Perceptual and Physiological Consequences of Dark Adaptation: A TMS-EEG Study.

Existing literature on sensory deprivation suggests that short-lasting periods of dark adaptation (DA) can cause changes in visual cortex excitability. DA cortical effects have previously been assessed through phosphene perception, i.e., the ability to report visual sensations when a transcranial magnetic stimulation (TMS) pulse is delivered over the visual cortex. However, phosphenes represent an indirect measure of visual cortical excitability which relies on a subjective report. Here, we aimed at overcoming this limitation by assessing visual cortical excitability by combining subjective (i.e., TMS-induced phosphenes) and objective (i.e., TMS-evoked potentials - TEPs) measurements in a TMS-EEG protocol after 30 min of DA. DA effects were compared to a control condition, entailing 30 min of controlled light exposure. TMS was applied at 11 intensities in order to estimate the psychometric function of phosphene report and explore the relationship between TEPs and TMS intensity. Compared to light adaptation, after DA the slope of the psychometric function was significantly steeper, and the amplitude of a TEP component (P60) was lower, only for high TMS intensities. The perceptual threshold was not affected by DA. These results support the idea that DA leads to a change in the excitability of the visual cortex, accompanied by a behavioral modification of visual perception. Furthermore, this study provides a first valuable description of the relationship between TMS intensity and visual TEPs.

Chemical stimulation of rat retinal neurons: feasibility of an epiretinal neurotransmitter-based prosthesis.

OBJECTIVE: No cure currently exists for photoreceptor degenerative diseases, which cause partial or total blindness in millions of people worldwide. Electrical retinal prostheses have been developed by several groups with the goal of restoring vision lost to these diseases, but electrical stimulation has limitations. It excites both somas and axons, activating retinal pathways nonphysiologically, and limits spatial resolution because of current spread. Chemical stimulation of retinal ganglion cells (RGCs) using the neurotransmitter glutamate has been suggested as an alternative to electrical stimulation with some significant advantages. However, sufficient scientific data to support developing a chemical-based retinal prosthesis is lacking. The goal of this study was to investigate the feasibility of a neurotransmitter-based retinal prosthesis and determine therapeutic stimulation parameters. APPROACH: We injected controlled amounts of glutamate into rat retinas from the epiretinal side ex vivo via micropipettes using a pressure injection system and recorded RGC responses with a multielectrode array. Responsive units were identified using a spike rate threshold of 3 Hz. MAIN RESULTS: We recorded both somal and axonal units and demonstrated successful glutamatergic stimulation across different RGC subtypes. Analyses show that exogenous glutamate acts on RGC synapses similar to endogenous glutamate and, unlike electrical prostheses, stimulates only RGC somata. The spatial spread of glutamate stimulation was ≈ 290 µm from the injection site, comparable to current electrical prostheses. Further, the glutamate injections produced spatially differential responses in OFF, ON, and ON-OFF RGC subtypes, suggesting that differential stimulation of the OFF and ON systems may be possible. A temporal resolution of 3.2 Hz was obtained, which is a rate suitable for spatial vision. SIGNIFICANCE: We provide strong support for the feasibility of an epiretinal neurotransmitter-based retinal prosthesis. Our findings suggest that chemical stimulation of RGCs is a viable alternative to electrical stimulation and could offer distinct advantages such as the selective stimulation of RGC somata.

Phosphene thresholds evoked with single and double TMS pulses.

OBJECTIVE: To evaluate the quantitative advantage of double pulses vs. single pulses in TMS phosphenes evoked from the occipital cortex. METHODS: In 10 healthy subjects single pulse thresholds were compared with thresholds from double pulses of equal strength at a stimulus onset asynchrony (SOA) of 2, 5, 10, and 20ms, both with biphasic and monophasic pulse forms. In a second experiment fusion time, i.e. the double pulse SOA where the percept passes from one into two phosphenes was determined. RESULTS: Thresholds obtained with double pulses did not depend on SOA. They were lowered to about 90% of single pulse thresholds. Biphasic pulses yielded lower thresholds (89%) than monophasic pulses. Fusion time was about 45ms but highly varied inter-individually and did not depend on stimulation intensity. CONCLUSIONS: Although double pulses are more efficient compared to single pulses the advantage is rather small. Previous recommendations to apply double pulses in phosphene studies cannot be confirmed, at least for SOAs up to 20ms. The independence of fusion time to stimulus intensity indicates a non-linear relation between network activity and the percept of phosphene persistence. SIGNIFICANCE: Phosphene threshold studies do not gain advantages by the application of double pulses.

