Atypical Retinotopic Organization of Visual Cortex in Patients with Central Brain Damage: Congenital and Adult Onset

Retinotopic maps in healthy subjects primarily represent the contralateral field

As a control condition, we performed fMRI-based visual field mapping in six healthy subjects to characterize the normal ipsilateral field representation. Figure 2 summarizes our findings for a representative healthy control subject (C1). Voxels that were activated by a rotating checkered wedge stimulus are color coded to show their preferred stimulus polar angle and displayed as an overlay on spherically inflated cortical surface models of each hemisphere (Fig. 2A,E). Both hemispheres were primarily activated by stimuli in the contralateral (opposite) visual hemifield but also had a small amount of activation extending along the vertical meridian into the ipsilateral (same-side) field. For instance, the left hemisphere (Fig. 2A) contained representations of the right visual field (red-oranges, yellow-greens) and the vertical meridian (white solid lines) with a very small representation of the ipsilateral field (blue-purples and darker greens). Notably, the ipsilateral field representation can be difficult to detect within visual areas V1–V3. Since spatial and temporal “smoothing” during common postprocessing methods may contribute to this effect, smoothed flat maps are only used here for display purposes, and all quantitative analyses (see below) were based on the unsmoothed 3D volumetric data. As an analysis tool, the normally small size of the ipsilateral field representation within healthy subjects enables any additions within patients to be particularly apparent.

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Figure 2.

Polar angle retinotopy for C1. A, E, Color-coded polar angle maps from the left (A) and right (E) hemispheres displayed on partially inflated (left) and spherical (right) cortical surface models (posterior pole: white star). Visual area boundaries are marked by representations of the horizontal (dotted white) and vertical (solid white) meridian representations. B, F, Functional field maps depicting a back-projection of the retinotopic maps from the left (B) and right (F) hemispheres onto maps of C1's visual field. Each circle in the FFMap is associated with a voxel in the brain that was maximally activated by a stimulus at the symbol's location in the visual field. The color of the symbols is as for A and E. C, G, Polar histograms depicting the amount (in cubic millimeters) of brain tissue (voxels) in the left (C) and right (G) hemispheres representing different angular positions in the visual field of C1 (gray shading) and averaged for all healthy controls (light blue shading, dotted lines show ±SEM). D, H, Bar graphs depicting the total amount of tissue representing each visual hemifield in the left (D) and right (H) hemispheres of C1 (gray shading) and averaged for all healthy controls (light blue shading; error bars indicate ±SEM). L, Left; R, right; RH, right hemisphere; LH, left hemisphere.

Retinotopic maps for this same subject showing voxels activated by the expanding ring stimuli and color coded by visual field eccentricity are depicted as an overlay on spherically inflated cortical surface models in Figure 3. Note the mirror symmetric representations of visual field eccentricity between hemispheres and the large cortical magnification of the center of gaze (reds, oranges) near the occipital pole (white star) compared with more peripheral eccentricities (greens, blues). To visualize relationships between the cortical retinotopic maps and the subject's visual field, we used the polar angle and eccentricity data to back-project the retinotopic maps from each hemisphere onto a map of the subject's visual field, as illustrated in Figure 2, B and F. Each circle symbol has a one-to-one relationship with a voxel in the early visual cortex VOI (Fig. 1, red outline, row C1) that was activated by both the rotating wedge and expanding ring stimuli. In correspondence with Figure 2, A and E, symbols are color coded by visual field polar angle. As expected, the resulting functional field maps showed a full representation of the contralateral visual field (within the tested eccentricities) in each hemisphere. The ipsilateral field locations that maximally activated voxels in visual cortex were also apparent. For instance, the left hemisphere functional field map (Fig. 2B) contained a fairly uniform distribution of symbols mostly restricted to the right side of the map and a small number of symbols extending into the ipsilateral field along the vertical meridian. Note that the diameter of each symbol reflects a 70% confidence interval for the true visual field location and are not an estimate of population receptive field size.

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Figure 3.

Eccentricity maps for healthy control (C1). Color-coded eccentricity maps from the left (top) and right (bottom) hemispheres of C1 displayed on spherical cortical surface models (posterior pole: white star). Visual area boundaries are as in Figure 2, A and E. RH, Right hemisphere; LH, left hemisphere.

