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Background: Retinal prostheses offer hope for individuals with degenerative retinal diseases by stimulating the remaining retinal cells to partially restore their vision. This review delves into the current advancements in retinal prosthesis technology, with a special emphasis on the pivotal role that image processing and machine learning techniques play in this evolution., Methods: We provide a comprehensive analysis of the existing implantable devices and optogenetic strategies, delineating their advantages, limitations, and challenges in addressing complex visual tasks. The review extends to various image processing algorithms and deep learning architectures that have been implemented to enhance the functionality of retinal prosthetic devices. We also illustrate the testing results by demonstrating the clinical trials or using Simulated Prosthetic Vision (SPV) through phosphene simulations, which is a critical aspect of simulating visual perception for retinal prosthesis users., Results: Our review highlights the significant progress in retinal prosthesis technology, particularly its capacity to augment visual perception among the visually impaired. It discusses the integration between image processing and deep learning, illustrating their impact on individual interactions and navigations within the environment through applying clinical trials and also illustrating the limitations of some techniques to be used with current devices, as some approaches only use simulation even on sighted-normal individuals or rely on qualitative analysis, where some consider realistic perception models and others do not., Conclusion: This interdisciplinary field holds promise for the future of retinal prostheses, with the potential to significantly enhance the quality of life for individuals with retinal prostheses. Future research directions should pivot towards optimizing phosphene simulations for SPV approaches, considering the distorted and confusing nature of phosphene perception, thereby enriching the visual perception provided by these prosthetic devices. This endeavor will not only improve navigational independence but also facilitate a more immersive interaction with the environment., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Transcranial magnetic stimulation (TMS) is commonly delivered at an intensity defined by the resting motor threshold (rMT), which is thought to represent cortical excitability, even if the TMS target area falls outside of the motor cortex. This approach rests on the assumption that cortical excitability, as measured through the motor cortex, represents a 'global' measure of excitability. Another common approach to measure cortical excitability relies on the phosphene threshold (PT), measured through the visual cortex of the brain. However, it remains unclear whether either estimate can serve as a singular measure to infer cortical excitability across different brain regions. If PT and rMT can indeed be used to infer cortical excitability across brain regions, they should be correlated. To test this, we systematically identified previous studies that measured PT and rMT to calculate an overall correlation between the two estimates. Our results, based on 16 effect sizes from eight studies, indicated that PT and rMT are correlated (ρ = 0.4), and thus one measure could potentially serve as a measure to infer cortical excitability across brain regions. Three exploratory meta-analyses revealed that the strength of the correlation is affected by different methodologies, and that PT intensities are higher than rMT. Evidence for a PT-rMT correlation remained robust across all analyses. Further research is necessary for an in-depth understanding of how cortical excitability is reflected through TMS., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Early visual cortex (V1-V3) is believed to be critical for normal visual awareness by providing the necessary feedforward input. However, it remains unclear whether visual awareness can occur without further involvement of early visual cortex, such as re-entrant feedback. It has been challenging to determine the importance of feedback activity to these areas because of the difficulties in dissociating this activity from the initial feedforward activity. Here, we applied single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal cortex to elicit phosphenes in the absence of direct visual input to early visual cortex. Immediate neural activity after the TMS pulse was assessed using the event-related optical signal (EROS), which can measure activity under the TMS coil without artifacts. Our results show that: 1) The activity in posterior parietal cortex 50 ms after TMS was related to phosphene awareness, and 2) Activity related to awareness was observed in a small portion of V1 140 ms after TMS, but in contrast (3) Activity in V2 was a more robust correlate of awareness. Together, these results are consistent with interactive models proposing that sustained and recurrent loops of activity between cortical areas are necessary for visual awareness to emerge. In addition, we observed phosphene-related activations of the anteromedial cuneus and lateral occipital cortex, suggesting a functional network subserving awareness comprising these regions, the parietal cortex and early visual cortex., (Published by Elsevier Ltd.)

The visual system has long been considered equivalent across hemispheres. However, an increasing amount of data shows that functional differences may exist in this regard. We therefore tried to characterize the emergence of visual perception and the spatiotemporal dynamics resulting from the stimulation of visual cortices in order to detect possible interhemispheric asymmetries. Eighteen participants were tested. Each of them received 360 transcranial magnetic stimulation (TMS) pulses at phosphene threshold intensity over left and right early visual areas while electroencephalography was being recorded. After each single pulse, participants had to report the presence or absence of a phosphene. Local mean field power analysis of TMS-evoked potentials showed an effect of both site (left vs. right TMS) of stimulation and hemisphere (ipsilateral vs. contralateral to the TMS): while right TMS determined early stronger activations, left TMS determined later stronger activity in contralateral electrodes. The interhemispheric signal propagation index revealed differences in how TMS-evoked activity spreads: left TMS-induced activity diffused contralaterally more than right stimulation. With regard to phosphenes perception, distinct electrophysiological patterns were found to reflect similar perceptual experiences: left TMS-evoked phosphenes are associated with early occipito-parietal and frontal activity followed by late central activity; right TMS-evoked phosphenes determine only late, fronto-central, and parietal activations. Our results show that left and right occipital TMS elicits differential electrophysiological patterns in the brain, both per se and as a function of phosphene perception. These distinct activation patterns may suggest a different role of the two hemispheres in processing visual information and giving rise to perception., (© 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Stimuli that potentially require a rapid defensive or avoidance action can appear from the periphery at any time in natural environments. de Wit et al. ( Cortex 127: 120-130, 2020) recently reported novel evidence suggestive of a fundamental neural mechanism that allows organisms to effectively deal with such situations. In the absence of any task, motor cortex excitability was found to be greater whenever gaze was directed away from either hand. If modulation of cortical excitability as a function of gaze location is a fundamental principle of brain organization, then one would expect its operation to be present outside of motor cortex, including brain regions involved in perception. To test this hypothesis, we applied single-pulse transcranial magnetic stimulation (TMS) to the right lateral occipital lobe while participants directed their eyes to the left, straight-ahead, or to the right, and reported the presence or absence of a phosphene. No external stimuli were presented. Cortical excitability as reflected by the proportion of trials on which phosphenes were elicited from stimulation of the right visual cortex was greater with eyes deviated to the right as compared with the left. In conjunction with our previous findings of change in motor cortex excitability when gaze and effector are not aligned, this eye position-driven change in visual cortex excitability presumably serves to facilitate the detection of stimuli and subsequent readiness to act in nonfoveated regions of space. The existence of this brain-wide mechanism has clear adaptive value given the unpredictable nature of natural environments in which human beings are situated and have evolved. NEW & NOTEWORTHY For many complex tasks, humans focus attention on the site relevant to the task at hand. Humans evolved and live in dangerous environments, however, in which threats arise from outside the attended site; this fact necessitates a process by which the periphery is monitored. Using single-pulse transcranial magnetic stimulation (TMS), we demonstrated for the first time that eye position modulates visual cortex excitability. We argue that this underlies at least in part what we term "surveillance attention."

