Modulation of visual cortical excitability in migraine with aura: effects of 1 Hz repetitive transcranial magnetic stimulation

Recent studies showed hyperexcitability of the occipital cortex in subjects affected by migraine with aura. It has been shown that 1 Hz repetitive transcranial magnetic stimulation (rTMS) reduces excitability of visual cortex in normal subjects. The aim of the study was to investigate the effects of low frequency (1 Hz) rTMS on visual cortical excitability by measuring changes in phosphene threshold (PT) in subjects with migraine with aura. Thirteen patients with migraine with aura and 15 healthy controls were examined. Using a standardized transcranial magnetic stimulation protocol of the occipital cortex, we assessed the PT (the lowest magnetic stimulation intensity at which subjects just perceived phosphenes) before and after a 1-Hz rTMS train delivered at PT intensity for 15 min. The difference in the proportion of subjects reporting phosphenes in migrainer and control groups was significant (migrainers: 100% vs controls 47%; P<0.05), and 1 Hz rTMS over the occipital cortex led to a significantly increased visual cortex excitability expressed as a decrease in PT in subjects affected by migraine with aura. Conversely, after a 1-Hz TMS train normal subjects showed increased PT values, which suggests a decreased visual cortex excitability. Our findings confirm that the visual cortex is hyperexcitable in migrainers and suggest a failure of inhibitory circuits, which are unable to be upregulated by low frequency rTMS.     

On the functionality of the visually deprived occipital cortex in early blind persons

In early blind mammals, the deprived visual cortex undergoes anatomical and functional alterations. Its functional role was investigated in the early human blind by using patterns of cortical activation as measured by scalp-recorded event-related slow negative DC potential shifts. The blind showed higher occipital negativity than did sighted persons both during a tactile reading task and a non-reading tactile control task. Results point to a possible role for the blind's visual cortex in tactile processes.     

Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people

Previous neuroimaging studies of language processing in blind individuals described cortical activation of primary (V1) and higher tier visual areas, irrespective of the age of blindness onset. Specifically, participants were given nouns and asked to generate an associated verb. These results confirmed the presence of adaptations in the visual cortex of blind people and suggested that these responses represented linguistic operations. The present functional magnetic resonance imaging study attempted to further characterize these responses as being preferential for semantic or phonological processing. Three groups of participants (sighted, early onset, and late-onset blind) heard lists of related words and attended to either a common meaning (semantic task) or common rhyme (phonological task) that linked the words. In all three groups, the semantic task elicited stronger activity in the left anterior inferior frontal gyrus and the phonological task evoked stronger activity bilaterally in the inferior parietal cortex and posterior aspects of the left inferior frontal gyrus. Only blind individuals showed activity in occipital, temporal, and parietal components of visual cortex. The spatial extent of visual cortex activity was greatest in early blind, who exhibited activation in all ventral and dorsal visual cortex subdivisions (V1 through MT) for both tasks. Preferential activation appeared for the semantic task. Late blind individuals exhibited responses in ventral and dorsal V1, ventral V2, VP and V8, but only for the semantic task. Our findings support prior evidence of visual cortex activity in blind people engaged in auditory language processing and suggest that this activity may be related to semantic processing.     

TMS of the occipital cortex induces tactile sensations in the fingers of blind Braille readers

Various non-visual inputs produce cross-modal responses in the visual cortex of early blind subjects. In order to determine the qualitative experience associated with these occipital activations, we systematically stimulated the entire occipital cortex using single pulse transcranial magnetic stimulation (TMS) in early blind subjects and in blindfolded seeing controls. Whereas blindfolded seeing controls reported only phosphenes following occipital cortex stimulation, some of the blind subjects reported tactile sensations in the fingers that were somatotopically organized onto the visual cortex. The number of cortical sites inducing tactile sensations appeared to be related to the number of hours of Braille reading per day, Braille reading speed and dexterity. These data, taken in conjunction with previous anatomical, behavioural and functional imaging results, suggest the presence of a polysynaptic cortical pathway between the somatosensory cortex and the visual cortex in early blind subjects. These results also add new evidence that the activity of the occipital lobe in the blind takes its qualitative expression from the character of its new input source, therefore supporting the cortical deference hypothesis.     

