Phosphene Threshold Research Articles

Peri-ictal changes of cortical excitability in children suffering from migraine without aura

In adult patients with migraine, transcranial magnetic stimulation (TMS) has been used to examine cortical excitability between attacks, but there have been discrepant results. No TMS study has examined cortical excitability in children or adolescents with migraine. Here, we employed TMS to study regional excitability of the occipital (phosphene threshold [PT] and suppression of visual perception) and motor (resting motor threshold and cortical silent period) cortex in ten children suffering from migraine without aura and ten healthy age-matched controls. Patients were studied 1–2days before and after a migraine attack as well as during the inter-migraine interval. The motion aftereffect was also investigated at each time-point as an index of cortical reactivity to moving visual stimuli. Migraineurs had lower PTs compared to healthy participants at each time-point, indicating increased occipital excitability. This increase in occipital excitability was attenuated 1–2days before a migraine attack as indicated by a relative increase in PTs. The increase in PTs before the next attack was associated with a stronger TMS-induced suppression of visual perception and a prolongation of the motion aftereffect. Motor cortex excitability was not altered in patients and did not change during the migraine cycle. These findings show that pediatric migraine without aura is associated with a systematic shift in occipital excitability preceding the migraine attack. Similar systematic fluctuations in cortical excitability might be present in adult migraineurs and may reflect either a protective mechanism or an abnormal decrease in cortical excitability that predisposes an individual to a migraine attack.

Dissociation of Neural Mechanisms Underlying Orientation Processing in Humans

Orientation selectivity is a fundamental, emergent property of neurons in early visual cortex, and the discovery of that property has dramatically shaped how we conceptualize visual processing. However, much remains unknown about the neural substrates of this basic building block of perception, and what is known primarily stems from animal physiology studies. To probe the neural concomitants of orientation processing in humans, we employed repetitive transcranial magnetic stimulation (rTMS), which can significantly attenuate neuronal spiking activity, hemodynamic responses, and local field potentials within a focused cortical region. Using rTMS to suppress neural responses evoked by stimuli falling within a local region of the visual field, we were able to dissociate two distinct components of the neural circuitry underlying orientation processing: selectivity and contextual effects. Orientation selectivity gauged by masking was unchanged by rTMS, whereas an otherwise robust orientation repulsion illusion was weakened after rTMS. This dissociation implies that orientation processing in humans relies on distinct mechanisms, only one of which was impacted by rTMS. These results are consistent with models positing that orientation selectivity is governed by patterns of convergence of thalamic afferents onto cortical neurons, with intracortical activity then shaping population responses amongst those cortical neurons.

The mental number line modulates visual cortical excitability

The mental number line has been shown to exert an influence on the visuo-spatial allocation of attention, with presentation of numbers from the low and high ends of the mental number line inducing covert shifts of spatial attention to the left and right side of visual space, respectively. In the present study we used transcranial magnetic stimulation (TMS) to investigate whether this attentional modulation influences excitability of the early visual cortex. By using the phosphene threshold as a measure of visual cortical excitability, we show (in 10 subjects) that number priming modulates excitability of the early visual cortex in a topographic fashion: low numbers, associated with left side of space, increase the excitability of the right early visual cortex (the stimulation of which induces phosphenes in the left hemifield) and decrease the excitability of the left early visual cortex (the stimulation of which induces phosphenes in the right hemifield). The opposite pattern of results was observed for high numbers. Our results suggest that the attentional shifts induced by the mental number line are manifested at the earliest cortical stages of visual processing.

Evaluation of patient suitability for a retinal prosthesis using structural and functional tests of inner retinal integrity

The purpose of this study was to assess inner retinal structure and function in patients with retinitis pigmentosa (RP) using optical coherence tomography (OCT) imaging of the retina, and electrical stimulation of the retina with a contact lens electrode. OCT images of 17 RP patients were acquired at the macula and at four quadrants of the peripheral retina in both eyes. Analysis was made of the residual inner retinal thickness and nerve fibre layer thickness in RP patients, and this was compared to normal controls. Eight of these patients further underwent contact lens electrical stimulation of one eye and thresholds for phosphene perception were obtained. OCT imaging showed a significant amount of inner retinal preservation in the peripheral retina and the macula of RP patients despite severe visual acuity and visual field loss. Phosphene thresholds were obtained across the range of pulse durations tested but were much higher than those obtained in normal controls. Phosphene thresholds in RP patients moderately correlated with inner retinal thicknesses as measured by OCT. Preservation of inner retinal structure in patients with RP and the responsiveness of these eyes to electrical stimulation suggest adequate inner retinal preservation for a retinal prosthesis to be successful.

