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Intracortical microstimulation (ICMS) in the primary visual cortex (V1) can generate the visual perception of a small point of light, termed phosphene, and evoke saccades directed to the receptive field of the stimulated neurons. Although ICMS is widely used, a direct measurement of the spatio-temporal patterns of neural activity evoked by ICMS and their relation to the neural responses evoked by visual stimuli or how they relate to ICMS-evoked saccades are still missing. To investigate this, we combined ICMS with voltage-sensitive dye imaging in V1 of behaving monkeys and measured neural activity at a high spatial (meso-scale) and temporal resolution. We then compared the population response evoked by small visual stimuli to those evoked by microstimulation. Both stimulation types evoked population activity that spread over few millimeters in V1 and propagated to extrastriate areas. However, the population responses evoked by ICMS have shown faster dynamics for the activation transients and the horizontal propagation of activity revealed a wave-like propagation. Finally, neural activity in the ICMS condition was higher for trials with evoked saccades as compared with trials without saccades. Our results uncover the spatio-temporal patterns evoked by ICMS and their relation to visual processing and saccade generation.

Background. Glaucoma is one of the most acute medical and social problems that cause enormous economic damage to society. Secondary glaucoma is the result of complications of such eye diseases as inflammation of the choroid of the eye, retinal vascular thrombosis. The purpose was to determine the effect of Briroza and Rozacom on the condition of the visual analyzer in patients with secondary glaucoma. Material and methods. The study involved 58 patients (58 eyes) with a unilateral process. All patients were divided into three groups. Groups 1 and 2 consisted of the patients with se-condary glaucoma after anterior recurrent iridocyclitis — 32 patients (32 eyes) in remission and relapse, respectively. Group 3 included patients with secondary (neovascular) glaucoma, which resulted from the central vein stenosis (CVS) and its branches — 26 patients (26 eyes). Results. In the first and second groups, Briroza administration resulted in the intraocular pressure decrease by 21.6 % (p = 0.001) — 21.0 ± 3.5 mm Hg. After a course of treatment in groups 1 and 2, electrical phosphene excitation decreased significantly by 22.4 % (p < 0.05). The critical frequency of flicker-induced phosphene in the mode 3 and 1.5 increased by 20.6 % (p < 0.05) and 47 % (p < 0.05), which indicates an increase in the functional activity of visual analyzer. Conclusions. The inclusion of the drugs Briroza and Rozacom twice a day for 2 months in the treatment of patients with secondary glaucoma is effective due to the increased functional activity of the visual analyzer and normalization of intraocular pressure in patients with secondary glaucoma.

Neural implants have the potential to restore visual capabilities in blind individuals by electrically stimulating the neurons of the visual system. This stimulation can produce visual percepts known as phosphenes. The ideal location of electrical stimulation for achieving vision restoration is widely debated and dependent on the physiological properties of the targeted tissue. Here, the neurophysiology of several potential target structures within the visual system will be explored regarding their benefits and downfalls in producing phosphenes. These regions will include the lateral geniculate nucleus, primary visual cortex, visual area 2, visual area 3, visual area 4 and the middle temporal area. Based on the existing engineering limitations of neural prostheses, we anticipate that electrical stimulation of any singular brain region will be incapable of achieving high-resolution naturalistic perception including color, texture, shape and motion. As improvements in visual acuity facilitate improvements in quality of life, emulating naturalistic vision should be one of the ultimate goals of visual prostheses. To achieve this goal, we propose that multiple brain areas will need to be targeted in unison enabling different aspects of vision to be recreated.

