Phosphene Perception Relates to Visual Cortex Glutamate Levels and Covaries with Atypical Visuospatial Awareness.

Phosphenes are illusory visual percepts produced by the application of transcranial magnetic stimulation to occipital cortex. Phosphene thresholds, the minimum stimulation intensity required to reliably produce phosphenes, are widely used as an index of cortical excitability. However, the neural basis of phosphene thresholds and their relationship to individual differences in visual cognition are poorly understood. Here, we investigated the neurochemical basis of phosphene perception by measuring basal GABA and glutamate levels in primary visual cortex using magnetic resonance spectroscopy. We further examined whether phosphene thresholds would relate to the visuospatial phenomenology of grapheme-color synesthesia, a condition characterized by atypical binding and involuntary color photisms. Phosphene thresholds negatively correlated with glutamate concentrations in visual cortex, with lower thresholds associated with elevated glutamate. This relationship was robust, present in both controls and synesthetes, and exhibited neurochemical, topographic, and threshold specificity. Projector synesthetes, who experience color photisms as spatially colocalized with inducing graphemes, displayed lower phosphene thresholds than associator synesthetes, who experience photisms as internal images, with both exhibiting lower thresholds than controls. These results suggest that phosphene perception is driven by interindividual variation in glutamatergic activity in primary visual cortex and relates to cortical processes underlying individual differences in visuospatial awareness.

Early auditory processing in area V5/MT+ of the congenitally blind brain.

Previous imaging studies of congenital blindness have studied individuals with heterogeneous causes of blindness, which may influence the nature and extent of cross-modal plasticity. Here, we scanned a homogeneous group of blind people with bilateral congenital anophthalmia, a condition in which both eyes fail to develop, and, as a result, the visual pathway is not stimulated by either light or retinal waves. This model of congenital blindness presents an opportunity to investigate the effects of very early visual deafferentation on the functional organization of the brain. In anophthalmic animals, the occipital cortex receives direct subcortical auditory input. We hypothesized that this pattern of subcortical reorganization ought to result in a topographic mapping of auditory frequency information in the occipital cortex of anophthalmic people. Using functional MRI, we examined auditory-evoked activity to pure tones of high, medium, and low frequencies. Activity in the superior temporal cortex was significantly reduced in anophthalmic compared with sighted participants. In the occipital cortex, a region corresponding to the cytoarchitectural area V5/MT+ was activated in the anophthalmic participants but not in sighted controls. Whereas previous studies in the blind indicate that this cortical area is activated to auditory motion, our data show it is also active for trains of pure tone stimuli and in some anophthalmic participants shows a topographic mapping (tonotopy). Therefore, this region appears to be performing early sensory processing, possibly served by direct subcortical input from the pulvinar to V5/MT+.

Reorganization of retinotopic maps after occipital lobe infarction.

We studied patient JS, who had a right occipital infarct that encroached on visual areas V1, V2v, and VP. When tested psychophysically, he was very impaired at detecting the direction of motion in random dot displays where a variable proportion of dots moving in one direction (signal) were embedded in masking motion noise (noise dots). The impairment on this motion coherence task was especially marked when the display was presented to the upper left (affected) visual quadrant, contralateral to his lesion. However, with extensive training, by 11 months his threshold fell to the level of healthy participants. Training on the motion coherence task generalized to another motion task, the motion discontinuity task, on which he had to detect the presence of an edge that was defined by the difference in the direction of the coherently moving dots (signal) within the display. He was much better at this task at 8 than 3 months, and this improvement was associated with an increase in the activation of the human MT complex (hMT(+)) and in the kinetic occipital region as shown by repeated fMRI scans. We also used fMRI to perform retinotopic mapping at 3, 8, and 11 months after the infarct. We quantified the retinotopy and areal shifts by measuring the distances between the center of mass of functionally defined areas, computed in spherical surface-based coordinates. The functionally defined retinotopic areas V1, V2v, V2d, and VP were initially smaller in the lesioned right hemisphere, but they increased in size between 3 and 11 months. This change was not found in the normal, left hemisphere of the patient or in either hemispheres of the healthy control participants. We were interested in whether practice on the motion coherence task promoted the changes in the retinotopic maps. We compared the results for patient JS with those from another patient (PF) who had a comparable lesion but had not been given such practice. We found similar changes in the maps in the lesioned hemisphere of PF. However, PF was only scanned at 3 and 7 months, and the biggest shifts in patient JS were found between 8 and 11 months. Thus, it is important to carry out a prospective study with a trained and untrained group so as to determine whether the patterns of reorganization that we have observed can be further promoted by training.