TMS, phosphenes and visual mental imagery: A mini-review and a theoretical framework

AbstractWe reviewed the existing research linking visual mental imagery and phosphenes induced by TMS. We examined and contrasted conditions (and parameters) under which intensity and amplitude of TMS application at various cortical sites along the ventral and dorsal visual pathways: 1) induces the experience of visual images during perception and mental imagery, 2) interferes with or facilitates perception and/or imagery in concurrent and dual task conditions, 3) correlates with self-reports such as vividness ratings, and 4) reduces or has other selective effects on phosphene threshold in concomitance with perception and imagery. We propose an interpretation of the results of this mini-review within a new biophysical framework for visual mental imagery based on Bokkon’s redox molecular model of explicit optical coding of visual information in early visual areas (V1) and the propagation of conscious visual content at other levels in the stream of visual processing and in other parts of the brain.

TMS, phosphenes and visual mental imagery: A mini-review and a theoretical framework

We reviewed the existing research linking visual mental imagery and phosphenes induced by TMS. We examined and contrasted conditions (and parameters) under which intensity and amplitude of TMS application at various cortical sites along the ventral and dorsal visual pathways: 1) induces the experience of visual images during perception and mental imagery, 2) interferes with or facilitates perception and/or imagery in concurrent and dual task conditions, 3) correlates with self-reports such as vividness ratings, and 4) reduces or has other selective effects on phosphene threshold in concomitance with perception and imagery. We propose an interpretation of the results of this mini-review within a new biophysical framework for visual mental imagery based on Bokkon’s redox molecular model of explicit optical coding of visual information in early visual areas (V1) and the propagation of conscious visual content at other levels in the stream of visual processing and in other parts of the brain.

Correlation of Increase in Phosphene Threshold With Reduction of Migraine Frequency: A Comment

Correlation of Increase in Phosphene Threshold With Reduction of Migraine Frequency: A Comment

Does the menstrual cycle influence the motor and phosphene thresholds in migraine?

The excitability of the visual and motor cortical areas is altered in migraineurs. Controversial results of previous studies on cortical excitability may depend on the hormonal status of female subjects. The present study aimed to determine whether the different phases of the menstrual cycle influence the phosphene thresholds (PT) and resting motor thresholds (RMT) in migraineurs. Thirty-two migraine patients participated in this study. Three to six PT and RMT measurements were done in headache-free intervals during the follicular, middle and luteal phases of the female cycle, or in active dosage and withdrawal phases in patients who were taking low dosage oral contraceptives. Generally, PTs showed higher individual variabilities than RMTs. Additionally, we have observed that the RMTs and PTs were significantly independent from hormonal changes. However, patients who were taking a low dosage of oral contraceptives had lower PTs compared with patients who were not taking oral contraceptives. RMTs show the opposite tendency. The results imply that PTs and RMTs can be reliably measured independently from the menstrual hormone status in female migraineurs.

Emergence and transmission of visual awareness through optical coding in the brain: A redox molecular hypothesis on visual mental imagery