To quantify the ipsilateral representation and its range of variability within healthy subjects, we converted the functional field maps into polar histograms that show the amount (in cubic millimeters) of brain tissue (voxels) representing different angular positions in the subject's visual field (Fig. 2C,G). The majority of early visual cortex in each hemisphere of C1 (Fig. 2C,G, gray shading) and the control group as a whole (Fig. 2C,G, light blue shading) was devoted to representation of the contralateral field, but a small amount of tissue was devoted to the ipsilateral field, particularly near the vertical meridian. Not only was the amount of activation in the contralateral field larger than in the ipsilateral field, but the variability also was larger (Fig. 2C,G, black dashed lines: ±SEM). Note that, to create the average polar histogram for control subjects (Fig. 2C,G, light blue shading), data were pooled from both hemispheres after “flipping” the field representation of one hemisphere. The same average histogram is shown in Figure 2, C and G, but is “mirrored” across the vertical meridian. The total amount of activation for each visual hemifield was summed and displayed as a bar graph (Fig. 2D,H). On average for the control group, 10% of the tissue in the early visual cortex VOIs represented the ipsilateral field (1519 ± 165 mm³) compared with the contralateral field (15,075 ± 1065 mm³).

Patients had diverse central pathologies, ages of onset, and retinotopic maps

From an initial dataset of 45 patients with brain pathology, 27 patients were selected with clear anatomical evidence of pathology involving visual cortex and/or underlying white matter tracts. As detailed in Table 1, 2 patients (P2, P27) had congenital cerebral malformations, and the remaining 25 patients had adult-onset pathologies including the following: arteriovenous malformation (AVM), epilepsy, stroke, tumor, trauma, and surgically induced collateral damage. The pathology resulted in direct damage to visual cortex within the VOI (generally V1–V3) in 15 patients [Table 1, direct damage (DD) = yes]. The involved hemisphere was functionally “disconnected” from the opposite hemisphere (e.g., it was mostly nonfunctional or had a developmental absence of a corpus callosum) in seven patients [Table 1, functional disconnection (Func Dis) = yes]. The mean patient age at the time of study was 39.7 years (SD = 12.6 years). The time between the onset of pathology (for known cases, n = 8) and the time of study ranged from 0.5 to 25 years (mean = 8.3 years, SD = 8.2 years).

Using the same fMRI-based analyses in patients as those used for the healthy control subjects (see above), the retinotopic organization of visual cortex was examined in all 27 patients for gross evidence of anomalies in the ipsilateral field representation. Initial screening was based on a manual, qualitative inspection of retinotopically encoded fMRI activation within each hemisphere of each patient independently. Briefly, we observed three different retinotopic outcomes in patients: (1) 3 patients had atypical [Table 1, atypical (type A)] retinotopic organization consisting of an expanded ipsilateral field representation compared with healthy controls; (2) another 22 patients had typical (type T) retinotopic organization compared with healthy subjects, except for the presence of retinotopic deletions related to their pathologies; and (3) the 2 remaining patients had evidence for pathology-related hemodynamic artifacts (type X) in their retinotopic maps, defined as BOLD activation that was not reflective of the underlying neural network, and were subsequently removed from further analysis. Both of the latter patients had pathology affecting the normal hemodynamics within visual cortex and, unlike type A patients, had clusters of topographically inconsistent fMRI activation in these regions of cortex that were equally affected in the eccentricity and polar angle task data (i.e., the delay values of voxels in each task were offset by the same amount).

A subset of patients with central damage had an expanded ipsilateral field representation

Patient 1: surgically induced collateral damage

P1 was a 37-year-old female with epileptic foci. She underwent a temporal–occipital resection of the right hemisphere including partial resection of the optic radiations (Fig. 1, void, row P1). Only a portion of medial visual cortex remained intact within the right hemisphere (Fig. 4E, black patch depicts damaged brain region) and was primarily activated by regions of the contralateral field (Fig. 4F, greens, cyans, blues) at peripheral eccentricities (Fig. 5A, bottom row). (Note that the reds and yellows on the cortical surface model in Fig. 4E appear to be a partial volume effect from the opposite hemisphere and were eliminated by the VOI mask used for the FFMaps and quantitative analysis). The FFMap in Figure 4F, a back-projection of the visual activation in the right hemisphere, corresponds to the central 9° of visual field perimetry in Figure 5B (blue dotted outline). The FFMap symbols correspond to regions of the visual field in which the patient's behavioral sensitivity to points of flashed light was degraded or absent (Fig. 5B, black patches in left hemifield). Given the extensive damage to the right hemisphere, visual activation may have been disconnected from behavioral awareness at higher stages in the visual pathway. Quantitatively, the amount of visual activation within this hemisphere was minute (Fig. 4G,H, gray shading) compared with normal controls (Fig. 4G,H, light blue shading), reflecting the effects of direct damage to that hemisphere.

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Figure 4.

Polar angle retinotopy for patient with surgical ablation of epileptic focus in right hemisphere (P1). A–H, Figure layout is the same as in Figure 2, with the following exceptions. A, Black dashed outlines indicate approximate location of expanded ipsilateral representation. B, Black dashed outlines highlight inset showing expanded ipsilateral representation especially near fovea. B, F, Blue dashed outlines encircle the regions corresponding with the visual field perimetry in Figure 5B. E, Dark shading indicates regions of brain damage. Location of V1 in the right hemisphere was estimated by fundus of calcarine sulcus. RH, Right hemisphere; LH, left hemisphere.