Isoluminant coloured stimuli are undetectable in blindsight even when they move.

Moving stimuli are the most effective of all in eliciting blindsight. The detection of static luminance-matched coloured stimuli is negligible or even impossible in blindsight. However, moving coloured stimuli on an achromatic background have not been tested. We therefore tested two blindsighted hemianopes, one of them highly experienced and the other much less so, to determine whether they could perform what should be one of the simplest of all motion tasks: detecting when an array of coloured stimuli moves. On each trial, they were presented in the hemianopic field with an array of spots, all red or green or blue or achromatic, in a circular window and on a white surround. The spots moved coherently in the first or second of two short intervals. The subject had to indicate the interval in which the motion had occurred. The luminance of the spots was varied across different blocks of trials, but the background luminance remained the same throughout. For each colour, there was a ratio of luminance between the spots and the white surround at which performance was not significantly better than chance, although at other ratios, performance was good to excellent, with the exception of blue spots in one subject. We conclude that detecting global coherent motion in blindsight is impossible when it is based on chromatic contrast alone.

Modulation of cortical excitability can speed up blindsight but not improve it.

Blindsight has been widely investigated and its properties documented. One property still debated and contested is the puzzling absence of phenomenal visual percepts of visual stimuli that can be detected with perfect accuracy. We investigated the possibility that phenomenal visual percepts of exogenous visual stimuli in patient GY might be induced by using transcranial direct current stimulation. High contrast and low contrast stimuli were presented as a moving grating in his blind hemifield. When left area MT/V5 was anodally stimulated during the presentation of high-contrast gratings, he never reported a phenomenal percept of a moving grating but showed perfect blindsight performance. When applied along with low contrast gratings, for which accuracy was titrated to 60-70 %, performance did not improve but responses were significantly faster. Cathodal stimulation had no effect. Results are explained in the framework of GY's reorganized cortical connexions and oscillatory patterns known to be involved in awareness in GY. The apparent presence of phenomenal visual percepts in earlier studies is shown to be a semantic confusion about what he means when he says that he sees in his blind field.

Language networks in anophthalmia: maintained hierarchy of processing in 'visual' cortex.

Imaging studies in blind subjects have consistently shown that sensory and cognitive tasks evoke activity in the occipital cortex, which is normally visual. The precise areas involved and degree of activation are dependent upon the cause and age of onset of blindness. Here, we investigated the cortical language network at rest and during an auditory covert naming task in five bilaterally anophthalmic subjects, who have never received visual input. When listening to auditory definitions and covertly retrieving words, these subjects activated lateral occipital cortex bilaterally in addition to the language areas activated in sighted controls. This activity was significantly greater than that present in a control condition of listening to reversed speech. The lateral occipital cortex was also recruited into a left-lateralized resting-state network that usually comprises anterior and posterior language areas. Levels of activation to the auditory naming and reversed speech conditions did not differ in the calcarine (striate) cortex. This primary 'visual' cortex was not recruited to the left-lateralized resting-state network and showed high interhemispheric correlation of activity at rest, as is typically seen in unimodal cortical areas. In contrast, the interhemispheric correlation of resting activity in extrastriate areas was reduced in anophthalmia to the level of cortical areas that are heteromodal, such as the inferior frontal gyrus. Previous imaging studies in the congenitally blind show that primary visual cortex is activated in higher-order tasks, such as language and memory to a greater extent than during more basic sensory processing, resulting in a reversal of the normal hierarchy of functional organization across 'visual' areas. Our data do not support such a pattern of organization in anophthalmia. Instead, the patterns of activity during task and the functional connectivity at rest are consistent with the known hierarchy of processing in these areas normally seen for vision. The differences in cortical organization between bilateral anophthalmia and other forms of congenital blindness are considered to be due to the total absence of stimulation in 'visual' cortex by light or retinal activity in the former condition, and suggests development of subcortical auditory input to the geniculo-striate pathway.