Background. The standard of therapy for diabetic optic neuropathy (DON), taking into account the stage and type of the disease, does not currently exist. The purpose was to assess the clinical efficacy of thioctic acid, ethylmethylhydroxypyridine succinate, brimonidine tartrate, and combination of vitamins В 1 , В 6 , В 12 in the comprehensive treatment for initial stage of axial DON. Material and methods. Forty patients (63 eyes) were followed up after being diagnosed with initial stage of axial DON. The main group consisted of 20 patients (33 eyes) who were administered two repeated courses during a year: 1) tioctic acid (berlithion) at a dose of one 300 mg tablet a day for 42 days; 2) combination of vitamins В 1 , В 6 , В 12 (milgamma) 2 ml intramuscularly once per 3 days for 21 days, followed by switching to oral regimen of 1 tablet 3 times a day for 21 days; 3) ethyl­methylhydroxypyridine succinate (mexidol) 100 mg per day intramuscularly for 14 days; 4) topical application of 0.2% brimonidine tartrate 1–2 eyedrops twice a day on a constant basis, as adjunctive to hypoglycemic therapy. The control group (20 patients, 30 eyes) received hypoglycemic therapy only. In addition to routine eye examination, retinal and optic nerve optical coherent tomography, and electrophysiology studies were performed. Patients were examined at baseline, then 1.5, 6, 7.5, 12, 13.5, 18, 19.5, 24, and 25.5 months after treatment. Results. No progression of optic nerve damage was found in 27.3 % (9 eyes) of the main group; transition to subclinical stage was observed in 72.7 % (24 eyes). We found that our treatment attenuated the progression of optic nerve damage at the initial stage of axial DON in 72.7 % (24 eyes) of patients, with 43.8 % better visual acuity, 118.9 % lower electrically evoked phosphene threshold, 37.0 % lower focal loss volume of ganglion cell complex, and 34.8 % lower thickness of lamina cribrosa sclerae compared to controls in 25.5 months. Conclusions. Our comprehensive treatment was found to be clinically effective in attenuating the progression of optic nerve damage at the initial stage of axial DON.

Background: Visual cortical prostheses (VCPs) have the potential to restore visual function to patients with acquired blindness. Successful implementation of VCPs requires the ability to reliably map the location of the phosphene produced by stimulation of each implanted electrode. Objective: To evaluate the efficacy of different approaches to phosphene mapping and propose simple improvements to mapping strategy. Methods: We stimulated electrodes implanted in the visual cortex of five blind and fifteen sighted patients. We tested two fixation strategies, unimanual fixation, where subjects placed a single index finger on a tactile fixation point and bimanual fixation, where subjects overlaid their right index finger over their left on the tactile point. In addition, we compared absolute mapping in which a single electrode was stimulated on each trial, and relative mapping with sequences containing stimulation of three to five phosphenes on each trial. Trial-to-trial variability present in relative mapping sequences was quantified. Results: Phosphene mapping was less precise in blind subjects than in sighted subjects (2DRMS, 16 ± 2.9° vs. 1.9 ± 0.93°; t (18) = 18, p =

Abstarct Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied—at multiple international centres—58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer’s disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation—including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear—were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.

A walking support system with phosphenes for blind people has been investigated. Phosphene is a phenomenon where a flash of light is recognized in the brain by giving an electrical stimulus to human’s visual pathway. Phosphenes can be perceived even if their eyes are closed or they are blind. It has been clarified that phosphenes can be induced to several directions if electrodes placements are precisely selected. When phosphenes are presented to two directions for recognizing two obstacles, two pairs of electrodes must be applied. In such a case, however, the electrical interference occurs due to the short distance between electrodes. In the practical use of the phosphene-based walking support system, the avoidance of electrical interference is significant in order to present the phosphenes precisely. Therefore, in this paper, we first practically investigate the electrical interference by considering the difference in phosphene induction generated by a single pair of electrodes and by two pairs of electrodes. Then, the solutions to avoid the electrical interference are discussed.