Background: Virtually everyone is exposed to power-frequency MF (50/60 Hz), inducing in our body electric fields and currents, potentially modulating brain function. MF-induced electric fields within the central nervous system can generate flickering visual perceptions (magnetophosphenes), which form the basis of international MF exposure guidelines and recommendations protecting workers and the general public. However, magnetophosphene perception thresholds were estimated 40 years ago in a small, unreplicated study with significant uncertainties and leaving open the question of the involved interaction site., Methods: We used a stimulation modality termed transcranial alternating magnetic stimulation (tAMS), delivering in situ sinusoidal electric fields comparable to transcranial alternating current stimulation (tACS). Magnetophosphene perception was quantified in 81 volunteers exposed to MF (eye or occipital exposure) between 0 and 50 mT at frequencies of 20, 50, 60 and 100 Hz., Results: Reliable magnetophosphene perception was induced with tAMS without any scalp sensation, a major advantage as compared to tACS. Frequency-dependent thresholds were quantified using binary logistic regressions hence allowing to establish condition dependent probabilities of perception. Results support an interaction between induced current density and retinal rod cells., Conclusion: Beyond fundamental and immediate implications for international safety guidelines, and for identifying the interaction site underlying phosphene perception (ubiquitous in tACS experiments), our results support exploring the potential of tAMS for the differential diagnosis of retinal disorders and neuromodulation therapy., Competing Interests: Declaration of competing interest On the behalf of all the co-authors, I declare that neither me nor the co-authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study presents phosphenotron, a device for enhancing the sensory spatial resolution of phosphenes in the visual field (VF). The phosphenotron employs a non-invasive transcranial alternating current stimulation (NITACS) to modulate brain activity by applying weak electrical currents to the scalp or face. NITACS's unique application induces phosphenes, a phenomenon where light is perceived without external stimuli. Unlike previous invasive methods, NITACS offers a non-invasive approach to create these effects. The study focused on assessing the spatial resolution of NITACS-induced phosphenes, crucial for advancements in visual aid technology and neuroscience. Eight participants were subjected to NITACS using a novel electrode arrangement around the eye orbits. Results showed that NITACS could generate spatially defined phosphene patterns in the VF, varying among individuals but consistently appearing within their VF and remaining stable through multiple stimulations. The study established optimal parameters for vibrant phosphene induction without discomfort and identified electrode positions that altered phosphene locations within different VF regions. Receiver Operating characteristics analysis indicated a specificity of 70.7%, sensitivity of 73.9%, and a control trial accuracy of 98.4%. These findings suggest that NITACS is a promising, reliable method for non-invasive visual perception modulation through phosphene generation.

Recent advances in neuroscience have challenged the view of conscious visual perception as a continuous process. Behavioral performance, reaction times and some visual illusions all undergo periodic fluctuations that can be traced back to oscillatory activity in the brain. These findings have given rise to the idea of a discrete sampling mechanism in the visual system. In this study we seek to investigate the causal relationship between occipital alpha oscillations and Temporal Order Judgements using neural entrainment via rhythmic TMS in 18 human subjects (9 females). We find that certain phases of the entrained oscillation facilitate temporal order perception of two visual stimuli, whereas others hinder it. Our findings support the idea that the visual system periodically compresses information into discrete packages within which temporal order information is lost. SIGNIFICANCE STATEMENT: Neural entrainment via TMS serves as a valuable tool to interfere with cortical rhythms and observe changes in perception. Here, using α-rhythmic TMS-pulses, we demonstrate the effect of the phase of entrained oscillations on performance in a temporal order judgment task. In extension of previous work, we 1. causally influenced brain rhythms far more directly using TMS, and 2. showed that previous results on discrete perception cannot simply be explained by rhythmic fluctuations in visibility. Our findings support the idea that the temporal organization of visual processing is discrete rather than continuous, and is causally modulated by cortical rhythms. To our knowledge, this is the first study providing causal evidence via TMS for an endogenous periodic modulation of time perception., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Transcranial magnetic stimulation (TMS)-evoked phosphenes are oculocentric; their perceived location depends upon eye position. We investigated the accuracy and precision of TMS-evoked phosphene oculocentric mapping., Methods: We evoked central phosphenes by stimulating early visual cortical areas with TMS, systematically examining the effect of eye position by asking participants to report the location of the evoked phosphene. We tested whether any systematic differences in the precision or accuracy of responses occurred as a function of eye position., Results: Perceived phosphene locations map veridically to eye position, although there are considerable individual differences in the reliability of this mapping., Conclusions: Our results emphasize the need to carefully control eye movements when carrying out phosphene localization studies and suggest that individual differences in the reliability of the reported position of individual phosphenes must be considered., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Electrical stimulation involving visual areas of the brain produces artificial light percepts called phosphenes. These visual percepts have been extensively investigated in previous studies involving intracortical microsimulation (ICMS) and serve as the basis for developing a visual prosthesis for the blind. Although advances have been achieved, many challenges still remain with implementing a functional ICMS for visual rehabilitation purposes. Transcranial magnetic stimulation (TMS) over the primary occipital lobe offers an alternative method to produce phosphenes non-invasively. A main challenge facing blind individuals involves navigation. Within the scientific community, methods to evaluate the ability of a visual prosthesis to facilitate in navigation has been neglected. In this study, we investigate the effectiveness of evoking lateralized phosphenes to navigate a computer simulated virtual environment. More importantly, we demonstrate how virtual environments along with the development of a visual prosthesis share a mutual relationship benefiting both patients and researchers. Using two TMS devices, a pair of 40mm figure-of-eight coils were placed over each occipital hemisphere resulting in lateralized phosphene perception. Participants were tasked with making a series of left and right turns using peripheral devices depending on the visual hemifield in which a phosphene is present. If a participant was able to accurately perceive all ten phosphenes, the simulated target is able to advance and fully exit the virtual environment. Our findings demonstrate that participants can interpret lateralized phosphenes while highlighting the integration of computer based virtual environments to evaluate the capability of a visual prosthesis during navigation., Competing Interests: The authors have declared that no competing interests exist.