Retinal phosphenes and discrete dark noises in rods: a new biophysical framework.

Spontaneous rhodopsin activation produces discrete noises indistinguishable from single-photon responses. However, there is a serious discrepancy between the apparent energy barrier of thermal events compared with that of the photon-driven process. Current estimates of the activation energies of discrete dark noises in vertebrate rod and cone pigments are approximately 40-50 cal/mol for activation by photon and approximately 20-25 kcal/mol for activation by heat. To reconcile this discrepancy, it was assumed that thermal activation and photon activation of rhodopsin follow different molecular mechanisms. The most convincing hypothesis for a separate low-energy thermal pathway is that the discrete dark noises of rods arise in a small subpopulation of rhodopsins, where the Schiff base linking the chromophore to the protein part has been deprotonated. According to Narici et al.' experiments (2009, Radiation Measurements), phosphene perception in space travel is due to the ionizing radiation-induced free radicals that generate chemiluminescent photons from lipid peroxidation. These photons are absorbed by the photoreceptors chromophores, which modify the rhodopsin molecules (bleaching) and start the photo-transduction cascade resulting in the perception of phosphenes. Here, we point out that not only retinal phosphenes but also the discrete dark noise of rods can be due to the natural redox related (free radical) bioluminescent photons in the retina. In other words, under regulated conditions, lipid peroxidation is a natural process in cells and also in retinal membranes. Since the natural lipid peroxidation is one of the main sources of bioluminescent photons and the photoreceptors have the highest oxygen demand and polyunsaturated fatty acid (PUFA) concentration, there is a continuous, low level bioluminescent photon emission in the retina without any external photonic stimulation. During photopic or scotopic vision, evanescent bioluminescent photon emission is negligible. In contrast, in dark-adapted retinal cells this evanescent bioluminescent photon emission is not negligible. Therefore, our hypothesis is that the discrete dark noise of rods can be due to these bioluminescent photons.

Interhemispheric transfer of phosphenes generated by occipital versus parietal transcranial magnetic stimulation.

Phosphenes represent a perceptual effect of transcranial magnetic stimulation (TMS) or electric stimulation of visual cortical areas. One likely neural basis for the generation of static phosphenes is the primary visual cortex (V1) although evidence is controversial. A peculiar feature of V1 is that it has sparse callosal connections with the exception of a central portion of visual field representation. In contrast, visually responsive cortical areas in the parietal lobe have widespread callosal connections. Thus, interhemispheric transfer (IT) time of off-centre phosphenes should be slower when generated by V1 than by visual parietal areas. To verify this possibility, in Exp. 1 we measured IT of phosphenes generated by TMS applied to V1 and in Exp. 2 we measured IT of phosphenes obtained by TMS applied to posterior parietal cortex. In both experiments, we obtained static bright circular phosphenes appearing in the contralateral hemifield. We measured IT time behaviorally by comparing unimanual simple reaction time to the onset of a phosphene under crossed or uncrossed hemifield-hand condition (Poffenberger paradigm). In keeping with our prediction, we found a substantially longer IT time for V1 than for parietal phosphenes. Additionally, an IT similar to that obtained with V1 stimulation was found when participants were asked to imagine the phosphenes previously experienced during TMS. In conclusion, the present results suggest that IT of phosphenes either generated by V1 TMS or imagined is subserved by slower callosal channels than those of real visual stimuli or parietal phosphenes.

Correlation of increase in phosphene threshold with reduction of migraine frequency: observation of levetiracetam-treated subjects.

OBJECTIVES: To correlate the reduction in migraine frequency with change in phosphene threshold of transcranial magnetic stimulation during levetiracetam treatment. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Phosphene threshold increased during treatment with levetiracetam. At the 10% significance level, headache frequency and phosphene threshold were negatively correlated.

Development of an extraocular retinal prosthesis: evaluation of stimulation parameters in the cat.

Electrical stimulation of the retina with extraocular electrodes is a new approach to developing a retinal prosthesis for blind patients. We have evaluated stimulus and electrode configurations for an extraocular retinal prosthesis (ERP). In anesthetized cats, ERP disc electrodes of 1 mm, 2 mm and 3 mm diameter were sutured to the sclera over the lateral globe. Electrically evoked potentials (EEPs) were recorded over the ipsilateral visual cortex, which resulted from the retinal stimulation of the ERP electrodes with a return electrode placed at the medial canthus. Square pulses, triangular pulses and the effects of dark adaptation and electrode size on the amplitude and thresholds for a cortical response were investigated. Square pulses were more effective than triangular pulses for stimulating the retina. Dark adaptation leads to a large increase in the threshold for retinal stimulation. There was no difference in the threshold for stimulation between electrodes of 1 mm and 3 mm diameter. Stimulation of the retina with extraocular electrodes elicits an EEP that is similar to that generated by retinal stimulation with intraocular electrodes. The use of square pulses is preferred to triangular pulses to minimize the peak current density at the electrode-tissue interface. As there is little difference in the threshold current for retinal stimulation with 1 mm or 3 mm electrodes, 3 mm electrodes are preferred as this will decrease the charge density at the active surface of the electrode.