Purpose Bioelectronic retinal prostheses that stimulate the remaining inner retinal neurons, bypassing degenerated photoreceptors, have been demonstrated to restore some vision in patients blinded by retinitis pigmentosa (RP). These implants encode luminance of the visual scene into electrical stimulation, however, leaving out chromatic information. Yet color plays an important role in visual processing when it comes to recognizing objects and orienting to the environment, especially at low spatial resolution as generated by current retinal prostheses. In this study, we tested the feasibility of partially restoring color perception in blind RP patients, with the aim to provide chromatic information as an extra visual cue. Design Case series. Participants Seven subjects blinded by advanced RP and monocularly fitted with an epiretinal prosthesis. Methods Frequency-modulated electrical stimulation of retina was tested. Phosphene brightness was controlled by amplitude tuning, and color perception was acquired using the Red, Yellow, Green, and Blue (RYGB) hue and saturation scaling model. Main Outcome Measures Brightness and color of the electrically elicited visual perception reported by the subjects. Results Within the tested parameter space, 5 of 7 subjects perceived chromatic colors along or nearby the blue-yellow axis in color space. Aggregate data obtained from 20 electrodes of the 5 subjects show that an increase of the stimulation frequency from 6 to 120 Hz shifted color perception toward blue/purple despite a significant inter-subject variation in the transition frequency. The correlation between frequency and blue-yellow perception exhibited a good level of consistency over time and spatially matched multi-color perception was possible with simultaneous stimulation of paired electrodes. No obvious correlation was found between blue sensations and array placement or status of visual impairment. Conclusions These findings present a strategy for the generation and control of color perception along the blue-yellow axis in blind patients with RP by electrically stimulating the retina. It could transform the current prosthetic vision landscape by leading in a new direction beyond the efforts to improve the visual acuity. This study also offers new insights into the response of our visual system to electrical stimuli in the photoreceptor-less retina that warrant further mechanistic investigation.

It is generally believed that the phosphenes induced by transcranial electric current stimulation (tECS) are a product of retinal activation, even when electrode placement is directly over the primary visual cortex. However, the origins of these tECS-induced phosphenes have not yet been conclusively determined. In this study, phosphene detection thresholds using an FPz-Oz montage were compared with those from (i) an Oz-Cz montage to determine whether prefrontal regions, such as the retina, contribute to phosphenes and (ii) an FPz-Cz montage to determine whether the visual cortex in the occipital lobe contributes to phosphenes. Twenty-two participants received transcranial current stimulation with each of these montages (as well as a T3-T4 montage included for exploratory purposes) at 6, 10, 16, 20, 24, 28, and 32 Hz. To estimate differences in current density at the retina and occipital lobe across montages, modeling of current density at phosphene thresholds was measured across 20 head models. Consistent with the proposal that tECS-induced phosphenes are generated in the retina, increasing current density near the retina (FPz-Oz relative to Oz-Cz montage) reduced phosphene thresholds. However, increasing current density near the occipital cortex (FPz-Oz relative to FPz-Cz montage) also reduced phosphene thresholds while also requiring less current density at the retina according to the modeling estimates. This suggests that tECS of this occipital cortex also contributed to phosphene perception. © 2020 Bioelectromagnetics Society.

Retinal implants electrically stimulate surviving retinal neurons to restore vision in people blinded by outer retinal degeneration. Although the healthy retina is known to transmit a vast amount of visual information to the brain, it has not been studied whether prosthetic vision contains a similar amount of information. Here, we assessed the neural information transmitted by population responses arising in brisk transient (BT) and brisk sustained (BS) subtypes of ON and OFF retinal ganglion cells (RGCs) in the rabbit retina. To correlate the response heterogeneity and the information transmission, we first quantified the cell-to-cell heterogeneity by calculating the spike time tiling coefficient (STTC) across spiking patterns of RGCs in each type. Then, we computed the neural information encoded by the RGC population in a given type. In responses to light stimulation, spiking activities were more heterogeneous in OFF than ON RGCs (STTCAVG = 0.36, 0.45, 0.77 and 0.55 for OFF BT, OFF BS, ON BT, and ON BS, respectively). Interestingly, however, in responses to electric stimulation, both BT and BS subtypes of OFF RGCs showed remarkably homogeneous spiking patterns across cells (STTCAVG = 0.93 and 0.82 for BT and BS, respectively), whereas the two subtypes of ON RGCs showed slightly increased populational heterogeneity compared to light-evoked responses (STTCAVG = 0.71 and 0.63 for BT and BS, respectively). Consequently, the neural information encoded by the electrically-evoked responses of a population of 15 RGCs was substantially lower in the OFF than the ON pathway: OFF BT and BS cells transmit only ~23% and ~53% of the neural information transmitted by their ON counterparts. Together with previously-reported natural spiking activities in ON RGCs, the higher neural information may make ON responses more recognizable, eliciting the biased percepts of bright phosphenes.