Does the primary visual cortex mediate consciousness for higher-level stages of information processing by providing an outlet for mental imagery? Evidence based on neural electrical activity is inconclusive as reflected in the “imagery debate” in cognitive science. Neural information and activity, however, also depend on regulated biophoton (optical) signaling. During encoding and retrieval of visual information, regulated electrical (redox) signals of neurons are converted into synchronized biophoton signals by bioluminescent radical processes. That is, visual information may be represented by regulated biophotons of mitochondrial networks in retinotopically organized cytochrome oxidase-rich neural networks within early visual areas. Therefore, we hypothesize that regulated biophotons can generate intrinsic optical representations in the primary visual cortex and then propagate variably degraded versions along cytochrome oxidase pathways during both perception and imagery. Testing this hypothesis requires to establish a methodology for measurement of in vivo and/or in vitro increases of biophoton emission in humans' brain during phosphene inductions by transcranial magnetic stimulation and to compare the decrease in phosphene thresholds during transcranial magnetic stimulation and imagery. Our hypothesis provides a molecular mechanism for the visual buffer and for imagery as the prevalent communication mode (through optical signaling) within the brain. If confirmed empirically, this hypothesis could resolve the imagery debate and the underlying issue of continuity between perception and abstract thought.

Correlation of Increase in Phosphene Threshold With Reduction of Migraine Frequency: Observation of Levetiracetam‐Treated Subjects

To correlate the reduction in migraine frequency with change in phosphene threshold of transcranial magnetic stimulation during levetiracetam treatment. Several case series have suggested levetiracetam efficacy may be effective in the management of migraine. Phosphene threshold is reduced in patients with migraine with aura, migraine without aura, and menstrual migraine. Preventive treatment may raise phosphene threshold while reducing headache frequency. Subjects experiencing 4-10 migraine attacks per month and not currently receiving preventive treatment for the indication of migraine were recruited into an open-label trial using levetiracetam, and asked to record headache symptoms, severity, duration, and acute medication use in a daily diary. Following a 28-day qualifying baseline period, subjects were titrated over 6 weeks to either a total daily dose of 3000 mg or their maximum tolerated dose (minimum tolerated daily dose of 1000 mg required). Transcranial magnetic stimulation was performed at day 28 and days 26, 28, 84, and 154. The visual cortex of each subject was stimulated 2 times at 20% power. Power was increased by 10% increments until at least one of the 2 stimulations produced a positive phosphene response. Once a positive response was achieved, a random order of 5 stimulation intensities surrounding the initial positive threshold was generated and given 3 times per session. Stimulation intensities were -10%, -5%, 0%, +5%, and +10% in relation to the positive threshold achieved. To eliminate a learning curve distortion, only observations at days 28, 84, and 154 were used for analysis. The mean phosphene threshold was defined as the average of the lowest positive threshold of the 3 stimulation sequences per visit. Ordinary least squares regression was used to evaluate the association between the change in mean daily headache rate from visit 3 to visit 7 and the change in mean transcranial magnetic stimulation threshold during the same period. Sixty-one subjects were enrolled. Twenty-one subjects were discontinued (because of poor study compliance or attack frequency) during the baseline phase prior to study drug initiation, and an additional subject whose data were not analyzed because of suspect quality. During the first 6 weeks on study drug (titration phase), 8 subjects dropped out (20.5%). Full analysis of the remaining 31 subjects, who reached a maintenance dose after 6 weeks on study medication, was performed. Subjects were largely white, female, and had a mean age of 41 +/- 13 years. Increasing age (beta = 1.27, P = .09), nonwhite race (beta = 6.90, P = .03), and diagnosis of tension-type headache (beta = 6.12, P = .095) were found to be associated with a higher mean transcranial magnetic stimulation threshold. Conversely, increasing body mass index was found to be associated with a lower mean transcranial magnetic stimulation threshold (beta = -1.19, P = .005). The number of migraine attacks decreased from 4.24 during the baseline interval to 2.53 during the interval preceding visit 7 (P = .001). There was a small but significant increase in transcranial magnetic stimulation threshold from visit 3 to visit 5 (P = .03) and visit 3 to visit 7 (P = .03 omnibus test). However,the difference between visit 5 and visit 7 was not statistically significant (P = .88). The mean transcranial magnetic stimulation threshold did not change from visit 5 to visit 7. Phosphene threshold increased during treatment with levetiracetam. At the 10% significance level, headache frequency and phosphene threshold were negatively correlated.