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Figure 5.

Eccentricity maps and perimetry for P1. A, Figure panel layout is the same as in Figure 3, except that the black dashed outline and visual area boundaries are as in Figure 4A, E. B, VAP 10-2 test (based on the Humphrey 10-2 perimetry) performed binocularly (both eyes together). Gray scale indicates the relative visual sensitivity from 0 to 1. Blue dashed outline encircles the region corresponding with the FFMaps in Figure 4, B and F. L, Left field; R, right field; S, superior field; I, inferior field; RH, right hemisphere; LH, left hemisphere.

This patient's left hemisphere was anatomically intact and contained a retinotopic map of the contralateral field (Fig. 4A, magentas, red-oranges, yellow-greens), but with the addition of an atypical ipsilateral field representation (purples, blues, and greens, highlighted by black dashed outline) involving the central visual field (Fig. 5A, top, reds, oranges, yellows). The atypical representation extended ∼1.5° into the left visual field along the vertical meridian (Fig. 4B) and corresponds to the patient's remaining behavioral sensitivity in the left hemifield near the visual midline (Fig. 5B, white strip). While the right hemisphere would normally support this region, we noted above that this patient's damaged right hemisphere did not contain a significant representation of this portion of the visual field (Fig. 4F). Quantitatively, the left hemisphere had a markedly larger representation of the ipsilateral (left) hemifield compared with healthy controls (Fig. 4C,D, left field, gray vs blue: 5850 vs 1519 ± 165 mm³). Moreover, this larger ipsilateral field representation was accompanied by a smaller contralateral (right) field representation relative to controls (Fig. 4C,D, right field, gray vs blue: 12,488 vs 15,075 ± 1065 mm³), even though this hemisphere was anatomically intact.

Patient 2: congenital cerebral malformation

P2 was a 19-year-old acallosal female with congenital cerebral malformation and chronic epilepsy. Both parietal and occipital lobes were hypergyrated and malformed around a central expanded ventricle/void (Fig. 1, row P2). In the right hemisphere, despite the grossly distorted cortical surface, the topography of the polar angle (Fig. 6E) and eccentricity (Fig. 7A, bottom row) remained largely intact and comparable to that in healthy subjects. Typical sign reversals in the polar angle representation allowed the delineation of dorsal visual areas V1–V3 and ventral visual areas V1–V2 (Fig. 6E), which together contained a representation of the entire contralateral (left) hemifield (Fig. 6F). Quantitatively, the relative distribution of activation across angular locations in the visual field (Fig. 6G) was comparable to controls, though the total amount of visual activation was smaller (Fig. 6H, gray vs blue). This difference in total volume may reflect an overall reduction in occipital cortical tissue as a result of the cerebral malformation.

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Figure 6.

Polar angle retinotopy for patient with congenital cerebral malformation (P2). A–H, Figure layout is the same as in Figure 2, with the following exceptions. A, Black dashed outlines indicate the approximate location of expanded ipsilateral representation. B, Black dashed outlines highlight inset showing expanded ipsilateral representation especially near fovea. B, F, Blue dashed outlines encircle the regions corresponding with the visual field perimetry in Figure 7B. RH, Right hemisphere; LH, left hemisphere.

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Figure 7.

Eccentricity maps and microperimetry for P2. A, Figure panel layout is the same as in Figure 3, except that the black dashed outline and visual area boundaries are as in Figure 6A, E. B, Monocular microperimetry plots (LE, left eye; RE, right eye) based on HFA modified 10-2 test presented with an OPKO microperimeter. The color scale for perimetry test points indicates the relative visual sensitivity, from 0 to 1. Perimetry data points are overlaid on SLO retinal images, which are oriented to correspond to visual field locations. Fixation scatter is indicated by group of yellow and blue + symbols. Blue dashed outlines encircle the regions corresponding with the FFMaps in Figure 6, B and F. L, Left field; R, right field; S, superior field; I, inferior field; RH, right hemisphere; LH, left hemisphere.