Because current flow cannot be measured directly in the intact retina or brain, current density distribution models were developed to estimate it during magnetic or electrical stimulation. A paradigm is now needed to evaluate if current flow modeling can be related to physiologically meaningful signs of true current distribution in the human brain. We used phosphene threshold measurements (PTs) as surrogate markers of current-flow to determine if PTs, evoked by transcranial alternating current stimulation (tACS), can be matched with current density estimates generated by head model-based computer simulations. Healthy, male subjects (n=15) were subjected to three-staged PT measurements comparing six unilateral and one bilateral stimulation electrode montages according to the $10/20$ system: Fp2-Suborbital right (So), Fp2-right shoulder (rS), Fp2-Cz, Fp2- O2, So-rS, Cz-F8 and F7-F8. The stimulation frequency was set at 16 Hz. Subjects were asked to report the appearance and localization of phosphenes in their visual field for every montage. Current density models were built using multi-modal imaging data of a standard brain, meshed with isotropic conductivities of different tissues of the head using the SimBio and SCIRun software packages. We observed that lower PTs were associated with higher simulated current levels in the unilateral montages of the model head, and shorter electrode distances to the eye had lower PTs. The lowest mean PT and the lowest variability were found in the F7-F8 montage ( $95\pm 33~\mu \text{A}$ ). Our results confirm the hypothesis that phosphenes are primarily of retinal origin, and they provide the first in vivo evidence that computer models of current flow using head models are a valid tool to estimate real current flow in the human eye and brain.

Retinal prostheses aim at restoring partial sight to patients that are blind due to retinal degenerative diseases by electrically stimulating the surviving healthy retinal neurons. Ideally, the electrical stimulation of the retina is intended to induce localized, focused, percepts only; however, some epiretinal implant subjects have reported seeing elongated phosphenes in a single electrode stimulation due to the axonal activation of retinal ganglion cells (RGCs). This issue can be addressed by properly devising stimulation waveforms so that the possibility of inducing axonal activation of RGCs is minimized. While strategies to devise electrical stimulation waveforms to achieve a focal RGCs response have been reported in literature, the underlying mechanisms are not well understood. This article intends to address this gap; we developed morphologically and biophysically realistic computational models of two classified RGCs: D1-bistratified and A2-monostratified. Computational results suggest that the sodium channel band (SOCB) is less sensitive to modulations in stimulation parameters than the distal axon (DA), and DA stimulus threshold is less sensitive to physiological differences among RGCs. Therefore, over a range of RGCs distal axon diameters, short-pulse symmetric biphasic waveforms can enhance the stimulation threshold difference between the SOCB and the DA. Appropriately designed waveforms can avoid axonal activation of RGCs, implying a consequential reduction of undesired strikes in the visual field.

Visual motion or flashing lights can evoke auditory sensations in some people. This large-scale internet study aimed to validate a combined subjective/objective test of the genuineness of this putative form of synaesthesia (visually-evoked auditory response, vEAR). Correlations were measured between each individual's ratings of the vividness of auditory sensations evoked by a series of looping videos, and measurement of the videos' physical low-level motion energy, calculated using Adelson and Bergen’s (1985) computational model of low-level visual motion processing. The strength of this association for each individual provided a test of how strongly subjective vEAR was driven by objective motion energy (‘ME-sensitivity’). A second aim was to infer whether vEAR depends on cortical excitation and/or disinhibition of early visual and/or auditory brain areas. To achieve this, correlations were measured between the above vEAR measures and visual contrast surround-suppression, which is thought to index lateral inhibition in the early visual system. As predicted by a disinhibition account of vEAR, video ratings were overall higher in individuals showing weaker surround-suppression. Interestingly, surround-suppression and ME-sensitivity did not correlate. Additionally, both surround-suppression and ME-sensitivity each independently predicted different clusters of trait measures selected for their possible association with cortical excitability and/or disinhibition: Surround-suppression was associated with vEAR self-ratings and auditory-evoked visual phosphenes, while ME-sensitivity was independently associated with ratings of other traits including susceptibility to migraine and pattern glare. Altogether, these results suggest there are two independent mechanisms underlying vEAR and its associated traits, based putatively on cortical disinhibition versus excitability.

