral cortex. Proc Natl Acad Sci USA 1996;93:2382–6. Dougherty RF, Koch VM, Brewer AA, Fischer B, Modersitzki J, Wandell BA. Visual field representations and locations of visual areas V1/2/3 in human visual cortex. J Vis 2003;3:586–98.

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