The fate of the oculomotor system in clinical bilateral anophthalmia.

The interdependence of the development of the eye and oculomotor system during embryogenesis is currently unclear. The occurrence of clinical anophthalmia, where the globe fails to develop, permits us to study the effects this has on the development of the complex neuromuscular system controlling eye movements. In this study, we use very high-resolution T2-weighted imaging in five anophthalmic subjects to visualize the extraocular muscles and the cranial nerves that innervate them. The subjects differed in the presence or absence of the optic nerve, the abducens nerve, and the extraocular muscles, reflecting differences in the underlying disruption to the eye's morphogenetic pathway. The oculomotor nerve was present in all anophthalmic subjects and only slightly reduced in size compared to measurements in sighted controls. As might be expected, the presence of rudimentary eye-like structures in the socket appeared to correlate with development and persistence of the extraocular muscles in some cases. Our study supports in part the concept of an initial independence of muscle development, with its maintenance subject to the presence of these eye-like structures.

Are hemianopic monkeys and a human hemianope aware of visual events in the blind field?

In three hemianopic monkeys and one normal monkey who subsequently became hemianopic and in one human hemianope we measured reaction times to touch the remembered position of a brief visual target presented in the normal hemifield or in the blind hemifield, or on the blank trials where no visual target occurred and the correct response was to touch a separate and permanently outlined part of the display. This is the same procedure as first used to demonstrate blindsight in these hemianopic monkeys. In the present experiment physically salient high-contrast (0.95) grating stimuli, which we have previously shown are easily detected and localized in the blind field, were used, and the monkeys' reaction times were also measured. With rare exceptions the monkeys indicated that the visual targets in the blind field were blanks, but their otherwise identical motor responses to targets and blanks had significantly different latencies, which were longer for real targets than for blanks. The results indicate that when the monkeys detect that the stimulus has occurred but do not perceive it as a light, or are just guessing, reaction times are longer. Even when the target in the blind field was moving, it was categorized as a blank. In the human hemianope both high- and low-contrast stimuli were used, and the subject had to indicate whether he had been 'aware' or 'unaware' of the target, after making the reaching response. The latencies when he was correct and aware were significantly shorter than when he was unaware and 'just guessing'. However, he was also significantly faster to respond correctly to the blind-field target when he was unaware and correct than when he was unaware and incorrect, a difference reflected in his percentage correct scores even when totally unaware. Collectively, the results support the notion that the hemianopic monkeys, like the human hemianope, know that something has happened in the blind field as long as the stimuli are physically salient even though the stimuli are categorized as blanks, presumably because, like the human hemianope, there was no phenomenal visual percept.

Transneuronal retrograde degeneration of retinal ganglion cells and optic tract in hemianopic monkeys and humans.