Visual blindness affects many millions globally and severely impacts quality of life. One approach to overcome visual blindness is the direct electrical microstimulation of brain circuits normally engaged in visual function. Attempts to do so with traditional brain-machine interfaces (BMI) in monkeys and humans have evoked percepts (phosphenes) described as crude featureless spots of light. Here, we propose to qualitatively enhance these percepts by recruiting submillimeter units of cortical representation (cortical columns) which encode rich visual features such as color, motion, shape, and faces. A three step roadmap is proposed, comprising: (1) the mapping of column-based networks (columnar connectomes), (2) connectome-guided studies of circuitry and perception, and (3) column-targeted design of optical BMIs. We predict this approach will increase the specificity and sophistication needed for realistic, vibrant visual perception.

Pure representationalism or intentionalism for phenomenal experience is the theory that all introspectible qualitative aspects of a conscious experience can be analyzed as qualities that the experience non-conceptually represents the world to have. Some philosophers have argued that experiences such as afterimages, phosphenes and double vision are counterexamples to the representationalist theory, claiming that they are non-representational states or have non-representational aspects, and they are better explained in a qualia-theoretical framework. I argue that these states are fully representational states of a certain kind, which I call “automatically non-endorsed representations”, experiential states the veridicality of which we are almost never committed to, and which do not trigger explicit belief or disbelief in the mind of the subject. By investigating descriptive accounts of afterimages by two qualia theorists, I speculate that the mistaken claims of some anti-representationalists might be rooted in confusing two senses of the term “seeming”., Čisti reprezentacionalizam ili intencionalizam u pogledu pojavnog iskustva teorija je prema kojoj se svi introspektivno dostupni kvalitativni aspekti svjesnog iskustva mogu analizirati kao kvalitete svijeta koje iskustvo na nepojmovni način reprezentira. Neki filozofi su argumentirali da iskustva poput paslika, fosfena i dvostrukog vida predstavljaju protuprimjer reprezentacionalističkoj teoriji, tvrdeći da su to nereprezentacijska stanja ili da posjeduju nereprezentacijske aspekte, te da ih je bolje objasniti u okviru teorije kvalija. Argumentiram da su ova stanja u potpunosti reprezentacijska stanja određene vrste koju nazivam „automatski neprihvaćenim reprezentacijama“. To su iskustvena stanja koja najčešće ne prihvaćamo kao istinita i koja ne aktiviraju eksplicitna vjerovanja u umu subjekta. Kroz istraživanje opisnih objašnjenja paslika koje nudi dvoje teoretičara kvalija, predlažem da je moguće da su pogrešne tvrdnje nekih antireprezentacionalista ukorijenjene u miješanju dvaju smisla riječi „naizgled“.