In contrast to the right hemisphere, the left hemisphere of P2 contained gross distortions of both the cortical surface (Fig. 1, row P2) and the retinotopic organization in the polar angle maps (Fig. 6A, black dashed outline). Only visual areas V1 and ventral V2–V3 could be estimated from sign reversals in the contralateral (right) visual field representation. In healthy individuals, the dorsal V1/V2 boundary is typically associated with a field sign reversal and a progression within V2 back toward the horizontal meridian (Fig. 2A). However, in P2, the map does not change sign but progresses (counterclockwise in Fig. 2) through an expanded representation of the lower right quadrant (red-oranges) with a seamless transition into the left hemifield inferior quadrant (purples, blues) and then into the left superior quadrant (cyans, greens). This atypical, yet coherent progression thus constitutes a complete, ordered transit through both hemifields. However, the ipsilateral representation was primarily associated with central eccentricities (Fig. 7A, black dashed outline). In the FFMap (Fig. 6B, black dashed outline), this appears as symbols populating the left central field except near the vertical meridian, where it expanded more peripherally. Since these visual field regions were also represented in the right hemisphere (Fig. 6, compare B, F), we were not able to determine unequivocally whether the atypical representation was contributing to the patient's visual sensitivity to these regions during microperimetry testing, as shown in Figure 7B by the green dots in the left hemifield that are superimposed onto images of the retina of this patient. (The microperimetry in Fig. 7B corresponds to the central 7° of the FFMaps in Fig. 6 B,F, indicated by the blue dotted outline. Retinal images are shown for the left and right eyes, tested separately, and have been oriented to reflect visual field space, as is typically done for conventional perimetry displays.) Quantitatively, the amount of ipsilateral (left) field activation in the left hemisphere was larger than observed in healthy controls (Fig. 6C,D, left field, gray vs blue: 3881 vs 1519 ± 165 mm³). As in the first patient, the enlarged representation of the ipsilateral field in this hemisphere was accompanied by a smaller representation of the contralateral field (Fig. 6C,D, right field, gray vs blue: 7256 vs 15,075 ± 1065 mm³).

Patient 3: brain tumor

Figure 8 summarizes the results for P3, a 52-year-old male with an anaplastic astrocytoma and compromised tissue in the left occipital, parietal, and temporal lobes (Figs. 1, row P3, 8A, white dashed outline). Since the extensive cortical damage prevented construction of a cortical surface model for the left hemisphere, anatomical MR images showing three views are displayed instead. The fMRI overlay is color coded by the visual field polar angle (Fig. 8A). A small region of cortex in the left hemisphere (Fig. 8A, green crosshairs) was activated appropriately by stimuli in the upper right visual quadrant between 12° and 21° in eccentricity (Fig. 8B). But, the patient responded unreliably to stimuli in this quadrant during perimetry testing (Fig. 9B). (The FFMap in Fig. 8B corresponds to the central 21° of the perimetry from Fig. 9B,F, as indicated by the blue dotted outlines. Perimetry is shown for the left and right eyes tested separately.) Quantitatively, the amount of visual activation within the left hemisphere was minute compared with normal controls (Fig. 8C,D, gray vs blue).

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Figure 8.

Polar angle retinotopy for patient with a brain tumor in left hemisphere (P3). A–H, Figure layout is the same as in Figure 2, with the following exceptions. A, Extensive left hemisphere damage prevented construction of a cortical surface model, so three anatomical views of color-coded polar angle maps are displayed. White dashed outline shows the region of cortical damage. L, Left; R, right; S, superior; I, inferior; A, anterior; P, posterior; RH, right hemisphere; LH, left hemisphere. E, Black dashed outlines indicate the approximate location of expanded ipsilateral representation. F, Black dashed outlines highlight the inset showing expanded ipsilateral representation, especially near the vertical meridian. B, F, Blue dashed outlines encircle the regions corresponding with the visual field perimetry in Figure 9B.

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Figure 9.

Eccentricity maps and perimetry for P3. A, Figure panel layout is the same as in Figure 3, with the following exceptions. A, Top row, Extensive left hemisphere damage prevented construction of cortical surface model, so three views of anatomical color-coded eccentricity maps are displayed. White dashed outline shows region of cortical damage. L, Left; R, right; S, superior; I, inferior; A, anterior; P, posterior. A, Bottom row, Black dashed outline and visual area boundaries as in Figure 8E. B, Monocular Humphrey 30–2 perimetry plots (LE, left eye; RE, right eye). Gray scale indicates the relative visual sensitivity, from 0 to 1. Blue dashed outlines encircle the regions corresponding with the FFMaps in Figure 8, B and F. L, Left field; R, right field; S, superior field; I, inferior field; RH, right hemisphere; LH, left hemisphere.

The right hemisphere of this patient was anatomically intact and contained a full retinotopic map of the contralateral field (Fig. 8E, purples, blues, greens) but with an apparently expanded representation of the ipsilateral field (Fig. 8E, reds, oranges). In contrast to P1 and P2, the ipsilateral field expansion appeared integrated within the normal vertical meridian representations of the contralateral field, rather than as a topographically displaced (ectopic) zone. This is perhaps more evident in the functional field map (Fig. 8F), which shows the expanded ipsilateral representation extending from the center of gaze to approximately 10° eccentricity in the lower right quadrant (black dashed outline) and clustered between 8° and 21° in eccentricity in the upper right quadrant. As already noted, the patient did not respond reliably to points of light flashed in the right visual field, though some degraded visual sensitivity may have remained (Fig. 9B, white patches in right hemifield). Quantitatively, the contralateral (left) visual field representation in the right hemisphere was comparable to healthy controls (Fig. 8G,H, left field, gray vs blue: 15,694 vs 15,075 ± 1065 mm³), but the ipsilateral (right) field representation was markedly larger than controls (Fig. 8G,H, right field, gray vs blue: 4838 vs 1519 ± 165 mm³).