Early 'visual' cortex activation correlates with superior verbal memory performance in the blind

The visual cortex may be more modifiable than previously considered. Using functional magnetic resonance imaging (fMRI) in ten congenitally blind human participants, we found robust occipital activation during a verbal-memory task (in the absence of any sensory input), as well as during verb generation and Braille reading. We also found evidence for reorganization and specialization of the occipital cortex, along the anterior-posterior axis. Whereas anterior regions showed preference for Braille, posterior regions (including V1) showed preference for verbal-memory and verb generation (which both require memory of verbal material). No such occipital activation was found in sighted subjects. This difference between the groups was mirrored by superior performance of the blind in various verbal-memory tasks. Moreover, the magnitude of V1 activation during the verbal-memory condition was highly correlated with the blind individual's abilities in a variety of verbal-memory tests, suggesting that the additional occipital activation may have a functional role.     

Electrophysiological correlates of visually processing subject's own name

The study aimed to test the modulation induced by 1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) of the occipital cortex on the alpha phase synchronization under repetitive flash stimuli in 15 migraine without aura patients compared to 10 controls. The EEG was recorded by 7 channels, while flash stimuli were delivered at 9, 18, 21 and 24 Hz in basal, rTMS (15 min of 1 Hz stimulation of the occipital cortex) and sham conditions. Migraine patients displayed increased alpha-band phase synchronization under visual stimulation, while an overall desynchronizing effect was evident in controls. The rTMS resulted in a slight increase of synchronization index in migraine patients, which did not cause significant differences in respect to the basal and sham conditions. The synchronizing-desynchronizing changes of alpha rhythm under repetitive flash stimulation, seem independent from the state of occipital cortex excitability. Other mechanisms beyond cortical excitability may contribute to explain migraine pathogenesis.     

Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation

The aim of the present study was to explore further the effects of light deprivation (LD) on visual cortex excitability. Healthy subjects reporting reliable induction of phosphenes by occipital transcranial magnetic stimulation (TMS) underwent 60 min of complete LD. Phosphene threshold (PT) was measured before ( T ₀), after 45 min ( T ₁) and 60 min ( T ₂) of LD, and then every 10 min after light re-exposure until recovery to T ₀ values. Repetitive TMS (rTMS) (at 1 or 10 Hz) was applied in separate sessions during the last 15 min of LD. PTs significantly decreased after 45 min of LD. rTMS differentially modified the effects of 60 min LD on PTs depending on stimulation frequency. One hertz rTMS did not change the decreasing of PT values as observed in baseline condition, but significantly prolonged the time to recover T ₀ PT values after light re-exposure. By contrast, 10 Hz rTMS significantly increased PT and the time to recover T ₀ PT values after light re-exposure was shortened. The results of this study show that the modulatory effects of different rTMS frequencies on visual cortex critically depend on the pre-existing excitability state of inhibitory and facilitatory circuits, and provide novel insights into the neurophysiological changes that take place in the visual cortex following functional visual deafferentation.     

Adaptive changes in early and late blind: a FMRI study of verb generation to heard nouns

Literacy for blind people requires learning Braille. Along with others, we have shown that reading Braille activates visual cortex. This includes striate cortex (V1), i.e., banks of calcarine sulcus, and several higher visual areas in lingual, fusiform, cuneus, lateral occipital, inferior temporal, and middle temporal gyri. The spatial extent and magnitude of magnetic resonance (MR) signals in visual cortex is greatest for those who became blind early in life. Individuals who lost sight as adults, and subsequently learned Braille, still exhibited activity in some of the same visual cortex regions, especially V1. These findings suggest these visual cortex regions become adapted to processing tactile information and that this cross-modal neural change might support Braille literacy. Here we tested the alternative hypothesis that these regions directly respond to linguistic aspects of a task. Accordingly, language task performance by blind persons should activate the same visual cortex regions regardless of input modality. Specifically, visual cortex activity in blind people ought to arise during a language task involving heard words. Eight early blind, six late blind, and eight sighted subjects were studied using functional magnetic resonance imaging (fMRI) during covert generation of verbs to heard nouns. The control task was passive listening to indecipherable sounds (reverse words) matched to the nouns in sound intensity, duration, and spectral content. Functional responses were analyzed at the level of individual subjects using methods based on the general linear model and at the group level, using voxel based ANOVA and t-test analyses. Blind and sighted subjects showed comparable activation of language areas in left inferior frontal, dorsolateral prefrontal, and left posterior superior temporal gyri. The main distinction was bilateral, left dominant activation of the same visual cortex regions previously noted with Braille reading in all blind subjects. The spatial extent and magnitude of responses was greatest on the left in early blind individuals. Responses in the late blind group mostly were confined to V1 and nearby portions of the lingual and fusiform gyri. These results confirm the presence of adaptations in visual cortex of blind people but argue against the notion that this activity during Braille reading represents somatosensory (haptic) processing. Rather, we suggest that these responses can be most parsimoniously explained in terms of linguistic operations. It remains possible that these responses represent adaptations which initially are for processing either sound or touch, but which are later generalized to the other modality during acquisition of Braille reading skills.     