Blindness affects 40 million people across the world. A neuroprosthesis could one day restore functional vision in the blind. We implanted a 1024-channel prosthesis in areas V1 and V4 of the visual cortex of monkeys and used electrical stimulation to elicit percepts of dots of light (called phosphenes) on hundreds of electrodes, the locations of which matched the receptive fields of the stimulated neurons. Activity in area V4 predicted phosphene percepts that were elicited in V1. We simultaneously stimulated multiple electrodes to impose visible patterns composed of a number of phosphenes. The monkeys immediately recognized them as simple shapes, motions, or letters. These results demonstrate the potential of electrical stimulation to restore functional, life-enhancing vision in the blind., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Orienting covert exogenous (involuntary) attention to a target location improves performance in many visual tasks [1, 2]. It is unknown whether early visual cortical areas are necessary for this improvement. To establish a causal link between these areas and attentional modulations, we used transcranial magnetic stimulation (TMS) to briefly alter cortical excitability and determine whether early visual areas mediate the effect of exogenous attention on performance. Observers performed an orientation discrimination task. After a peripheral valid, neutral, or invalid cue, two cortically magnified gratings were presented, one in the stimulated region and the other in the symmetric region in the opposite hemifield. Observers received two successive TMS pulses around their occipital pole while the stimuli were presented. Shortly after, a response cue indicated the grating whose orientation observers had to discriminate. The response cue either matched-target stimulated-or did not match-distractor stimulated-the stimulated side. Grating contrast was varied to measure contrast response functions (CRF) for all combinations of attention and TMS conditions. When the distractor was stimulated, exogenous attention yielded response gain-performance benefits in the valid-cue condition and costs in the invalid-cue condition compared with the neutral condition at the high contrast levels. Crucially, when the target was stimulated, this response gain was eliminated. Therefore, TMS extinguished the effect of exogenous attention. These results establish a causal link between early visual areas and the modulatory effect of exogenous attention on performance., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sensory perception can be modulated by the phase of neural oscillations, especially in the theta and alpha ranges. Oscillatory activity in the visual cortex can be entrained by transcranial alternating current stimulation (tACS) as well as periodic visual stimulation (i.e., flicker). Combined tACS and visual flicker stimulation modulates BOLD response, and concurrent 4-Hz auditory click train, and tACS modulate auditory perception in a phase-dependent way. In this study, we investigated whether phase synchrony between concurrent tACS and periodic visual stimulation (i.e., flicker) can modulate performance on a visual matching task. Participants completed a visual matching task on a flickering visual stimulus while receiving either in-phase (0°) or asynchronous (180°, 90°, or 270°) tACS at alpha or theta frequency. Stimulation was applied over either occipital cortex or dorsolateral pFC. Visual performance was significantly better during theta frequency tACS over the visual cortex when it was in-phase (0°) with visual stimulus flicker, compared with antiphase (180°). This effect did not appear with alpha frequency flicker or with dorsolateral pFC stimulation. Furthermore, a control sham group showed no effect. There were no significant performance differences among the asynchronous (180°, 90°, and 270°) phase conditions. Extending previous studies on visual and auditory perception, our results support a crucial role of oscillatory phase in sensory perception and demonstrate a behaviorally relevant combination of visual flicker and tACS. The spatial and frequency specificity of our results have implications for research on the functional organization of perception.

Prosthetic vision is being applied to partially recover the retinal stimulation of visually impaired people. However, the phosphenic images produced by the implants have very limited information bandwidth due to the poor resolution and lack of color or contrast. The ability of object recognition and scene understanding in real environments is severely restricted for prosthetic users. Computer vision can play a key role to overcome the limitations and to optimize the visual information in the prosthetic vision, improving the amount of information that is presented. We present a new approach to build a schematic representation of indoor environments for simulated phosphene images. The proposed method combines a variety of convolutional neural networks for extracting and conveying relevant information about the scene such as structural informative edges of the environment and silhouettes of segmented objects. Experiments were conducted with normal sighted subjects with a Simulated Prosthetic Vision system. The results show good accuracy for object recognition and room identification tasks for indoor scenes using the proposed approach, compared to other image processing methods., Competing Interests: The authors have declared that no competing interests exist.

Transcranial magnetic stimulation is used to explore visual cortex hyperexcitability in migraine. We hypothesized that the phosphene threshold in subjects suffering from migraines with and without aura would be lower than in controls, and this phenomenon could be linked to higher pain and disability levels. We also implied that subjects with lower phosphene threshold could see more phosphenes of different colors and shapes. Our primary objective was to compare the phosphene threshold between migraine without aura, migraine with aura, and control groups and investigate which factors contribute to different phosphene parameters in migraineurs. Secondary objectives were to compare color, shape, and number of phosphenes between groups and assess pain and disability level correlation with the phosphene characteristics. Phosphene threshold in migraine without aura, migraine with aura, and control groups were 68 ± 9.5% vs. 75 ± 12%, vs. 80 ± 11%, respectively. Other phosphene parameters (number, color and shape) did not differ between groups. Average pain level during the attack did not correlate with phosphene threshold significantly, though the non-significant trend for negative correlation of migraine disability assessment scale score and a phosphene threshold has been found the higher was migraine disability assessment scale value, the lower was phosphene threshold (β = -0.255; P = 0.139). Other variables: gender, age, migraine subtype, migraine duration and use of hormone contraceptives - were not related to the phosphene threshold value. Our study provides additional data on visual cortex hyperexcitability in migraineurs, regarding transcranial magnetic stimulation with a figure-of-eight coil. Visual cortex excitability might be linked to higher disability., Competing Interests: The authors declare no conflict of interest., (© 2019 Ekkert et al. Published by IMR press.)