Developing optogenetics in non-human primates (NHPs) is essential for translating its successful implementation in rodents to clinical applications in humans. However, information about how optogenetics influences the primate cortex remains limited. Here, we evaluate how optogenetic stimulation of the primate primary visual cortex (V1) affects local and large-scale network activation concerned with visual perception. To this end we injected an optogenetic construct (AAV9-hSyn-ChR2-eYFP) into the V1 cortex of four macaque monkeys (macaca mulatta) and measured the effects of optogenetic V1 stimulation using functional magnetic resonance imaging (fMRI), laminar electrophysiology, and behavioural assessment. In three macaques, blood-oxygen-dependent (BOLD) fMRI activity could be reliably elicited with optogenetic stimulation in V1 and several connected extrastriate brain areas, including V2/V3, motion-sensitive area MT and the frontal-eye-fields (FEF), in particular when pulsed stimulation at 40 Hz was applied. BOLD modulation was associated with consistent neural spiking activity measured in V1 of two macaques. More detailed analysis revealed strongest neuronal activation in layer 4B and infragranular layers, which tightly reflected the histological expression pattern of the optogenetic construct in V1. Driving this visual network proved sufficient to elicit a visual percept (‘phosphene’) in one macaque during a perceptual choice task. Taken together, our findings reveal the laminar and large-cortical activation pattern related to visual phosphene generation and emphasize the need for further improving optogenetic methods in NHPs as a step towards applications in humans.

Transcorneal electrical stimulation (TES) is a novel treatment approach for patients with retinitis pigmentosa (RP). With progression of RP, loss of photoreceptors leads to less oxygen consumption and lower demand in the retina. Retinal oximetry (RO), as a non-invasive method to analyse oxygen saturation in retinal vessels, promises to be a useful therapy monitoring tool. The aim of our study was to observe changes in RO that would be attributed to therapeutic intervention. A total of 43 eyes of 22 subjects (11♀ 11♂) suffering from RP were examined at baseline, after the first stimulation, 1 week and 6 months after TES (OkuStim®). Stimulation was performed for 30 min weekly at 200% of the individual phosphene threshold, simultaneously on both eyes. The oxygen saturation was examined at baseline and following TES stimulation with the oxygen saturation tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The global oxygen saturation parameters (in %), within 1.0–1.5 optic disc diameters from the disc margin, in retinal arterioles (A-SO2) and venules (V-SO2) were estimated and their difference (A-V SO2) was calculated. In addition, we evaluated the diameters (in μm) in the corresponding arterioles (D-A) and venules (D-V). ANOVA-based linear mixed-effects models were calculated with SPSS®. Six months after TES treatment, the mean A-SO2 increased (from 96.48 ± 12.27 to 100.15 ± 5.56%, p = 0.09), while the V-SO2 decreased (from 61.61 ± 12.78 to 59.79 ± 11.15%, p = 0.48). The A-V SO2, which represents the oxygen consumption of the retina, showed a statistically significant increase from 34.87 ± 9.38% at baseline to 41.36 ± 9.18% after 6 months (p = 0.02). TES had no influence on the D-A and D-V (p > 0.6). These data indicate that TES therapy in RP leads to an increased oxygen consumption of the retina. RO may thus serve as a sensitive monitoring method for TES therapy in RP.

In outer retinal degenerative diseases such as retinitis pigmentosa, choroideremia, and geographic atrophy, 30% of the ganglion cell layer in the macula remains intact. With subretinal and epiretinal prostheses, these inner retinal cells are stimulated with controlled electrical current by either a microphotodiode placed in the subretinal area or a microelectrode array tacked to the epiretinal region. As the patient learns to interpret the resulting phosphene patterns created in the brain through special rehabilitation exercises, their orientation, mobility, and quality of life increase. Implants that stimulate the lateral geniculate nucleus or visual cortex are currently being studied for diseases in which the ganglion cells and optic nerve are completely destroyed.

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.

Sounds can modulate activity in visual cortex, facilitating the detection of visual targets. However, these sound-driven modulations are not thought to evoke conscious visual percepts in the general population. In individuals with synesthesia, however, multisensory interactions do lead to qualitatively different experiences such as sounds evoking flashes of light. Why, if multisensory interactions are present in all individuals, do only synesthetes experience abnormal qualia? Competing models differ in the time required for synesthetic experiences to emerge. The cross-activation model suggests synesthesia arises over months or years from the development of abnormal neural connections. Here we demonstrate that after ∼5 min of visual deprivation, sounds can evoke synesthesia-like percepts (vivid colors and Kluver form-constants) in ∼50% of non-synesthetes. These results challenge aspects of the cross-activation model and suggest that synesthesia exists as a latent feature in all individuals, manifesting when the balance of activity across the senses has been altered.