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.

Making the blindsighted see.

A lesion of striate cortex, area V1, produces blindness in the retinotopically corresponding part of the visual field, although in some cases visual abilities in the blind field remain that are paradoxically devoid of conscious visual percepts ("blindsight"). Here we demonstrate that the blindsight subject GY can experience visual sensations of phosphenes in his blind field induced by transcranial magnetic stimulation (TMS). Such blind field percepts could only be induced when stimulation was applied bilaterally, i.e. over GY's area V5/MT in both hemispheres. Consistent with an earlier report [Cowey, A., & Walsh, V. (2000). Magnetically induced phosphenes in sighted, blind and blindsighted observers. Neuroreport, 11, 3269-3273], GY never experienced phosphenes when stimulation was restricted to his ipsilesional V5/MT. To the best of our knowledge this is the first time GY has experienced visual qualia in his blind hemifield. The present report characterizes the necessary conditions for such conscious experience in his hemianopic visual field and interprets them as demonstrating that only via a contribution from GY's intact hemisphere can activation in the damaged hemisphere reach visual awareness.

Electrophysiological responses of the mouse retina to 12C ions.

Phosphenes ("light flashes") have been reported by most astronauts on space missions and by healthy subjects whose eyes were exposed to ionizing radiation in early experiments in particle accelerators. The conditions of occurrence suggested retinal effects of heavy ions. To develop an in vivo animal model, we irradiated the eyes of anesthetized wild-type mice with repeated bursts of 12C ions delivered under controlled conditions in accelerator. 12C ions evoked electrophysiological retinal mass responses and activated the visual system as indicated by responses recorded from the visual cortex. No retinal immunohistological damage was detected. Mice proved a suitable animal model to study radiation-induced phosphenes in vivo and our findings are consistent with an origin of phosphenes in radiation activating the retina.

Phosphene induction by microstimulation of macaque V1.

Non-human primates are being used to develop a cortical visual prosthesis for the blind. We use the properties of electrical microstimulation of striate cortex (area V1) of macaque monkeys to make inferences about phosphene induction. Our analysis is based on well-established properties of V1: retino-cortical magnification factor, receptive-field size, and the characteristics of hypercolumns. We argue that phosphene size is dependent on the amount of current delivered to V1 and on the retino-cortical magnification factor. We suggest that to improve the correspondence between the site of stimulation within V1 and the visual field location of an elicited phosphene both eyes must be put under experimental control given that phosphene location is retinocentric and given that the vergence angle between the eyes might affect the position of a phosphene in depth. Knowing how electrical microstimulation interacts with cortical tissue to evoke percepts in behaving macaque monkeys is fundamental to the establishment of an effective cortical visual prosthesis for the blind.

Modulation of phosphene perception during saccadic eye movements: a transcranial magnetic stimulation study of the human visual cortex.

Saccadic suppression allows for perceptual stability during rapid movements of the eyes. One of the neural mechanisms may involve saccade-related modulation of neural activity in the visual cortex. Using the perception of phosphenes induced by transcranial magnetic stimulation (TMS) applied over the visual cortex (VC) as an index of cortical excitability, we sought to determine if VC excitability was modulated at varying times relative to saccade onset. We used two measures of excitability: (1) stimulator intensity required to induce phosphenes in 50% of trials, also called the phosphene threshold (PT), and (2) the subjective intensity of the phosphene. We found that there was no change in PT for different saccade-TMS onset asynchronies while there was an increase in perceived phosphene-intensity near the time of saccade onset (F(7,42) = 4.34, P = 0.001). Contrary to what would be expected from a saccadic suppression model, our results suggest that excitability of the visual cortex is slightly enhanced at the time of saccade onset.

Hypo-excitability of cortical areas in patients affected by Friedreich ataxia: a TMS study.