Paired-pulse transcranial magnetic stimulation (ppTMS) has been used extensively to probe local facilitatory and inhibitory function in motor cortex. We previously developed a reliable ppTMS method to investigate these functions in visual cortex and found reduced thresholds for net intracortical inhibition compared to motor cortex. The current study used this method to investigate the temporal dynamics of local facilitatory and inhibitory networks in visual cortex in 28 healthy subjects. We measured the size of the visual disturbance (phosphene) evoked by stimulating visual cortex with a fixed intensity, supra-threshold test stimulus (TS) when that TS was preceded by a sub-threshold conditioning stimulus (CS). We manipulated the inter-stimulus interval (ISI) and assessed how the size of the phosphene elicited by the fixed-intensity TS changed as a function of interval for two different CS intensities (45% and 75% of phosphene threshold). At 45% of threshold, the CS produced uniform suppression of the phosphene elicited by the TS across ISIs ranging from 2 to 200 ms. At 75% of threshold, the CS did not have a significant effect on phosphene size across the 2-15 ms intervals. Intervals of 50-200 ms exhibited statistically significant suppression of phosphenes, however, suppression was not uniform with some subjects demonstrating no change or facilitation. This study demonstrates that the temporal dynamics of local inhibitory and facilitatory networks are different across motor and visual cortex and that optimal parameters to index local inhibitory and facilitatory influences in motor cortex are not necessarily optimal for visual cortex. We refer to the observed inhibition as visual cortex inhibition (VCI) to distinguish it from the phenomenon reported in motor cortex., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Selecting optimal stimulation parameters from numerous possibilities is a major obstacle for assessing the efficacy of non-invasive brain stimulation., Objective: We demonstrate that Bayesian optimization can rapidly search through large parameter spaces and identify subject-level stimulation parameters in real-time., Methods: To validate the method, Bayesian optimization was employed using participants' binary judgements about the intensity of phosphenes elicited through tACS., Results: We demonstrate the efficiency of Bayesian optimization in identifying parameters that maximize phosphene intensity in a short timeframe (5 min for >190 possibilities). Our results replicate frequency-dependent effects across three montages and show phase-dependent effects of phosphene perception. Computational modelling explains that these phase effects result from constructive/destructive interference of the current reaching the retinas. Simulation analyses demonstrate the method's versatility for complex response functions, even when accounting for noisy observations., Conclusion: Alongside subjective ratings, this method can be used to optimize tACS parameters based on behavioral and neural measures and has the potential to be used for tailoring stimulation protocols to individuals., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

It is well known that applying transcranial alternating current stimulation (tACS) to the scalp can generate artefactual visual perceptions of flashing or shimmering light known as phosphenes. The thresholds for generating these phosphenes have been used by international standards bodies to provide conservative estimates of the field strength required to interfere with human neural functioning and set safety limits accordingly. However, the precise relationship between electric currents and phosphene perception thresholds remains uncertain. The present study used tACS to systematically investigate the effects of the location and the frequency of stimulation on phosphene perception thresholds. These thresholds were obtained from 24 participants using a within-subject design as a function of scalp stimulation sites (FPz-Cz versus Oz-Cz) and stimulation frequency (2-30 Hz in steps of 2 Hz). Phosphene perception thresholds were consistently lower for FPz-Cz stimulation, and regardless of tACS location were lowest for 16 Hz stimulation. Threshold variation between participants was very small, which is meaningful when setting standards based on phosphenes. Bioelectromagnetics. 2019;40:365-374. © 2019 Bioelectromagnetics Society., (© 2019 Bioelectromagnetics Society.)

Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects. SIGNIFICANCE STATEMENT Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are unknown, making it difficult to optimize in any given application. We studied the physical mechanism by which ultrasound is converted into an effective energy form to cause neurostimulation in the retina and find that ultrasound acts via radiation force leading to a mechanical displacement of tissue. We further show that standing waves have a strong modulatory effect on activity. Our quantitative model by which ultrasound generates radiation force and leads to neural activity will be important in optimizing ultrasonic neurostimulation across a wide range of applications., (Copyright © 2019 the authors.)

Objective: Microstimulation to the cortical tissue applied with penetrating electrodes delivers current that spreads concentrically around the electrode tip and is known to evoke focal visual sensations, i.e. phosphenes. However, to date, there is no direct evidence depicting the spatiotemporal properties of neuronal activity induced immediately after microstimulation and how such activity drives the subsequent local cortical circuits., Approach: In the present study, we imaged the spatiotemporal distribution of action potentials (APs) directly induced by microstimulation and the subsequent trans-synaptic signal propagation using a voltage-sensitive dye (VSD) and a calcium-sensitive dye (CaSD) in slice preparations of the mouse primary visual cortex., Main Results: The directly induced APs were confined to the close vicinity of the electrode tip, and the effective distance of excitation was proportional to the square root of the current intensity. The excitation around the electrode tip in layer IV mainly propagated to layer II/III to further induce the subsequent focal activation in downstream local cortical circuits. The extent of activation in the downstream circuits was restrained by competitive interactions between excitatory and inhibitory signals. Namely, the spread of the excitation to lateral neighbor neurons along the layer II/III was confined by the delayed inhibition that also spread laterally at a faster rate., Significance: These observations indicate that dynamic interactions between excitatory and inhibitory signals play a critical role in the focal activation of a cortical circuit in response to intracortical microstimulation and, therefore, in evoking a localized phosphene.

There is very little published literature on treatment strategies for functional visual loss. We present two people with long duration of functional visual loss who achieved complete recovery with a novel combination of therapeutic approaches. These included: (1) the clinician being transparent regarding positive signs such as optokinetic nystagmus, in order to persuade family members of the diagnosis, (2) regularly positively acknowledging everyday events that indicated visual ability, (3) using occipital transcranial magnetic stimulation to induce phosphenes as an artificial temporary visual experience and (4) using hypnotherapy to promote visual recovery. We discuss these individual therapeutic approaches in further detail including their background and rationale and include patients' reflection on their treatment experiences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Visual snow syndrome (VS) is mainly characterized by flickering, little dots in both visual fields. The recognition of the clinical entity of VS has been increasing recently. Diagnosis is based on patient reports and not better accounted for by another diagnosis., Background: The exact pathophysiology of this syndrome is still unknown. In this study, our aim was to investigate the role of neurophysiological assessments of the occipital cortex in VS patients with (VS m ) or without migraine (VS wom ) and the healthy control (HC)., Methods: To assess the occipital cortex hyperexcitability, we conducted a prospective, observational study to investigate the habituation/potentiation response by repetitive pattern reversal visual evoked potentials (rVEP) and examined the phosphene thresholds (PT) by transcranial magnetic stimulation in VS patients with or without migraine who were admitted to our tertiary headache clinic and the healthy control., Results: Twenty-nine volunteers were recruited. The VS m (n = 10), the VS wom (n = 7), and the HC group (n = 12) did not differ demographically. Flickering and floaters were reported in all VS patients and flickering in the dark was the most distressing symptomatology in both VS groups. Higher VAS scores for palinopsia (trailing), photophobia, and concentration difficulty were more frequently self-reported by VS m patients. The HC demonstrated habituation; however, there was loss of habituation response and decreased PTs in both groups of VS patients. The N1P1 VEP amplitude ratios of the 10th/1st block from right and left eye stimulation disclosed higher values (lack of habituation) in VS m (1.04 ± 0.2 and 1.06 ± 0.2) and the VS wom (1.05 ± 0.2 and 0.96 ± 0.08) patients compared to the healthy control (0.75 ± 0.1 and 0.79 ± 0.1), P = .002 from right eye and P = .003 from left eye. In the post hoc analysis the VS patients did not differ according to the presence of migraine from right or left eye stimulations (both P > .999). The left occipital cortex PTs were lower in VS m (58.00 ± 6.60) and VS wom (62.14 ± 11.53) and higher in the HC (71.33 ± 5.56) P = .009. In the post hoc analysis the VS patients did not differ according to the presence of migraine (P > .999). The right occipital cortex PTs were lower in VS m (60.30 ± 8.15) and VS wom (62.00 ± 10.95), higher in the HC (69.67 ± 8.04); however, statistically, groups did not differ (P = .087)., Conclusions: The loss of habituation and lower threshold for occipital cortex excitability were demonstrated electrophysiologically in VS patients. While statistically significant loss of habituation was seen in both VS patients (with or without migraine) in the right eye, statistically significant loss of habituation in the left eye and decreased threshold of left occipital cortex excitability was seen in visual snow with migraine patients. These findings may provide new insights on "visual snow" pathophysiology and serve as an objective and quantitative assessment tool in VS patients., (© 2019 American Headache Society.)