Transneuronal retrograde degeneration of retinal ganglion cells after removal of primary visual cortex (area V1) is well established by quantitative neurohistological analysis of the ganglion cell layer in monkeys, but remains controversial in human patients. Therefore, we first histologically examined retinal degeneration in sectioned archived retinae of 26 macaque monkeys with unilateral V1 ablation and post-surgical survival times ranging from 3 months to 14.3 years. In addition, the cross-sectional area of the optic tract was measured in archived coronal histological sections of the brain of every hemianopic monkey and in sections from 10 control monkeys with non-visual bilateral cortical lesions. The ratios of nasal and temporal retinal ganglion cell counts in the contralesional eye and ipsi/contralateral optic tract areas were calculated and compared. They show that the decline was initially more pronounced for the optic tract, slackened after 3 years post-lesion and was steeper for the ganglion cells thereafter. Nevertheless, both measures were highly correlated. Second, we calculated ratios from structural magnetic resonance images to see whether the optic tracts of four human hemianopes would show similar evidence of transneuronal degeneration of their ipsilesional optic tract. The results were consistent with extensive and time-dependent degeneration of the retinal ganglion cell layer. The measures of the optic tracts provide evidence for comparable transneuronal retinal ganglion cell degeneration in both primate species and show that structural magnetic resonance image can both reveal and assess it.

Awareness-related activity in prefrontal and parietal cortices in blindsight reflects more than superior visual performance.

Many imaging studies report activity in the prefrontal and parietal cortices when subjects are aware as opposed to unaware of visual stimuli. One possibility is that this activity simply reflects higher signal strength or the superior task performance that is associated with awareness. To find out, we studied the hemianope GY who has unilateral destruction of almost all primary visual cortices. He exhibits 'blindsight', that is, he claims to have no conscious visual phenomenology (i.e., no visual qualia), for stationary stimuli presented to his right visual field (the blind field), although he can press keys to distinguish between different stimuli presented there. We presented to him a visual discrimination task, and equated performance for stimuli presented to the left or right visual field by presenting low contrast stimuli to his normal (left) field and high contrast stimuli to his blind (right) field. Superior accuracy can be a serious confound, and our paradigm allows us to control for it and avoid this confound. Even when performance was matched, and the signal strength was lower, visual stimulation to the normal (conscious) field led to higher activity in the prefrontal and parietal cortices. These results indicate that the activity in the prefrontal and parietal areas that has been reported in previous studies of awareness is not just due to a (signal strength or performance) confounds. One possibility is that it reflects the superior 'metacognitive' capacity that is associated with awareness, because GY was better able to distinguish between his own correct and incorrect responses for stimuli presented to his normal field than to his blind field.

TMS-induced blinking assessed with high-speed video: optical disruption of visual perception.

It is known that TMS can induce blinking, but it is unknown to what extent and at what time TMS-induced blinking can cover the pupil. We applied single-pulse TMS with a leftward and rightward monophasic current through a round coil over the occipital pole in 8 healthy subjects, using high-speed video to monitor left or right eye with a spatial resolution of 0.1 mm and a temporal resolution of 2 ms. We plotted eyelid position relative to upper and lower pupil borders as a function of time after TMS for each subject and current direction. We found 2 blinks in every subject, an isolated late blink with one current direction and a superimposed early and late blink with the other current direction, in accordance with our previously reported association between a leftward and rightward lower coil rim current and an early blink in right and left eye, respectively. Blink extent varied, but 4 subjects showed total pupil covering with both current directions. Blink timing varied, but pupil covering was initiated as early as 32 ms after TMS and pupil uncovering was completed as late as 200 ms after TMS. We found no saccades. We conclude that TMS can cause an important optical disruption of visual perception.

Detection of first- and second-order coherent motion in blindsight.