Group-level analysis

We performed a quantitative, group-level analysis of the ipsilateral field representation to test the significance of the atypical organization in hemispheres from patients P1–P3 compared with healthy subjects (Fig. 10A,B, IPS, red vs light blue shading). On average, the amount of tissue activated by the ipsilateral field in hemispheres with atypical organization was 3.2 times larger than in healthy controls (Fig. 10B, IPS, red vs light blue shading: 4838 ± 572 vs 1519 ± 165 mm³). The distributions of the volume of cortex activated by the ipsilateral hemifield were significantly different between groups (two-tailed Wilcoxon rank sums, n_A = 3, n_C = 12, W = 42, p = 0.004). Moreover, no hemisphere of any individual healthy control had an ipsilateral representation as large as those in the atypical patients (controls, 788–2363 mm³; atypical patients, 3881–5850 mm³).

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Figure 10.

Fixation records for patients P1 and P2 with atypical cortical organization. A, B, Fixation samples (small blue + symbols) superimposed on SLO retinal images of P1 (A) and P2 (B). Red + symbol denotes the average fixation location during the 5–7 min sample period. Large white crosshairs denote the center of the foveal pit as determined by OCT images shown below and to the left and right of SLO images. Inner and outer white circles shows the 2°, and 4° radii from the foveal pit. S, Superior; I, inferior; T, temporal; N, nasal.

The amount of gray matter in human visual cortex can vary by at least twofold to threefold (Duncan and Boynton, 2003). We reasoned that hemispheres with a greater volume of visually activated cortex would have a generalized expansion of the polar histogram such that both the ipsilateral and contralateral representations would be expanded. Conceivably, our three patients with retinotopic anomalies might have had larger brains. However, it is important to point out that the polar histograms from hemispheres with retinotopic additions (red shading) did not demonstrate a uniform scaling compared with healthy controls (light blue shading), but rather a differential positive scaling of the ipsilateral field and negative scaling of the contralateral representation. On average, the total amount of visually activated cortex (ipsilateral plus contralateral fields) was 16,651 ± 2837 mm³ in atypical patients and 16,594 ± 1133 mm³ in healthy controls. The distributions of the total volume of activated cortex were not significantly different between groups (two-tailed Wilcoxon rank sums, n_A = 3, n_C = 12, W = 24.5, p = 0.9626). Thus, there was no single multiplicative scaling factor that could be applied to the histograms from anomalous hemispheres that would make them comparable to those of the healthy controls.

Additionally, our results were not dependent upon minor differences that might have occurred in the VOI boundaries between atypical patients and healthy controls. To confirm that the VOIs in healthy controls were not “missing” tissue activated by the ipsilateral field (e.g., in a higher visual area) that might have been included in atypical patients, the same set of analyses described previously were repeated in healthy controls except using expanded VOIs that included all of visual cortex. We observed a scaling of the total amount of visual activation in both the ipsilateral and contralateral visual field, rather than a selective increase of the ipsilateral field. Particularly, the amount of tissue activated by the ipsilateral field in controls with expanded VOIs was 2081 ± 285 mm³ compared with the 4838 ± 572 mm³ in atypical patients (Fig. 10A,B, IPS, dark blue vs red). The distributions of the volume of cortex activated by the ipsilateral field remained significantly different between groups (two-tailed Wilcoxon rank sums, n_A = 3, n_C = 12, W = 41, p = 0.009).

Majority of patients with central damage had typical retinotopic organization

The remaining 22 patients had typical retinotopic organization compared with healthy subjects except for the presence of retinotopic deletions caused by their pathologies. While hemispheres with direct damage did contain “deletions” within their retinotopic maps, the topography for the remainder of the map was comparable to healthy controls. As an alternate control group, an averaged polar histogram was computed from the hemispheres of patients with typical retinotopic organization that did not contain direct pathology (Fig. 10C,D, typical patients shaded light yellow). Compared with healthy controls, patient hemispheres with typical organization had a generally smaller amount of tissue activated by both the ipsilateral and contralateral fields (Fig. 10D, light yellow vs blue; IPS: 1242 ± 173 vs 1519 ± 165 mm³; CON: 10,164 ± 757 vs 15,075 ± 1065 mm³). While the distributions of the volume of cortex activated by the ipsilateral field were not significantly different between groups (two-tailed Wilcoxon rank sums, n_C = 12, n_T = 22, W = 247, z = 1.318, p = 0.187), the distributions of the volume of cortex activated by the contralateral field differed significantly between groups (two-tailed Wilcoxon rank sums, n_C = 12, n_T = 22, W = 303, z = 3.334, p = 0.001).