Alterations of the visual pathways in congenital blindness

We used whole brain MRI voxel-based morphometry (VBM) to study the anatomical organization of the visual system in congenitally blind (CB) adults. Eleven CB without a history of visual perception were compared with 21 age- and sex-matched normal-sighted controls (NS). CB showed significant atrophy of the geniculo-striate system, encompassing the optic nerves, the optic chiasm, the optic radiations and the primary visual cortex (BA17). The volume decrease in BA17 reached 25% in both hemispheres. The pulvinar and its projections to the associative visual areas were also dramatically altered, BA18/19 and the middle temporal cortex (MT) showing volume reductions of up to 20%. Additional significant white matter alterations were observed in the inferior longitudinal tract and in the posterior part of the corpus callosum, which links the visual areas of both hemispheres. Our data indicate that the afferent projections to the visual cortex in CB are largely atrophied. Despite the massive volume reductions in the occipital lobes, there is compelling evidence from the literature (reviewed in Noppeney 2007; Ptito and Kupers 2005) that blind subjects activate their visual cortex when performing tasks that involve somatosensory or auditory inputs, suggesting a reorganization of the neural pathways that transmit sensory information to the visual cortex.     

Adaptive changes in early and late blind: a fMRI study of Braille reading.

Braille reading depends on remarkable adaptations that connect the somatosensory system to language. We hypothesized that the pattern of cortical activations in blind individuals reading Braille would reflect these adaptations. Activations in visual (occipital-temporal), frontal-language, and somatosensory cortex in blind individuals reading Braille were examined for evidence of differences relative to previously reported studies of sighted subjects reading print or receiving tactile stimulation. Nine congenitally blind and seven late-onset blind subjects were studied with fMRI as they covertly performed verb generation in response to reading Braille embossed nouns. The control task was reading the nonlexical Braille string "######". This study emphasized image analysis in individual subjects rather than pooled data. Group differences were examined by comparing magnitudes and spatial extent of activated regions first determined to be significant using the general linear model. The major adaptive change was robust activation of visual cortex despite the complete absence of vision in all subjects. This included foci in peri-calcarine, lingual, cuneus and fusiform cortex, and in the lateral and superior occipital gyri encompassing primary (V1), secondary (V2), and higher tier (VP, V4v, LO and possibly V3A) visual areas previously identified in sighted subjects. Subjects who never had vision differed from late blind subjects in showing even greater activity in occipital-temporal cortex, provisionally corresponding to V5/MT and V8. In addition, the early blind had stronger activation of occipital cortex located contralateral to the hand used for reading Braille. Responses in frontal and parietal cortex were nearly identical in both subject groups. There was no evidence of modifications in frontal cortex language areas (inferior frontal gyrus and dorsolateral prefrontal cortex). Surprisingly, there was also no evidence of an adaptive expansion of the somatosensory or primary motor cortex dedicated to the Braille reading finger(s). Lack of evidence for an expected enlargement of the somatosensory representation may have resulted from balanced tactile stimulation and gross motor demands during Braille reading of nouns and the control fields. Extensive engagement of visual cortex without vision is discussed in reference to the special demands of Braille reading. It is argued that these responses may represent critical language processing mechanisms normally present in visual cortex.     

The role of human extra-striate visual areas V5/MT and V2/V3 in the perception of the direction of global motion: a transcranial magnetic stimulation study

Several published single case studies reveal a double dissociation between the effects of brain damage in separate extra-striate cortical visual areas on the perception of global visual motion defined by a difference in luminance (first-order motion) versus motion defined by a difference in contrast (second-order motion). In particular, the medial extrastriate cortical region V2/V3 seems to be crucial for the perception of first-order motion, but not for second-order, whereas a lateral and more anterior portion of the cortex close to the temporo–parieto–occipital junction (in the territory of the human motion area hV5/MT⁺) seems to be essential only for the perception of second-order motion. In order to test the hypothesis of a functional specialization of different visual areas for different types of motion, we applied repetitive transcranial magnetic stimulation (rTMS) unilaterally over areas V2/V3, V5/MT, or posterior parietal cortex (PPC) while subjects performed a 2AFC task with first- or second-order global motion displays in the contralateral visual field. Results showed a comparable disruption of the two types of motion, with both rTMS over V2/V3 or over MT/V5, and little or no effect with rTMS over PPC. The results suggest that either the previous psychophysical results with neurological patients are incorrect (highly unlikely) or that the lateral and medial regions are directly connected (as they are in macaque monkeys) such that stimulating one automatically affects the other, in this instance disruptively     