Background and Purpose: Two plausible mechanisms to explain the appearance of visual phosphenes are: direct activation of the photochemicals in the retina and the generation of Cherenkov radiation in the vitreous humour. In this clinical trial we investigated the occurrence of visual phosphenes in external photon beam radiation therapy., Material and Methods: Logistic regression analysis is used to examine whether seeing light flashes and seeing steady light depended on the ambient light intensity and the dose., Results: In total, 465 treatments of 25 patients were analysed. The odds of seeing light flashes multiply by 0,926 as the ambient light intensity increases by 10 lux. Similarly, the odds multiply by 1,604 as the dose to the retina increases by 10 cGy. The odds of seeing steady light multiply by 1,540 as the dose to the vitreous humour increases by 10 cGy., Conclusions: We postulate that one should reduce the dose rate, instruct patients to keep the eyes open and increase the illuminance in the treatment room to reduce the probability of experiencing visual phosphenes. We hypothesize that melanopsin is involved in the visual phosphenes and that fatigue of patients might be correlated with the observation of visual phosphenes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Phosphene generation is an objective physical measure of potential transcranial alternating current stimulation (tACS) biological side effects. Interpretations from phosphene analysis can serve as a first step in understanding underlying mechanisms of tACS in healthy human subjects and assist validation of computational models., Objective/hypothesis: This preliminary study introduces and tests methods to analyze predicted phosphene occurrence using computational head models constructed from tACS recipients against verbal testimonies of phosphene sensations. Predicted current densities in the eyes and the occipital lobe were also verified against previously published threshold values for phosphenes., Methods: Six healthy subjects underwent 10 Hz tACS while being imaged in an MRI scanner. Two different electrode montages, T7-T8 and Fpz-Oz, were used. Subject ratings of phosphene experience were collected during tACS and compared against current density distributions predicted in eye and occipital lobe regions of interest (ROIs) determined for each subject. Calculated median current densities in each ROI were compared to minimum thresholds for phosphene generation., Main Results: All subjects reported phosphenes, and predicted median current densities in ROIs exceeded minimum thresholds for phosphenes found in the literature. Higher current densities in the eyes were consistently associated with decreased phosphene generation for the Fpz-Oz montage. There was an overall positive association between phosphene perceptions and current densities in the occipital lobe., Conclusions: These methods may have promise for predicting phosphene generation using data collected during in-scanner tACS sessions and may enable better understanding of phosphene origin. Additional empirical data in a larger cohort is required to fully test the robustness of the proposed methods. Future studies should include additional montages that could dissociate retinal and occipital stimulation.

The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild-type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20 Hz; envelope frequency constantly kept at 1.2 Hz) and intensities (10, 20, 50 μA) were recorded and compared with those obtained with light stimulation (1.2 Hz sinusoidal blue, red light). A strong correlation between the sinusoidal stimulation (electrical as well as light) and the pupillary sinusoidal response was found. The difference between the lag of electrical and light stimulation allowed the estimation of an intensity threshold for pupillary responses to transcorneal electrostimulation (mean ± SD: 30 ± 10 μA (10 Hz); 38 ± 10 μA (20 Hz)). A comparison between the results of the two stimulation frequencies showed a not statistically significant smaller lag for 10 Hz (10 Hz: 633 ± 90 ms; 20 Hz: 725 ± 178 ms; 50 μA intensity). Analogous in vitro experiments on murine retinas indicated a selective stimulation of photoreceptors and bipolar cells (lower frequencies) and retinal ganglion cells (higher frequencies) and lower stimulation thresholds for the retinal network with sinusoidal compared to pulsatile stimulation - emphasizing that sinusoidal waveforms are well-suited to our purposes. We demonstrate that pupillary responses to sinusoidal transcorneal electrostimulation are measurable as an objective marker in healthy young subjects, even at very low stimulus intensities. By using this unique approach, we unveil the potential for an estimation of the individual intensity threshold and a selective activation of different retinal cell types in humans by varying the stimulation frequency. This technique may have broad clinical utility as well as specific relevance in the monitoring of patients with hereditary retinal disorders, especially as implemented in study protocols for novel therapies, e.g. retinal prostheses or gene therapies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Transcranial random noise stimulation (tRNS) can cause long term increase of corticospinal excitability when used to prime the motor cortex, before measuring the motor response in the hand muscles with TMS (Terney et al., 2008). In cognitive studies, tRNS has been used to improve visual attention and mathematical skills, an enhancement effect that might suggest sustained cortical plasticity changes (Cappelletti et al., 2013; Snowball et al., 2013). However, while the behavioral evidence of increased performance is becoming substantiated by empirical data, it still remains unclear whether tRNS over visual areas causes an increase in cortical excitability similar to what has been found in the motor cortex, and if that increase could be a potential physiological explanation for behavioral improvements found in visual tasks., Objective/hypothesis: In the present study, we aimed to investigate whether priming the visual cortex with tRNS leads to increased and sustained excitability as measured with visual phosphenes., Methods: We measured phosphene thresholds (PTs) using an objective staircase method to quantify the magnitude of cortical excitability changes. Single-pulse TMS was used to elicit phosphenes before, immediately after, and every 10 min up to one hour after the end of 20 min tRNS, anodal tDCS (a-tDCS) or sham., Results: Results showed that phosphene thresholds were significantly reduced up to 60 min post stimulation relative to baseline after tRNS, a behavioral marker of increased excitability of the visual cortex, while a-tDCS had no effect. This result is very similar in magnitude and duration to what has been found in the motor cortex., Conclusions: Our findings demonstrate promising potential of tRNS as a tool to increase and sustain cortical excitability to promote improvement of cognitive functions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The aim of this study was to evaluate the effects of transcorneal electrical stimulation in subjects with primary open-angle glaucoma. Five eyes of four male subjects with primary open-angle glaucoma (average age: 52.25 ± 14.68 years) were enrolled. The subjects underwent transcorneal electrical stimulation every 3 months according to the following procedure. A Dawson-Trick-Litzkow electrode was placed on the cornea, and biphasic electric current pulses (10 ms, 20 Hz) were delivered using a stimulator (BPG-1,BAK Electronics) and a stimulus isolation unit (BSI-2). A current that evoked a phosphene that the subject perceived in the whole visual area was delivered continuously for 30 min. Humphrey visual field testing was performed after every third transcorneal electrical stimulation treatment. Changes in mean deviation (MD) values were evaluated with a linear regression model. Transcorneal electrical stimulation was performed 18.2 ± 9.4 times over a period of 49.8 ± 23.0 months. The average pretranscorneal electrical stimulation intraocular pressure, best corrected visual acuity, and MD values were 11.8 ± 1.79 mmHg, 0.14 ± 0.19 (logMAR) and -17.28 ± 6.24 dB, respectively. No significant differences were observed in intraocular pressure before and after transcorneal electrical stimulation. However, there was a significant positive linear relationship between changes in MD values and the number of transcorneal electrical stimulation treatments (R 2 = 0.176, P = 0.005, Spearman correlation R =0.294, P = 0.008). Transcorneal electrical stimulation treatment may improve glaucomatous visual field defects in subjects with primary open-angle glaucoma. Large-scale studies are necessary to confirm these preliminary findings.