We predicted that visual cortex in typical patients may tend to be less responsive during the fMRI task, regardless of visual hemifield. We hypothesized that, if this were the case, the differences between typical patients and healthy controls could be removed by applying a single scaling factor to both the ipsilateral and contralateral field representations of typical patients. To test this hypothesis, we normalized the contralateral field histogram of typical patients to that of healthy controls. This required a scaling factor of ∼1.5, which was then applied to the ipsilateral field histogram of typical patients. After this step, no significant differences remained between the typical patients (Fig. 10C,D, normalized typical patients, dark yellow; IPS: 1842 ± 257 mm³; CON: 15,075 ± 1123 mm³) and healthy controls in the distributions of the volume of cortex activated by each hemifield (two-tailed Wilcoxon rank sums, n_C = 12, n_TN = 22; IPS: W = 198, z = −0.433, p = 0.665; CON: W = 213, z = −0.090, p = 0.928). This suggests that most patients with pathology of one hemisphere tended to have topographically normal retinotopic organization in the unaffected hemisphere, though with uniformly less fMRI activation overall.

Last, almost none of the typical patient cases were anatomically and functionally comparable to those of atypical patients. To review, all three atypical patients had evidence for a substantial functional “disconnection” of the vertical meridian representations between hemispheres, due to either (1) a mostly nonfunctional visual cortex (evidenced by the lack of BOLD-fMRI activation and visual field perimetry response) and direct damage within the visual cortex VOI (P1 and P3), or (2) the developmental absence of a corpus callosum (P1). While five patients (P4–P9) with typical retinotopic organization contained a hemisphere that was mostly nonfunctional (Table 1, Func Dis = yes), the pathology in three of the five patients (P6–P9) did not result in direct damage within the visual cortex VOI (Table 1, DD = no). Rather, these patients had damage to the LGN and/or optic radiations that removed the afferent drive to visual cortex. In the other two of five patients (P4 and P5), the pathology resulted in direct damage within the visual cortex VOI (Table 1, DD = yes). Interestingly, though, both of these patients had ipsilateral field representations (P4, 3263 mm³; P5, 3431 mm³) that trended toward atypical: they were substantially larger than that of any healthy subject (788–2363 mm³), though not as large as that of any patient hemisphere in our atypical group (3881–5850 mm³). These findings suggest that simply removing the retino-geniculate input may not be sufficient to acquire an expanded ipsilateral field representation. In such cases, the remaining intrinsic activation within the intact cortex may be sufficient to prevent initial unmasking of the ipsilateral field. Therefore, although two hemispheres can appear to be nonfunctional because they lack fMRI response and the patients have a hemianopia, their potential for expansion of the ipsilateral field representation may be quite different given the underlying pathology/anatomical involvement.

Expanded ipsilateral field representation in atypical patients was not accounted for by eccentric fixation

An important concern is that abnormal fixation in patients with visual pathology could cause artifactual distortions in visual field maps measured with fMRI. Use of a nonfoveal region for fixation, termed an eccentric preferred retinal locus (PRL), is a common adaptive strategy of patients with central visual field deficits. The PRL allows them to place more of the scene of interest within the intact portion of their visual field (for review, see Crossland et al., 2011). While a normal subject will use their central fovea to fixate the center of a visual display, a patient that uses a PRL to the right of their fovea will rotate their eyes to the left to place their PRL at the center of the display. This creates an asymmetrical representation of the visual display on the retina and, consequently, could create an apparent asymmetry in the measured cortical representation (Baseler et al., 2002).

The use of an eccentric PRL, however, is not consistent with the results of our study. Patients can be classified as having predominately normal central fixation if >50% of their preferred fixation points fall within 2° of the fovea (Fujii et al., 2003). We used an OPKO combined SLO with OCT and microperimetry to track fixation on the retina of two patients with atypical organization (the third patient was no longer available) and found that both had predominately normal central fixation (70–81% of fixation points fell within a 2° diameter of the fovea). More specifically, for both eyes of P1, the centroid of fixation (Fig. 11A, red + symbol) was 0.64° to the left of the central foveal pit (white crosshair) identified in OCT. The average distance of fixation points (blue + symbols) from the centroid was 0.38 ± 0.06° in the left eye and 0.46 ± 0.11° in the right eye. For P2, the centroid of fixation (Fig. 11B, red + symbol) was 0.33° to the left of the central foveal pit (white crosshair) in the left eye and 0.27° to the right in the right eye. The average distance of fixation points (blue + symbols) from the centroid was 0.66 ± 0.05° in the left eye and 0.75 ± 0.05° in the right eye. Note that the direction of fixation in the right eye of P2 is in the opposite direction to that which, if large enough, could theoretically create an artifactual asymmetry involving an expanded representation of the left hemifield in the left hemisphere (as observed in this patient).