The Perceptual and Functional Consequences of Parietal Top-Down Modulation on the Visual Cortex

The posterior parietal cortex (PPC) has been proposed to play a critical role in exerting top-down influences on occipital visual areas. By inducing activity in the PPC (angular gyrus) using transcranial magnetic stimulation (TMS), and using the phosphene threshold as a measure of visual cortical excitability, we investigated the functional role of this region in modulating the activity of the visual cortex. When triple-pulses of TMS were applied over the PPC unilaterally, the intensity of stimulation required to elicit a phosphene from the visual cortex (area V1/V2) was reduced, indicating an increase in visual cortical excitability. The increased excitability that was observed with unilateral TMS was abolished when TMS was applied over the PPC bilaterally. Our results provide a demonstration of the top-down modulation exerted by the PPC on the visual cortex and show that these effects are subject to interhemispheric competition.

Effects of Topiramate on Migraine Frequency and Cortical Excitability in Patients with Frequent Migraine

We studied the excitability of the visual and motor cortex in 36 patients with frequent migraine without aura (30 women, mean age 38.6 +/- 10.0 years) before and after treatment with topiramate (100 mg/day) using transcranial magnetic stimulation. Treatment with topiramate resulted in reduction of both headache frequency (12.0 +/- 1.3 to 5.8 +/- 3.2 migraine days per month; P = 0.004) and cortical excitability: motor cortex thresholds increased on the right side from 43.8 +/- 7.5% to 47.7 +/- 9.2% (P = 0.049) and on the left side from 43.4 +/- 7.0% to 47.2 +/- 9.6% (P = 0.047), and phosphene thresholds increased from 58.9 +/- 11.1% to 71.2 +/- 11.2% (P = 0.0001). Reduction of headache frequency correlated inversely with an increase of visual thresholds and did not correlate with motor thresholds. The effect of topiramate in migraine prevention is complex and can not be explained simply by inhibition of cortical excitability.

Gender-specific modulation of short-term neuroplasticity in the visual cortex induced by transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is a non-invasive method of modulating levels of cortical excitability. In this study, data gathered over a number of previously conducted experiments before and after tDCS, has been re-analyzed to investigate correlations between sex differences with respect to neuroplastic effects. Visual evoked potentials (VEPs), phosphene thresholds (PTs), and contrast sensitivity measurements (CSs) are used as indicators of the excitability of the primary visual cortex. The data revealed that cathodally induced excitability effects 10 min post stimulation with tDCS, showed no significant difference between genders. However, stimulation in the anodal direction revealed sex-specific effects: in women, anodal stimulation heightened cortical excitability significantly when compared to the age-matched male subject group. There was no significant difference between male and female subjects immediately after stimulation. These results indicate that sex differences exist within the visual cortex of humans, and may be subject to the influences of modulatory neurotransmitters or gonadal hormones which mirror short-term neuroplastic effects.

Bidirectional Modulation of Primary Visual Cortex Excitability: A Combined tDCS and rTMS Study

In the motor cortex (M1), transcranial direct current stimulation (tDCS) can effectively prime excitability changes that are evoked by a subsequent train of repetitive transcranial magnetic stimulation (rTMS). The authors examined whether tDCS can also prime the cortical response to rTMS in the human visual cortex. In nine healthy subjects, the authors applied tDCS (10 minutes; +/-1 mA) to the occipital cortex. After tDCS, they applied a 20-second train of 5 Hz rTMS at 90% of phosphene threshold (PT) intensity. A similar rTMS protocol had previously demonstrated a strong priming effect of tDCS on rTMS-induced excitability changes in M1. PTs were determined with single-pulse TMS before and immediately after tDCS and twice after rTMS. Anodal tDCS led to a transient decrease in PT, and subsequent 5 Hz rTMS induced an earlier return of the PT back to baseline. Cathodal tDCS produced a short-lasting increase in PT, but 5 Hz rTMS did not influence the tDCS-induced increase in PT. In a control experiment on four subjects, a 20-second train of occipital 5 Hz rTMS left the PT unchanged, whereas a 60-second train produced a similar decrease in PT as anodal tDCS alone. Compared with previous work on the M1, tDCS and rTMS of the visual cortex only produce short-lasting changes in cortical excitability. Moreover, the priming effects of tDCS on subsequent rTMS conditioning are relatively modest. These discrepancies point to substantial differences in the modifiability of human motor and visual cortex.