This article profiles visual auras among traumatized Cambodian refugees attending a psychiatric clinic. Thirty-six percent (54/150) had experienced an aura in the previous 4 weeks, almost always phosphenes (48% [26/54]) or a scintillating scotoma (74% [40/54]). Aura and PTSD were highly associated: patients with visual aura in the last month had greater PTSD severity, 3.6 (SD = 1.8) versus 1.9 (SD = 1.6), t = 10.2 (df = 85), p < 0.001, and patients with PTSD had a higher rate of visual aura in the last month, 69% (22/32) versus 13% (7/55), odds ratio 15.1 (5.1-44.9), p < 0.001. Patients often had a visual aura triggered by rising up to the upright from a lying or sitting position, i.e., orthostasis, with the most common sequence being an aura triggered upon orthostasis during a migraine, experienced by 60% of those with aura. The visual aura was often catastrophically interpreted: as the dangerous assault of a supernatural being, most commonly the ghost of someone who died in the Pol Pot period. Aura often triggered flashback. Illustrative cases are provided. The article suggests the existence of local biocultural ontologies of trauma as evinced by the centrality of visual auras among Cambodian refugees.

Cortical visual prostheses are intended to restore vision by targeted electrical stimulation of the visual cortex. The perception of spots of light, called phosphenes, resulting from microstimulation of the visual pathway, suggests the possibility of creating meaningful percept made of phosphenes. However, to date electrical stimulation of V1 has still not resulted in perception of phosphenated images that goes beyond punctate spots of light. In this review, we summarize the clinical and experimental progress that has been made in generating phosphenes and modulating their associated perceptual characteristics in human and macaque primary visual cortex (V1). We focus specifically on the effects of different microstimulation parameters on perception and we analyse key challenges facing the generation of meaningful artificial percepts. Finally, we propose solutions to these challenges based on the application of supervised learning of population codes for spatial stimulation of visual cortex.

Electrical stimulation of the cerebral cortex is a powerful tool for exploring cortical function. Stimulation of early visual cortical areas is easily detected by subjects and produces simple visual percepts known as phosphenes. A device implanted in visual cortex that generates patterns of phosphenes could be used as a substitute for natural vision in blind patients. We review the possibilities and limitations of such a device, termed a visual cortical prosthetic. Currently, we can predict the location and size of phosphenes produced by stimulation of single electrodes. A functional prosthetic, however, must produce spatial temporal patterns of activity that will result in the perception of complex visual objects. Although stimulation of later visual cortical areas alone usually does not lead to a visual percept, it can alter visual perception and the performance of visual behaviors, and training subjects to use signals injected into these areas may be possible.

Cellular luminescence is the emission of photons by living cells due to various biophysical and biochemical processes, mostly associated with cellular metabolism. In this review paper we summarize today's understanding of four luminescence-dependent phenomena in the eye, i.e., phosphenes, retinal discrete dark noise, negative afterimages and the development of retinogeniculate projections in the brain. We review the phenomena above in the context of knowledge gained from experimental and theoretical works. Finally, we discuss this knowledge in terms of its physiological significance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Recent studies claim that the perception of flashes of light (i.e., phosphenes) can be induced by stimulation of higher visual areas, including parietal cortex, suggesting a critical role of these regions in generating visual percepts. In this study, we show that transcranial magnetic stimulation (TMS) of even the vertex can induce phosphenes, but that their neural origins are likely to be a consequence of current spread into visual areas (e.g., retina or visual cortex). After vertex stimulation, subjects with smaller head circumferences-for whom the distances from the coil to retina and visual cortex are smaller-report a two-fold increase in perceiving phosphenes. In contrast, both smaller and larger headed individuals perceived phosphenes equivalently and on nearly all trials following TMS of early visual cortex. These results demonstrate a critical role of early visual areas but not higher ones in generating visual perceptions. These findings further suggest that phosphenes perceived from TMS of the vertex or parietal cortex arise from induced activity in the retina or nearby early visual cortex and warn against the use of the vertex as a control site for TMS experiments of visual perception.

Transcranial magnetic stimulation (TMS) of the occipital and parietal cortices can induce phosphenes, i.e. visual sensations of light without light entering the eyes. In this paper, we adopted a TMS-EEG interactive co-registration approach with a patient (AM) showing altitudinal hemianopia. Occipital and parietal cortices in both hemispheres were stimulated while concurrently recording EEG signal. Results showed that, for all sites, neural activity differentially encoding for the presence vs. absence of a conscious experience could be found in a cluster of electrodes close to the stimulation site at an early (70ms) time-period after TMS. The present data indicate that both occipital and parietal sites are independent early gatekeepers of perceptual awareness, thus, in line with evidence in favor of early correlates of perceptual awareness. Moreover, these data support the valuable contribution of the TMS-EEG approach in patients with visual field defects to investigate the neural processes responsible for perceptual awareness., (Copyright © 2017. Published by Elsevier Inc.)