Blindsight patients can detect fast moving stimuli presented within their blind field even when they deny any phenomenal visual experience. Although mounting evidence suggests the presence of different mechanisms and separate neural substrates underlying the processing of first-order (luminance-defined) and second-order (contrast-defined) motion, the perception of second-order motion in blindsight has scarcely been explored. In the present study, we investigated whether two blindsighted patients (GY and MS) can detect a variety of first- and second-order moving stimuli, and by using repetitive transcranial magnetic stimulation (rTMS), we assessed the role of V5/MT(+) and V3(+) in coherent motion processing. The hemianopes and four control subjects performed a two-interval forced-choice task in which they judged whether a pattern of coherently moving first-order or second-order textured squares moved in the first or second interval. They were not asked to report the direction of motion because neither of them could do so better than expected by chance. The results showed that MS, who has extensive destruction of the ventral cortical visual pathway as well as his V1 lesion, could not process second-order motion at all, whereas GY could perform second-order tasks but only at high-contrast modulation. This may have introduced first-order components in second-order moving stimuli and provided artifactual cues to motion. Moreover, rTMS delivered over area V5/MT(+) impaired detection of both first- and second-order motion in undamaged control subjects, whereas rTMS over V3(+) did not impair their performance in any of the stimuli employed. On the other hand, rTMS over V3(+) did impair GY's detection of first-order motion and high-contrast second-order moving textured squares that are likely to contain artifactual luminance cues. rTMS over V5/MT(+) impaired first-order motion detection in MS. Overall, the results suggest that neither of the blindsight patients can detect artifact-free second-order motion.

Post-decision wagering objectively measures awareness.

The lack of an accepted measure of awareness has made claims that accurate decisions can be made without awareness controversial. Here we introduce a new objective measure of awareness, post-decision wagering. We show that participants fail to maximize cash earnings by wagering high following correct decisions in blindsight, the Iowa gambling task and an artificial grammar task. This demonstrates, without the uncertainties associated with the conventional subjective measures of awareness (verbal reports and confidence ratings), that the participants were not aware that their decisions were correct. Post-decision wagering may be used to study the neural correlates of consciousness.

The blindsight saga.

Blindsight is the ability of patients with clinically blind field defects, caused by damage to the primary visual cortex V, to detect, localise and even discriminate visual stimuli that they deny seeing. Blindsight tells us much about the nature of visual processing in the absence of the primary visual cortex and is a paradigmatic example of implicit knowledge. It has attracted widespread interest and debate amongst philosophers, cognitive neuropsychologists and visual neuroscientists. Its downside is that possible artefacts abound, much more so than with examples of implicit memory or deaf hearing and numb touch. Unfortunately the artefacts are still frequently ignored, or dismissed as captious, with the result that many of the genuine qualities of blindsight remain uncertain. Now that blindsight in monkeys has been established the substantial literature on the effects of removing parts or all of V1 in monkeys on the residual physiological cerebral responses to visual stimuli in their field defects is at last directly relevant to human blindsight. Whether blindsight is, or could be, useful in everyday life is the next unsolved problem.

Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

Edges, colour and awareness in blindsight.

It remains unclear what is being processed in blindsight in response to faces, colours, shapes, and patterns. This was investigated in two hemianopes with chromatic and achromatic stimuli with sharp or shallow luminance or chromatic contrast boundaries or temporal onsets. Performance was excellent only when stimuli had sharp spatial boundaries. When discrimination between isoluminant coloured Gaussians was good it declined to chance levels if stimulus onset was slow. The ability to discriminate between instantaneously presented colours in the hemianopic field depended on their luminance, indicating that wavelength discrimination totally independent of other stimulus qualities is absent. When presented with narrow-band colours the hemianopes detected a stimulus maximally effective for S-cones but invisible to M- and L-cones, indicating that blindsight is mediated not just by the mid-brain, which receives no S-cone input, or that the rods contribute to blindsight. The results show that only simple stimulus features are processed in blindsight.

Similar effects of repetitive transcranial magnetic stimulation of MT+ and a dorsomedial extrastriate site including V3A on pattern detection and position discrimination of rotating and radial motion patterns.