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 (VSm ) or without migraine (VSwom ) 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 VSm (n = 10), the VSwom (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 VSm 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 VSm (1.04 ± 0.2 and 1.06 ± 0.2) and the VSwom (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 VSm (58.00 ± 6.60) and VSwom (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 VSm (60.30 ± 8.15) and VSwom (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.

Spontaneous alpha oscillations (~10 Hz) have been associated with various cognitive functions, including perception. Their phase and amplitude independently predict cortical excitability and subsequent perceptual performance. Yet, the causal role of alpha phase-amplitude tradeoffs on visual perception remains ill-defined. We aimed to fill this gap and tested two clear predictions from the Pulsed Inhibition theory according to which alpha oscillations are associated with periodic functional inhibition. (1) High alpha amplitude induces cortical inhibition at specific phases, associated with low perceptual performance, while at opposite phases, inhibition decreases (potentially increasing excitation) and perceptual performance increases. (2) Low alpha amplitude is less susceptible to these phasic (periodic) pulses of inhibition, leading to overall higher perceptual performance. Here, cortical excitability was assessed in humans using phosphene (illusory) perception induced by single pulses of transcranial magnetic stimulation (TMS) applied over visual cortex at perceptual threshold, and its post-pulse evoked activity recorded with simultaneous electroencephalography (EEG). We observed that pre-pulse alpha phase modulates the probability to perceive a phosphene, predominantly for high alpha amplitude, with a non-optimal phase for phosphene perception between −π/2 and −π/4. The pre-pulse non-optimal phase further leads to an increase in post-pulse evoked activity (ERP), in phosphene-perceived trials specifically. Together, these results show that alpha oscillations create periodic inhibitory moments when alpha amplitude is high, leading to periodic decrease of perceptual performance. This study provides strong causal evidence in favor of the Pulsed Inhibition theory.Visual AbstractSignificance StatementThe Pulsed Inhibition theory predicts that the functional inhibition induced by high alpha oscillations’ amplitude is periodic, with specific phases decreasing neural firing and perceptual performance. In turn, low alpha oscillations’ amplitude is less susceptible to phasic moments of pulsed inhibition leading to overall higher perceptual performance. Using TMS with simultaneous EEG recordings in humans, we found that specific phases of spontaneous alpha oscillations (~10 Hz) decrease cortical excitability and the subsequent perceptual outcomes predominantly when alpha amplitude is high. Our results provide strong causal evidence in favor of the Pulsed Inhibition theory.

A visual prosthesis is an auxiliary device for patients with blinding diseases that cannot be treated with conventional surgery or drugs. It converts captured images into corresponding electrical stimulation patterns, according to which phosphenes are generated through the action of internal electrodes on the visual pathway to form visual perception. However, due to some restrictions such as the few implantable electrodes that the biological tissue can accommodate, the induced perception is far from ideal. Therefore, an important issue in visual prosthesis research is how to detect and present useful information in low-resolution prosthetic vision to improve the visual function of the wearer. In recent years, with the development and broad application of computer vision methods, researchers have investigated the possibility of their utilization in visual prostheses by simulating prosthetic visual percepts. Through the optimization of visual perception by image processing, the efficiency of visual prosthesis devices can be further improved to better meet the needs of prosthesis wearers. In this article, recent works on prosthetic vision centering on implementing computer vision methods are reviewed. Differences, strengths, and weaknesses of the mentioned methods are discussed. The development directions of optimizing prosthetic vision and improving methods of visual perception are analyzed.