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Figure 11.

Patients with atypical cortical organization have larger ipsilateral field representations. A, B, Group-averaged polar histograms and bar graphs for hemispheres from patients with atypical retinotopic organization (red shading, n = 3), healthy controls (light blue shading, n = 12), and healthy controls with expanded VOIs including all of visual cortex (dark blue shading, n = 12). Black dashed lines in the inset in A and error bars in B show ±SEM. C, D, Group-averaged polar histograms and bar graphs for hemispheres from healthy controls (light blue shading, n = 12), patients with typical retinotopic organization (yellow, n = 22), and patients with typical retinotopic organization that have been normalized to match controls in the total volume of activation (dark yellow, n = 22). Note: different y-axis scales in B and D for the ipsilateral versus contralateral visual fields.

In sum, our data suggest that the ipsilateral field expansions were not the result of eccentric PRLs. While we cannot exclude the possibility that P1 and P2 used a fixation locus during the fMRI experiments different to what was measured here, we have used high-accuracy retinal imaging/tracking to provide the best estimate of their average locus of fixation while fixating a central marker, as they would within the fMRI scanner environment. We found that the center of mass of fixation in both patients was located within the confines of the foveal pit.

Interhemispheric competition: a mechanism for atypical organization?

As outlined in Figure 12, we can begin to understand our results within the framework of a competitive model that is based on the following four factors. (1) Retino-geniculate afferents to V1 have a region of overlap between hemispheres resulting in a dual representation (one in each hemisphere) of the vertical meridian plus a strip of the ipsilateral field. (2) Normally, interhemispheric connections passing through the corpus callosum simply continue the effects of connectivity that are present throughout the rest of visual cortex. Overall, the net effects of horizontal intracortical connectivity are generally suppressive. (3) Unilateral damage to visual cortex, or the transcallosal connections themselves, relieves the suppression at the “edge” of the visual field representation in the intact hemisphere. Since for V1 this edge represents the vertical meridian and adjacent ipsilateral field, the loss of tonic suppression allows it to expand. In the following section, each of these factors is considered in more detail.

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Figure 12.

Conceptual model of interhemispheric suppression and effects of unilateral damage on apparent retinotopy. A, Schematic of the retino-geniculate afferent pattern into V1, including a naso-temporal overlap zone (highlighted by red lines) providing a source of ipsilateral visual field input to V1 in each hemisphere. B, Tonic suppression along the edge of each hemisphere (left V1 only shown for clarity) reduces the apparent number of retino-geniculate afferents (black dashed curve) along the naso-temporal overlap zone. Inset: the effect of a loss of suppression is an increase in the apparent number of afferents. C, Schematic model of flattened visual cortex highlighting the V1/V2 border at the representation of the ipsilateral field (thin contrasting colored strip). Compared with healthy visual cortex (top), unilateral damage (bottom) to the right hemisphere causes expansion of the visual field representation near the vertical meridian, including the ipsilateral field.

1. The retino-geniculate afferent pattern (Fig. 12A) provides a small source of ipsilateral visual field representation within V1. This arises from a retinal zone along the vertical meridian (Fig. 12A, top, red lines) that contains a mixture of ganglion cells projecting either ipsilaterally (more temporally located cells) or contralaterally (more nasally located cells) through the optic chiasm (Stone et al., 1973; Bunt and Minckler, 1977; Bunt et al., 1977; Fukuda et al., 1989). The overlap zone (black dashed outline) spans ∼0.5° in radius near the fovea, extending to 1.5° more peripherally. Due to the naso-temporal overlap and the topographic nature of the retino–geniculo–striate pathway, the afferent pattern within V1 (Fig. 12A, bottom, red lines) should maintain a bilateral representation of the visual field vertical meridian. Accordingly, single-unit recording in the baboon identified an ipsilateral representation out to 2° within the first few millimeters of both V1 and V2 along the vertical meridian border (Kennedy et al., 1985). In Figure 12A, we modeled the afferent pattern to V1 as a smoothly decreasing, spatial gradient representing the contralateral visual field and adjacent ipsilateral field.

2. Within visual cortex, bilaterally represented regions of the visual field are interconnected through interhemispheric projections (Choudhury et al., 1965; Hubel and Wiesel, 1965; Zeki, 1970; Berlucchi, 1972; Sanides, 1978; Essen and Zeki, 1978; Newsome and Allman, 1980). Functionally, these interhemispheric connections have been hypothesized to reiterate the effects of horizontal connections and/or lateral spread of extrastriate feedback normally present throughout cortex (Van Essen et al., 1982). This characterization reflects the concept that interhemispheric connections are functionally comparable to intrahemispheric connections in that both are cortico–cortico pathways that have similar laminar distributions in primates (largely originating from layer III and terminating in layer IV and above) and a remarkable degree of fine structure in spatial distribution parallel to the cortical surface. Like interhemispheric horizontal connections, feedback projections also spread laterally and can cross via the corpus callosum to terminate in the opposite hemisphere. Therefore, we consider the cortical tissue in each hemisphere as effectively forming a single functional unit that is fully interconnected by a uniform network involving intrahemispheric and interhemispheric connections in a similar fashion.