The aim of the study was to explore excitability of a motor and a non-motor (visual) area in patients affected by Friedreich ataxia and to correlate neurophysiological data with clinical parameters. Seven patients (3M/4F) and ten healthy controls (5M/5F) participated in the study. The hot-spot for activation of right abductor pollicis brevis was checked by means of a figure-of-eight coil and the motor threshold (MT) on this point was recorded. The phosphene threshold (PT) was measured by means of a focal coil over the occipital cortex as the lower intensity of magnetic stimulation able to induce the perception of phosphenes. The patients showed a significantly higher mean PT (p<.03) and MT values (p<.001) than controls. In all but one patient unable to perceive phosphenes (42% vs. 50% of controls), TMS at 100% intensity did not elicit motor response at rest. The difference in percentage of patients (57.1%) and controls (100%) with motor responses was nearly significant. The size of GAA1 expansion showed significant correlations with PT and MT values. The results of our study showed that FA patients had reduced cortical activation, involving both the motor and the visual cortex. The cortical involvement in these patients seems to be mainly genetically determined. The study provides the first evidence of cortical dysfunction in patients with genetically defined Friedreich ataxia.

Phosphene induction and the generation of saccadic eye movements by striate cortex.

The purpose of this review is to critically examine phosphene induction and saccadic eye movement generation by electrical microstimulation of striate cortex (area V1) in humans and monkeys. The following issues are addressed: 1) Properties of electrical stimulation as they pertain to the activation of V1 elements; 2) the induction of phosphenes in sighted and blind human subjects elicited by electrical stimulation using various stimulation parameters and electrode types; 3) the induction of phosphenes with electrical microstimulation of V1 in monkeys; 4) the generation of saccadic eye movements with electrical microstimulation of V1 in monkeys; and 5) the tasks involved for the development of a cortical visual prosthesis for the blind. In this review it is concluded that electrical microstimulation of area V1 in trained monkeys can be used to accelerate the development of an effective prosthetic device for the blind.

Dosimetry considerations in the head and retina for extremely low frequency electric fields.

Magnetophosphenes are investigated from the viewpoint of electromagnetic dosimetry. Induced current density and internal electric fields at the threshold of perception are estimated by analytical and numerical calculations, assuming different models. Dosimetry for electrophosphenes is also discussed and compared with that for magnetophosphenes. The distribution of current density and internal electric fields is consistent with the experimental observation that flashing sensations reach their greatest intensity at the periphery of the visual field, for both electro and magnetophosphenes. The estimated thresholds in internal electric fields are consistent for magnetophosphenes and for electrophosphenes, respectively. The magnitudes of the thresholds, however, differ by about 10-fold. The thresholds in induced current density are critically dependent on the conductivity of the eye assumed for the calculations. The effect of thin membrane structure is also discussed with regard to the difference between electric field and magnetic field exposures.

Modulation of moving phosphene thresholds by transcranial direct current stimulation of V1 in human.

Small moving sensations, so-called moving phosphenes are perceived, when V5, a visual area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if only V5 takes part in movement perception or other visual areas are also involved in this process. In this study we tested the involvement of V1 in the perception of moving phosphenes by applying transcranial direct current stimulation (tDCS) to this area. tDCS is a non-invasive stimulation technique known to modulate cortical excitability in a polarity-specific manner. Moving and stationary phosphene thresholds (PT) were measured by TMS before, immediately after and 10, 20 and 30 min after the end of 10 min cathodal and anodal tDCS in nine healthy subjects. Reduced PTs were detected immediately and 10 min after the end of anodal tDCS while cathodal stimulation resulted in an opposite effect. Our results show that the excitability shifts induced by V1 stimulation can modulate moving phosphene perception. tDCS elicits transient, but yet reversible effects, thus presenting a promising tool for neuroplasticity research.

Visual and motor cortex excitability: a transcranial magnetic stimulation study.

OBJECTIVES: Phosphene thresholds (PTs) to transcranial magnetic stimulation over the occipital cortex and motor thresholds (MTs) have been used increasingly as measures of the excitability of the visual and motor cortex. MT has been utilized as a guide to the excitability of other, non-motor cortical areas such as dorsolateral prefrontal cortex. The aims of this study were to compare the PTs to MTs; to assess their stability across sessions; and to investigate their relation to MTs. METHODS: PTs and MTs were determined using focal transcranial magnetic stimulation over the visual and motor cortex. RESULTS: PTs were shown to be significantly higher than MTs. Both PTs and MTs were stable across sessions. No correlation between PTs and MTs could be established. CONCLUSIONS: Phosphene threshold is a stable parameter of the visual cortex excitability. MTs were not related to the excitability of non-motor cortical areas.