Time-dependent changes in cortical excitability after prolonged visual deprivation

Transcranial magnetic stimulation applied to the occipital cortex can elicit phosphenes. Changes in the phosphene threshold provide a measure of visual cortex excitability. Phosphene threshold was measured in participants blindfolded for five consecutive days to assess the effects of prolonged visual deprivation on visual cortical excitability. After 48 h of blindfolding, an acute decrease in phosphene threshold was observed, followed by a significant increase by day 5. Phosphene threshold returned to preblindfold levels within 2 h of light re-exposure. Thus, light deprivation is characterized by a transient increase in visual cortical excitability, followed by a sustained decrease in visual cortex excitability that quickly returns to baseline levels after re-exposure to light.

Clinical correlates of phosphene perception in migraine without aura: An Asian study

Although controversy exists with regard to the presence of hypoexcitability versus hyperexcitability of the visual cortex in migraine patients, there remain a group who do not perceive phosphenes (P-). However, its clinical implications have not been systematically addressed. In this study, we hypothesize that P- patients classified as migraine without aura (MO) have distinct clinical features. Twenty-nine Asian MO patients (7 men; mean age: 44; median: 45; range: 25 to 65) were consecutively entered into the study. Visual cortex transcranial magnetic stimulation (TMS) was performed in the migraine interictum. Of the 19 patients, 19 (66%) were able to perceive phosphenes (P+), while 10 (34%) were not able to after repeated TMS (P-). P- patients had significantly higher headache frequency (p=0.008) and pain score (p=0.002) compared with P+ patients. In addition, there was significant positive correlation of phosphene threshold with pain score (r=0.52, p=0.02) in P+ patients. There was no significant difference between P+ and P- patients in terms of age (t-test, p=0.6). Our study is inkeeping with the hypothesis that interictal visual cortex excitability is reduced in relation to the severity of migraine in Asian MO patients, and lack of phosphene perception may be related to significantly elevated thresholds beyond the output of TMS stimulators.

Transcranial Direct Current Stimulation Reveals Inhibitory Deficiency In Migraine

The issue of interictal excitability of cortical neurons in migraine patients is controversial: some studies have reported hypo-, others hyperexcitability. The aim of the present study was to observe the dynamics of this basic interictal state by further modulating the excitability level of the visual cortex using transcranial direct current stimulation (tDCS) in migraineurs with and without aura. In healthy subjects anodal tDCS decreases, cathodal stimulation increases transcranial magnetic stimulation (TMS)-elicited phosphene thresholds (PT), which is suggested as a representative value of visual cortex excitability. Compared with healthy controls, migraine patients tended to show lower baseline PT values, but this decrease failed to reach statistical significance. Anodal stimulation decreased phosphene threshold in migraineurs similarly to controls, having a larger effect in migraineurs with aura. Cathodal stimulation had no significant effect in the patient groups. This result strengthens the notion of deficient inhibitory processes in the cortex of migraineurs, which is selectively revealed by activity-modulating cortical input.

Correlation between motor and phosphene thresholds: A transcranial magnetic stimulation study

Transcranial magnetic stimulation (TMS) has become a common tool for the brain mapping of a wide variety of cognitive functions. Because TMS over cortical regions of interest other than motor cortex often does not produce easily observable effects, the ability to calibrate TMS intensity for stimulation over nonmotor regions can be problematic. Previous studies reported no correlation between motor thresholds (MT) over the motor cortex and phosphene thresholds (PT) over the visual cortex. However, different thresholding methods, lighting, and eye-closure conditions were used to determine MT and PT. We investigated the correlation between resting MT (rMT), active MT (aMT), and PT in 27 dark-adapted healthy volunteers. All thresholds were measured with eyes-open in the dark and determined by gradually reducing stimulation intensity downward. All subjects had aMT and rMT; 21 subjects had measurable PT. rMT was 70.4% +/- 9.8% (mean +/- SD of maximum stimulator output); aMT was 61.1% +/- 7.9%; PT was 82.2% +/- 10.1%. A significant positive correlation was found between aMT and PT (r = 0.53; P = 0.014) with a trend toward correlation between rMT and PT (r = 0.43; P = 0.052). Our results suggest that sensitivity to TMS over visual and motor cortices may be correlated under similar thresholding procedures. They also provide a rationale for the use of easily obtained aMT to calibrate TMS intensities in brain mapping studies that employ TMS in cortical regions besides motor cortex.