Modulation of visual cortex excitability in migraine with aura: Effects of valproate therapy

We explored the effects of valproate treatment on visual cortex excitability changes in migraine with aura patients. Abnormal cortical excitability has been suggested to play an important role in the etiopathogenesis of migraine; in particular, it has been suggested a failure of inhibitory circuits in migraine with aura. Valproate acts as a central GABA agonist and it is reasonable suppose that VPA could modify cortical excitability state. Phosphene threshold (PT) was assessed at baseline and after 1 Hz rTMS before and after one month therapy. We found that low-frequency rTMS in drug-free migraineurs decreased PT, while the treatment with the GABA agonist valproate is able to revert the effect of 1 Hz rTMS over the occipital cortex. If the paradoxical increasing of PT to 1 Hz rTMS is consequent upon the deficiency of intracortical inhibitory circuits in migraine, it seems reasonable to suppose that the effect of valproate is due to a recovery of activity of these circuits.     

Repetitive transcranial magnetic stimulation of human MT+ reduces apparent motion perception

We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) over the human cerebral cortex on apparent motion perception. Previous studies have shown that human extrastriate visual area MT+ (V5) processes not only real but also apparent motion. However, the functional relevance of MT+ on long-range apparent motion perception remains unclear. Here, we show direct evidence for the involvement of MT+ in apparent motion perception using rTMS, which is known to temporarily inhibit a localized region in the cerebral cortex. The results showed that apparent motion perception decreased after applying rTMS over MT+, but not after applying rTMS over the control region (inferior temporal gyrus). The decrease in performance caused by applying rTMS to MT+ suggests that MT+ is a causally responsible region for apparent motion perception, and thus, further supports the idea that MT+ plays a major role in the perception of motion.     

特殊感觉障碍人群(盲人)脑功能磁共振成像研究

目的：探讨特殊感觉障碍人群(盲人)大脑枕叶视皮层及相关结构在肓文阅读时充当的角色。方法：采用功能磁共振成像(fMRI)技术研究8名先天和后天盲人，在刺激(触摸中国盲文)和静止等两种对比条件下采集枕叶和有关皮层的回波平面图象。结果：盲人阅读中国盲文时在距状裂附近的纹状区、纹外区包括次级视觉中枢及与视觉信息处理有关的脑区均有激活信号出现，而正常人触摸盲文时上述脑区未出现明显激活信号。结论：枕叶可能参与肓文阅读过程的触觉信息识别：     

Auditory evoked visual awareness following sudden ocular blindness: an EEG and TMS investigation

Neurophysiological and neuroanatomical studies have provoked controversy about whether the visual cortex may be more modifiable than previously believed. Auditory processing is enhanced in blind compared to sighted people, and the enhancement might reflect encroachment of auditory transmission onto visual cortex. To address this issue, we recorded the auditory event-related potentials (ERPs) correlated with auditory related paradoxical visual awareness in a subject with traumatic total late-onset blindness. We found that (1) there was auditory related brain activity over the occipital visual scalp regions starting from a very early stage (< 80 ms) and (2) this occipital activity was significantly different between “visually aware” and “visually unaware” responses in the P1 (40–80 ms) component following meaningful stimuli. There was also a significant difference between responses with and without visual awareness in the N1 (100–120 ms) component following either tones or meaningful stimuli. The phosphenes accompanying auditory stimuli in the ERP experiment were always perceived to be directly in front of the subject and this was reproduced by transcranial magnetic stimulation over the blind primary visual cortex and by sudden sounds delivered to the side or behind the subject. The TMS induced phosphenes were restricted to the central part of the space and were, at least qualitatively, the same as those induced by sounds. The results are clear evidence that human perceptual functions can be reorganized after sudden, late-onset, total ocular blindness.     