Electrically stimulating early visual cortex results in a visual percept known as a phosphene. Although phosphenes can be evoked by a wide range of electrode sizes and current amplitudes, they are invariably described as small. To better understand this observation, we electrically stimulated 93 electrodes implanted in the visual cortex of 13 human subjects who reported phosphene size while stimulation current was varied. Phosphene size increased as the stimulation current was initially raised above threshold, but then rapidly reached saturation. Phosphene size also depended on the location of the stimulated site, with size increasing with distance from the foveal representation. We developed a model relating phosphene size to the amount of activated cortex and its location within the retinotopic map. First, a sigmoidal curve was used to predict the amount of activated cortex at a given current. Second, the amount of active cortex was converted to degrees of visual angle by multiplying by the inverse cortical magnification factor for that retinotopic location. This simple model accurately predicted phosphene size for a broad range of stimulation currents and cortical locations. The unexpected saturation in phosphene sizes suggests that the functional architecture of cerebral cortex may impose fundamental restrictions on the spread of artificially evoked activity and this may be an important consideration in the design of cortical prosthetic devices. SIGNIFICANCE STATEMENT Understanding the neural basis for phosphenes, the visual percepts created by electrical stimulation of visual cortex, is fundamental to the development of a visual cortical prosthetic. Our experiments in human subjects implanted with electrodes over visual cortex show that it is the activity of a large population of cells spread out across several millimeters of tissue that supports the perception of a phosphene. In addition, we describe an important feature of the production of phosphenes by electrical stimulation: phosphene size saturates at a relatively low current level. This finding implies that, with current methods, visual prosthetics will have a limited dynamic range available to control the production of spatial forms and that more advanced stimulation methods may be required., Competing Interests: The authors declare no competing financial interests., (Copyright © 2017 the authors 0270-6474/17/377188-10$15.00/0.)

Transcranial magnetic stimulation (TMS) of human occipital and posterior parietal cortex can give rise to visual sensations called phosphenes. We used near-threshold TMS with concurrent EEG recordings to measure how oscillatory brain dynamics covary, on single trials, with the perception of phosphenes after occipital and parietal TMS. Prestimulus power and phase, predominantly in the alpha band (8-13 Hz), predicted occipital TMS phosphenes, whereas higher-frequency beta-band (13-20 Hz) power (but not phase) predicted parietal TMS phosphenes. TMS-evoked responses related to phosphene perception were similar across stimulation sites and were characterized by an early (200 ms) posterior negativity and a later (>300 ms) parietal positivity in the time domain and an increase in low-frequency (∼5-7 Hz) power followed by a broadband decrease in alpha/beta power in the time-frequency domain. These correlates of phosphene perception closely resemble known electrophysiological correlates of conscious perception of near-threshold visual stimuli. The regionally differential pattern of prestimulus predictors of phosphene perception suggests that distinct frequencies may reflect cortical excitability in occipital versus posterior parietal cortex, calling into question the broader assumption that the alpha rhythm may serve as a general index of cortical excitability. SIGNIFICANCE STATEMENT Alpha-band oscillations are thought to reflect cortical excitability and are therefore ascribed an important role in gating information transmission across cortex. We probed cortical excitability directly in human occipital and parietal cortex and observed that, whereas alpha-band dynamics indeed reflect excitability of occipital areas, beta-band activity was most predictive of parietal cortex excitability. Differences in the state of cortical excitability predicted perceptual outcomes (phosphenes), which were manifest in both early and late patterns of evoked activity, revealing the time course of phosphene perception. Our findings prompt revision of the notion that alpha activity reflects excitability across all of cortex and suggest instead that excitability in different regions is reflected in distinct frequency bands., (Copyright © 2017 the authors 0270-6474/17/372824-10$15.00/0.)

Acquired auditory-visual synesthesia (AVS) is a rare neurological sign, in which specific auditory stimulation triggers visual experience. In this study, we used event-related fMRI to explore the brain regions correlated with acquired monocular sound-induced phosphenes, which occurred 2 months after unilateral visual loss due to an ischemic optic neuropathy. During the fMRI session, 1-s pure tones at various pitches were presented to the patient, who was asked to report occurrence of sound-induced phosphenes by pressing one of the two buttons (yes/no). The brain activation during phosphene-experienced trials was contrasted with non-phosphene trials and compared to results obtained in one healthy control subject who underwent the same fMRI protocol. Our results suggest, for the first time, that acquired AVS occurring after visual impairment is associated with bilateral activation of primary and secondary visual cortex, possibly due to cross-wiring between auditory and visual sensory modalities.