Anisotropy in the visual cortex investigated by neuronavigated transcranial magnetic stimulation

Responses to transcranial magnetic stimulation (TMS) of the motor cortex depend on the direction of the induced current with an optimum perpendicular to the orientation of the precentral gyrus. Little is known about anisotropy in other cortical regions. We measured phosphene thresholds in the visual cortex using a frameless neuronavigation system. Comparing horizontal and vertical current orientation as well as monophasic and biphasic pulses in 7 subjects, we found lower thresholds with biphasic pulses and a tendency for lower thresholds with horizontal currents. When varying current directions in steps of 45° centered on a hot spot over the occipital cortex, in 10 out of 12 measurements optimal current orientation ran perpendicular to the underlying gyrus (mean deviation 14.6°). Optimal current orientation was determined as the orientation of the second eigenvector from the covariance matrix of the stimulation sites that had been shifted along the respective current direction by the amount of the measured threshold. Individual cortical architecture was obtained by segmentation of a 3d anatomical MR scan, with large interindividual differences among the orientations of the stimulated gyrus. As with the motor system, the optimum threshold with biphasic pulses was flipped about 180° compared to the optimum with monophasic pulses (p<.02) throughout subjects, suggesting both similar anisotropic properties of networks in the visual and motor cortices and the existence of anisotropic behaviour in any cortical region. As a consequence, optimal TMS application should always take into account the individual orientation of the gyrus to be stimulated.

Spreading photoparoxysmal EEG response is associated with an abnormal cortical excitability pattern

Photosensitivity or photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an abnormal cortical response to intermittent photic stimulation (IPS). In PPR-positive individuals, IPS induces spikes, spike-waves or intermittent slow waves. The PPR may be restricted to posterior visual areas (i.e. local PPR with occipital spikes only) or spread to anterior non-visual cortical regions (i.e. PPR with propagation). The mechanisms underlying the PPR and causing its spread remain to be clarified. In unmedicated PPR-positive individuals and PPR-negative control participants without any history of previous seizures, we used focal transcranial magnetic stimulation (TMS) to investigate the excitability of the visual or primary motor cortex (M1). In the first experiment [18 healthy control subjects (i.e. without PPR in electroencephalography: 6 females, mean age 26.5 +/- 7.34 years) and 17 healthy participants with PPR (7 females, mean age 25.18 +/- 12.2 years) were studied], occipital TMS was used to elicit phosphenes or to suppress the visual perception of letter trigrams. PPR-positive individuals with propagation had lower phosphene thresholds and steeper stimulus-response curves than individuals without PPR or with occipital spikes only. Occipital TMS also induced a stronger suppression of visual perception in PPR-positive subjects with propagation relative to subjects without PPR or with occipital spikes. In the second experiment, we applied TMS over the right M1 without concurrent IPS and measured the motor threshold, the stimulus response curve, and the duration of the cortical silent period (CSP) in PPR positive individuals with propagation and in PPR-negative control participants [15 right-handed healthy subjects without PPR (3 males, mean age 17.7 +/- 3.6 years) and 14 right-handed healthy individuals showing a PPR with propagation (3 males, mean age 17.4 +/- 3.9 years)]. PPR-positive individuals showed no changes in these excitability measures relative to the PPR-negative control participants. We also measured the modifiability of the CSP by continuous IPS at a frequency of 18 or 50 Hz. While IPS reduced the duration of the CSP in PPR-negative control subjects, IPS had no effect on the duration of the CSP in PPR-positive individuals. Our results provide first time evidence that the propagation of the PPR is associated with increased excitability of the occipital but not the motor cortex. The stronger inhibitory effect of TMS on visual perception and the failure of IPS to shorten the CSP in PPR-positive participants may possibly reflect adaptive changes that prevent the provocation of seizures during the PPR.