Magnetic stimulation and the crossed–uncrossed difference (CUD) paradigm: selective effects in the ipsilateral and contralateral hemispheres

When a visual target is presented to one hemifield, manual responses made to the target using the ipsilateral hand (uncrossed responses) are faster than responses using the contralateral hand (crossed response), because there is no need for visuomotor information to be transferred between the hemispheres. This difference in response times is termed the crossed–uncrossed difference (CUD) and is a valuable means of estimating interhemispheric transfer time. We aimed to investigate the CUD by applying repetitive transcranial magnetic stimulation (rTMS) over the left and right occipital cortex during a lateralized target-detection task. Eleven neurologically healthy subjects, all right-handed, participated in the study. Relative to sham TMS we increased the CUD, by inhibiting the crossed latencies, but only when rTMS was applied to the hemisphere receiving visual information. These results replicate and extend previous findings and suggest the inhibitory rTMS effect under the crossed condition might be because the weak visual output is unable to activate the crossed pathway.     

The left visual-field advantage in rapid visual presentation is amplified rather than reduced by posterior-parietal rTMS

In the present task, series of visual stimuli are rapidly presented left and right, containing two target stimuli, T1 and T2. In previous studies, T2 was better identified in the left than in the right visual field. This advantage of the left visual field might reflect dominance exerted by the right over the left hemisphere. If so, then repetitive transcranial magnetic stimulation (rTMS) to the right parietal cortex might release the left hemisphere from right-hemispheric control, thereby improving T2 identification in the right visual field. Alternatively or additionally, the asymmetry in T2 identification might reflect capacity limitations of the left hemisphere, which might be aggravated by rTMS to the left parietal cortex. Therefore, rTMS pulses were applied during each trial, beginning simultaneously with T1 presentation. rTMS was directed either to P4 or to P3 (right or left parietal cortex) either as effective or as sham stimulation. In two experiments, either one of these two factors, hemisphere and effectiveness of rTMS, was varied within or between participants. Again, T2 was much better identified in the left than in the right visual field. This advantage of the left visual field was indeed modified by rTMS, being further increased by rTMS to the left hemisphere rather than being reduced by rTMS to the right. It may be concluded that superiority of the right hemisphere in this task implies that this hemisphere is less irritable by external interference than the left hemisphere.     

Low frequency transcranial magnetic stimulation on the posterior parietal cortex induces visuotopically specific neglect-like syndrome

The visuo-parietal (VP) region of the cerebral cortex is critically involved in the generation of orienting responses towards visual stimuli. In this study we use repetitive transcranial magnetic stimulation (rTMS) to unilaterally and non-invasively deactivate the VP cortex during a simple spatial visual detection task tested in real space. Adult cats were intensively trained over 4 months on a task requiring them to detect and orient to a peripheral punctuate static LED presented at a peripheral location between 0° and 90°, to the right or left of a 0° fixation target. In 16 different interleaved sessions, real or sham low frequency (1 Hz) rTMS was unilaterally applied during 20 min (1,200 pulses) to the VP cortex. The percentage of mistakes detecting and orienting to contralateral visual targets increased significantly during the 15–20 min immediately following real but not sham rTMS. Behavioral deficits were most marked in peripheral eccentricities, whereas more central locations were largely unaffected. Performance returned to baseline (pre-TMS) levels when animals were tested 45 min later and remained in pre-TMS levels 24 h after the end of the stimulation. Our results confirm that the VP cortex of the cat is critical for successful detection and orienting to visual stimuli presented in the corresponding contralateral visual field. In addition, we show that rTMS disrupts a robust behavioral task known to depend on VP cortex and does so for the far periphery of the visual field, but not for more central targets.Prof. Payne passed away May 2004. This article is submitted in his memory.     

Early extrastriate activity without primary visual cortex in humans

Damage to the primary visual cortex (V1) destroys the major source of anatomical input to extrastriate cortical areas (V2, V3, V4 and V5) and produces cortical blindness--an absence of any sensation of light and colour--in the visual field contralateral to the side of the lesion. Neuroimaging studies, nevertheless, have recently demonstrated dorsal and ventral extrastriate activation for stationary stimuli presented to the blind visual field in the absence of V1 activity in human subjects. To clarify the moment in time that visual information reaches extrastriate areas, by means of event-related potentials (ERPs) we tracked the temporal course of responses to complex visual stimuli (faces) presented in the blind field of a hemianopic patient. Stimulation of the normal visual field elicited a positive occipital deflection (P1) at 140 ms. A P1 response was also observed with stimulation of the blind field, although slightly delayed (20 ms) and reduced. Its topography and timing demonstrate that early neural activity for stationary stimuli takes place within extrastriate regions despite V1 denervation.     

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.