Today, there is an increased interest in research on lysergic acid diethylamide (LSD) because it may offer new opportunities in psychotherapy under controlled settings. The more we know about how a drug works in the brain, the more opportunities there will be to exploit it in medicine. Here, based on our previously published papers and investigations, we suggest that LSD-induced visual hallucinations/phosphenes may be due to the transient enhancement of bioluminescent photons in the early retinotopic visual system in blind as well as healthy people.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique whose effects on neural activity can be uncertain. Within the visual cortex, phosphenes are a useful marker of TMS: They indicate the induction of neural activation that propagates and creates a conscious percept. However, we currently do not know how susceptible different areas of the visual cortex are to TMS-induced phosphenes. In this study, we systematically map out locations in the visual cortex where stimulation triggered phosphenes. We relate this to the retinotopic organization and the location of object- and motion-selective areas, identified by functional magnetic resonance imaging (fMRI) measurements. Our results show that TMS can reliably induce phosphenes in early (V1, V2d, and V2v) and dorsal (V3d and V3a) visual areas close to the interhemispheric cleft. However, phosphenes are less likely in more lateral locations (hMT+/V5 and LOC). This suggests that early and dorsal visual areas are particularly amenable to TMS and that TMS can be used to probe the functional role of these areas., Competing Interests: The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Cambridge ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Transcranial alternating current stimulation (tACS) applies exogenous oscillatory electric field potentials to entrain neural rhythms and is used to investigate brain-function relationships and its potential to enhance perceptual and cognitive performance. However, due to current spread tACS can cause cutaneous activation of the retina and phosphenes. Several lines of evidence suggest that retinal phosphenes are capable of inducing neural entrainment, making the contributions of central and peripheral stimulation to the effects in the brain difficult to disentangle. In this literature review, the importance of this issue is further illustrated by the fact that photic stimulation can have a direct impact on perceptual and cognitive performance. This leaves open the possibility that peripheral photic stimulation can at least in part explain the central effects that are attributed to tACS. The extent to which phosphene perception contributes to the effects of exogenous oscillatory electric fields in the brain and influence perception and cognitive performance needs to be examined to understand the working mechanisms of tACS in neurophysiology and behaviour., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Previously published literatures of acute studies on few subjects have shown contradictory evidence on the reproducibility and characteristics of the elicited phosphenes, despite using the same stimulating parameters with epiretinal electrode arrays. In this study, we set out to investigate the long-term repeatilibity and reproducibility of phosphenes in subjects chronically implanted with the Argus II retinal prosthesis (Second Sight Medical Products, Inc., Sylmar, CA, USA)., Design: Retrospective interventional case series and reliability study., Methods: Six Argus II subjects of >5 years implantation from a single site participated. The 4-electrode cluster ("quad") closest to fovea was stimulated in each subject with a fixed biphasic current. Perceived phosphenes were depicted relative to subjective visual field center. The stimulus was applied at reducing time intervals from 20 minutes to 1 second. Two sets of stimulations were performed on the same day and 2 further sets repeated on a separate visit >1 week apart., Results: Each subject depicted phosphenes of consistent shapes and sizes, and reported seeing the same colors with the fixed stimulating parameters, irrespective of the interstimuli intervals. However, there is a wide intersubject variation in the phosphene characteristics. Four subjects drew phosphenes in the same visual field quadrant, as predicted by the quad-fovea location. Two subjects depicted phosphenes in the same hemifield as the expected locations., Conclusion: Phosphenes for each subject were consistently reproducible in all our chronically implanted subjects. This has important implications in the development of long-term pixelated prosthetic vision for future devices., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Particle therapy provides an opportunity to study the human response to space radiation in ground-based facilities. On this basis, a study of light flashes analogous to astronauts' phosphenes reported by patients undergoing ocular proton therapy has been undertaken. The influence of treatment parameters on phosphene generation was investigated for 430 patients treated for a choroidal melanoma at the proton therapy centre of the Institut Curie (ICPO) in Orsay, France, between 2008 and 2011. 60% of them report light flashes, which are predominantly (74%) blue. An analysis of variables describing the patient's physiology, properties of the tumour and dose distribution shows that two groups of tumour and beam variables are correlated with phosphene occurrence. Physiology is found to have no influence on flash triggering. Detailed correlation study eventually suggests a possible twofold mechanism of phosphene generation based on (i) indirect Cerenkov light in the bulk of the eye due to nuclear interactions and radioactive decay and (ii) direct excitation of the nerve fibres in the back of the eye and/or radical excess near the retina., (Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

Alterations in the visual system may underlie visual hallucinations in dementia with Lewy bodies (DLB). However, cortical excitability as measured by transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) activation of lower visual areas (V1-3) to visual stimuli appear normal in DLB. We explored the relationship between TMS-determined phosphene threshold and fMRI-related visual activation and found a positive relationship between the two in controls but a negative one in DLB. This double dissociation suggests a loss of inhibition in the visual system in DLB, which may predispose individuals to visual dysfunction and visual hallucinations., (© The Royal College of Psychiatrists 2015.)

Phosphenes are experienced sensations of light, when there is no light causing them. The physiological processes underlying this phenomenon are still not well understood. Previously, we proposed a novel biopsychophysical approach concerning the cause of phosphenes based on the assumption that cellular endogenous ultra-weak photon emission (UPE) is the biophysical cause leading to the sensation of phosphenes. Briefly summarized, the visual sensation of light (phosphenes) is likely to be due to the inherent perception of UPE of cells in the visual system. If the intensity of spontaneous or induced photon emission of cells in the visual system exceeds a distinct threshold, it is hypothesized that it can become a conscious light sensation. Discussing several new and previous experiments, we point out that the UPE theory of phosphenes should be really considered as a scientifically appropriate and provable mechanism to explain the physiological basis of phosphenes. In the present paper, we also present our idea that some experiments may support that the cortical phosphene lights are due to the glutamate-related excess UPE in the occipital cortex.

Introduction: In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality., Methods: We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation., Results: In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants., Conclusions: We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation., (© International Headache Society 2015.)

Purpose: To discover what cataract patients see during phacoemulsification and if these light phenomena influence their anxiety levels during surgery., Methods: In all, 200 patients were interviewed intraoperatively at the Eye Hospital, Petrisberg, Trier, Germany. The quality of the visual experiences was described and if these were pleasant, neutral or unpleasant. Systemic sedation was noted., Results: Among 200 patients (209 eyes): 88 were men (91 eyes; 44%) and 112 were women (118 eyes; 56%). Median age (years): men (71), women (70). Mean operating time was 8 min. 49/209 (23%) were not anxious before and during surgery. 110/209 (52%) were more anxious before than during surgery, 50/209 (24%) were still anxious during surgery, 27/209 (13%) got sedation with midazolam (1-5 mg). Colours in descending order seen: blue, red, pink, yellow, green, purple, turquois, and orange. The most dominant colour combination was red/blue. Structures were seen by 162/209 (78%). Most (61%) intraoperative visual experiences were pleasant, 38% were neutral, and 1% found them transiently unpleasant. Three patients felt blinded by the light of the operating microscope., Conclusions: The experience of colours and other light phenomena was pleasant for most patients during phacoemulsification under topical anaesthesia. They occur spontaneously when the patient is fixating on the operating light. They are not dependent on the individual or environment. Sedation only in 13%. Direct questioning for visual sensations by the operating surgeon may lead to less need for sedation and lead to less side effects for elderly and multimorbidity people postoperatively. The surgeon can use this knowledge to reassure patients during surgery.

Purpose: The Argus I implant is the first-generation epiretinal prosthesis approved for an investigational clinical trial by the United States Food and Drug Administration. Herein we report testing results obtained from a 10-year follow-up to study the physiologic effects of the bioelectronic visual implant after prolonged chronic electrical stimulation., Design: Case report., Participant: One man, 55 years of age when enrolled in the study, underwent surgical implantation of the Argus I in June 2004, followed by periodic tests from July 2004 through June 2014, spanning a total of 10 years., Methods: The decade-long follow-up consisted of implant system performance tests, subject visual function evaluation, and implant-retina interface analysis., Main Outcome Measures: Changes in electrode impedance and perceptual threshold over the time course; subject's performance on visual function task, orientation, and mobility tests; and optical coherence tomography data, fundus imaging, and fluorescein angiography results for the assessment of subject's implant-retina physical interface., Results: Electrically elicited phosphenes were present 10 years after implantation of an epiretinal stimulator. The test subject not only was able to perceive phosphenes, but also could perform visual tasks at rates well above chance., Conclusions: This decade-long follow-up report provides further support for the use of retinal prostheses as a long-lasting treatment for some types of blindness., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)