   Overall, the net effects of intrahemispheric connections are generally suppressive. It is typically thought that receptive fields of visual cortex neurons are organized into two or more spatially concentric zones (not necessarily circular) often referred to as the center, “near” surround, and “far” (or nonclassical) surround (Allman et al., 1985; Angelucci and Bressloff, 2006). Though interactions among these regions can be complex, it is common for the surrounds to exert an antagonistic (e.g., suppressive) effect on the center response, especially for stimulus patterns that extend uniformly over both center and surround regions. Indeed, recent recordings of synaptic conductances in awake (but not anesthetized) animals suggest that cortical responses to visual stimulation are typically dominated by synaptic inhibition that has “extremely broad spatial selectivity” (Haider et al., 2013). Such “suppressive” interactions can be mediated by a variety of quite general neurophysiological mechanisms, including lateral and feedback inhibition (Hartline, 1949; Kuffler, 1953; Angelucci and Bressloff, 2006), divisive normalization (Carandini and Heeger, 1994, 2012), or other nonlinear processes (Priebe and Ferster, 2012). A key feature of these mechanisms is often that the suppressive effects appear to be driven from surround distances that extend at least as far (Stettler et al., 2002) or farther than the distances covered by the center excitatory interactions. For instance, divisive normalization is based on the notion that each neuron's center response is “divided” by the activity of neighboring neurons pooled over an extended “surround.” Similarly, “biased competition” models of attention posit ubiquitous tonic suppression among arrays of multiple stimuli that is relieved only when one stimulus gains a competitive edge through attention (Desimone and Duncan, 1995; Luck et al., 1997). To the extent that such spatial interactions must be mediated in some fashion by laterally spreading connections either within or between cortical visual areas, it follows from above that these interactions also generally spread between the hemispheres.

   Of particular interest here is the zone of interhemispheric suppression along the edge of the visual field representation in each hemisphere (the bilaterally represented regions). In a healthy intact brain, the resulting effects of a tonic suppression along the edge of each hemisphere would be to decrease the apparent number of retino-geniculate afferents along the vertical meridian (Fig. 12B, black dashed curve) compared with that of the retino-geniculate afferents alone (Fig. 12B, solid black curve).

3. Based on this mechanism, the third and final factor posits that unilateral damage to visual cortex, or pathology of the corpus callosum, would disrupt the tonic suppression and cause retinotopic unmasking (increases in activation) along the vertical meridian representation (Fig. 12B, inset). Topographically, this would appear as an expansion of the ipsilateral visual field representation (yellow) plus an expansion of an adjacent zone of the contralateral field (blue). Figure 12C shows this effect in a schematic model of flattened visual cortex (Polimeni et al., 2006; Schira et al., 2007) that highlights the V1/V2 border at the representation of the vertical meridian. This competitive model is consistent with the retinotopic expansion of the existing vertical meridian representations observed in V1/V2 of P1–P3 as well as V3/V3A of P1 and P2. Additionally, patients P1 and P2 had an apparently ectopic (topographically displaced) representation of the ipsilateral visual field within lateral occipital cortex that is normally associated with visual areas V3/V3A (and possibly other areas). Interhemispheric competition within extrastriate cortical areas including crossed feedback projections from hierarchically higher to lower cortical levels may provide a functionally similar mechanism, but such speculations are reserved for the Discussion.

While the elimination of interhemispheric competition might constitute one plausible mechanism for the ipsilateral expansion observed here, other mechanisms might also contribute. Ample evidence suggests that the receptive fields of cells within a zone of deafferented visual cortex can undergo activity-dependent plastic reorganization (axonal sprouting and synaptogenesis), resulting in atypical cortical retinotopic patterns in which the receptive fields of initially deafferented neurons become responsive to stimuli presented near the margins of the scotoma. Such reorganization can be associated with the strengthening of long-range excitatory connections that normally support perceptual effects such as contour integration but after reorganization may support perceptual “filling-in” of contours crossing a scotoma (Gilbert and Li, 2012). In the present context, though, neurons representing the midline in the intact hemisphere are not deprived of their afferent input; they have lost only their “lateral” and feedback connections from the opposite hemisphere. It is not clear whether this would be sufficient to trigger strengthening of the remaining horizontal excitatory connections within the intact hemisphere. If it did, the anticipated effect would be to “pull” the receptive fields toward the intact contralateral hemifield, not the disconnected/lesioned ipsilateral field.