Our recent psychophysical experiments have identified differences in the spatial summation characteristics of pattern detection and position discrimination tasks performed with rotating, expanding, and contracting stimuli. Areas MT and MST are well established to be involved in processing these stimuli. fMRI results have shown retinotopic activation of area V3A depending on the location of the center of radial motion in vision. This suggests the possibility that V3A may be involved in position discrimination tasks with these motion patterns. Here we use repetitive transcranial magnetic stimulation (rTMS) over MT+ and a dorsomedial extrastriate region including V3A to try to distinguish between TMS effects on pattern detection and position discrimination tasks. If V3A were involved in position discrimination, we would expect to see effects on position discrimination tasks, but not pattern detection tasks, with rTMS over this dorsomedial extrastriate region. In fact, we could not dissociate TMS effects on the two tasks, suggesting that they are performed by the same extrastriate area, in MT+.

The cortical basis of global motion detection in blindsight.

The importance of stimulus qualities such as orientation, motion and luminance in blindsight are well known but their cortical basis has been much less explored. We therefore studied the performance of two blindsighted hemianopic subjects (GY and MS), in a task in which the subject had to decide in which of two adjunctive intervals a pattern of global spots moved coherently, at a variety of speeds, in the hemianopic field. Their ability was compared with that of two control subjects with normal vision. Both hemianopes performed this simple discrimination well in their blind fields but their performance was impaired by repetitive transcranial magnetic stimulation (rTMS) applied over cortical area hV5/MT(+) although not, or only slightly, by stimulation over the region of V3 or the vertex. The result is a direct demonstration that area hV5/MT(+) is necessary for global motion detection in blindsight.

Abnormal functional connectivity between ipsilesional V5/MT+ and contralesional striate cortex (V1) in blindsight.

Damage to the visual cortex can lead to changes in anatomical connectivity between the remaining areas. For example, after a unilateral lesion to striate cortex (V1), an abnormal anatomical pathway can develop between the lateral geniculate nucleus of the undamaged hemisphere and the motion area V5/MT+ in the damaged hemisphere, accompanied by a hypernormal callosal connection between the area V5/MT+ of the two hemispheres. Here we investigated, using transcranial magnetic stimulation (TMS), the functional significance of these pathways in the blindsight subject GY, in whom they were first demonstrated. We show that TMS applied over the extrastriate area V5/MT+ in GY's damaged hemisphere modulates the appearance of phosphenes induced from V1 in the normal hemisphere. In contrast, in neurologically normal control subjects, TMS applied over V5/MT+ never influenced the phosphenes induced from V1 in the other hemisphere. The findings indicate an abnormal functional connectivity between V5/MT in the damaged hemisphere and the early visual cortex in the normal hemisphere, consistent with GY's abnormal anatomical connectivity.

Changes in connectivity after visual cortical brain damage underlie altered visual function.

The full extent of the brain's ability to compensate for damage or changed experience is yet to be established. One question particularly important for evaluating and understanding rehabilitation following brain damage is whether recovery involves new and aberrant neural connections or whether any change in function is due to the functional recruitment of existing pathways, or both. Blindsight, a condition in which subjects with complete destruction of part of striate cortex (V1) retain extensive visual capacities within the clinically blind field, is an excellent example of altered visual function. Since the main pathway to the visual cortex is destroyed, the spared or recovered visual ability must arise from either an existing alternative pathway, or the formation of a new pathway. Using diffusion-weighted MRI, we show that both controls and blindsight subject GY, whose left V1 is destroyed, show an ipsilateral pathway between LGN (lateral geniculate nucleus) and human motion area MT+/V5 (bypassing V1). However, in addition, GY shows two major features absent in controls: (i) a contralateral pathway from right LGN to left MT+/V5, (ii) a substantial cortico-cortical connection between MT+/V5 bilaterally. Both observations are consistent with previous functional MRI data from GY showing enhanced ipsilateral activation in MT+/V5. There is also evidence for a pathway in GY from left LGN to right MT+/V5, although the lesion makes its quantification difficult. This suggests that employing alternative brain regions for processing of information following cortical damage in childhood may strengthen or establish specific connections.