ObjectiveOptic nerve’s intraneural stimulation is an emerging neuroprosthetic approach to provide artificial vision to totally blind patients. An open question is the possibility to evoke individual non-overlapping phosphenes via selective intraneural optic nerve stimulation. To begin answering this question, first, we aim at showing in preclinical experiments with animals that each intraneural electrode could evoke a distinguishable activity pattern in the primary visual cortex.ApproachWe performed both patterned visual stimulation and patterned electrical stimulation in healthy rabbits while recording evoked cortical activity with an electrocorticogram array in the primary visual cortex. Electrical stimulation was delivered to the optic nerve with the intraneural array OpticSELINE. We used a support vector machine algorithm paired to a linear regression model to classify cortical responses originating from visual stimuli located in different portions of the visual field and electrical stimuli from the different electrodes of the OpticSELINE.Main resultsCortical activity induced by visual and electrical stimulation could be classified with nearly 100% accuracy relative to the specific location in the visual field or electrode in the array from which it originated. For visual stimulation, the accuracy increased with the separation of the stimuli and reached 100% for separation higher than 7 degrees. For electrical stimulation, at low current amplitudes, the accuracy increased with the distance between electrodes, while at higher current amplitudes, the accuracy was nearly 100% already for the shortest separation.SignificanceOptic nerve’s intraneural stimulation with the OpticSELINE induced discernible cortical activity patterns. These results represent a leap forward for intraneural optic nerve stimulation towards artificial vision.

An author name was incorrectly spelled as Elena Diaz-de Cerio. The correct spelling is Elena Rodrigo-Diaz. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

To investigate effect on the intensity of pressure phosphenes (PP) of various methods of heating hands, as well as manual influence on cervical spine. This study included subjective assessments of the PP intensity in 10 healthy men, and chronometry of bioelectrical activity of brain and heart using electroencephalography (EEG) and electrocardiography (ECG). EEG and ECG frequency spectra respond synchronously to pressure, heat and light. The time of excitation of potential oscillations in the visual area of the cortex of both hemispheres is consistent with the delay in the onset of PP flaring. The effect of PP stimulation is enhanced when the hands and body are heated in a humid environment and at temperatures above 42 °C. Stimulation of PP by heating indicates the convergence of impulses from neurons of the lateral geniculate body (LGB) and nuclei of the thalamus, which are responsible for thermoreceptors in the skin of the palms and fingers. The thermal stimulation effect of PP is enhanced at temperatures above 42 °C due to the fact that thermoreceptors work as pain receptors. The mechanism of PP generation is dominated by the processes of redistribution and recombination of charges in the layers of the retina and LGB.

Epiretinal prostheses aim at electrically stimulating the inner most surviving retinal cells—retinal ganglion cells (RGCs)—to restore partial sight to the blind. Recent tests in patients with epiretinal implants have revealed that electrical stimulation of the retina results in the percept of color of the elicited phosphenes, which depends on the frequency of stimulation. This paper presents computational results that are predictive of this finding and further support our understanding of the mechanisms of color encoding in electrical stimulation of retina, which could prove pivotal for the design of advanced retinal prosthetics that elicit both percept and color. This provides, for the first time, a directly applicable “amplitude-frequency” stimulation strategy to “encode color” in future retinal prosthetics through a predictive computational tool to selectively target small bistratified cells, which have been shown to contribute to “blue-yellow” color opponency in the retinal circuitry. The presented results are validated with experimental data reported in the literature and correlated with findings in blind patients with a retinal prosthetic implant collected by our group.

Retinal degenerative diseases cause profound visual impairment in more than 10 million people worldwide, and retinal prostheses are being developed to restore vision to these individuals. Analogous to cochlear implants, these devices electrically stimulate surviving retinal cells to evoke visual percepts (phosphenes). However, the quality of current prosthetic vision is still rudimentary. Rather than aiming to restore “natural” vision, there is potential merit in borrowing state-of-the-art computer vision algorithms as image processing techniques to maximize the usefulness of prosthetic vision. Here we combine deep learning–based scene simplification strategies with a psychophysically validated computational model of the retina to generate realistic predictions of simulated prosthetic vision, and measure their ability to support scene understanding of sighted subjects (virtual patients) in a variety of outdoor scenarios. We show that object segmentation may better support scene understanding than models based on visual saliency and monocular depth estimation. In addition, we highlight the importance of basing theoretical predictions on biologically realistic models of phosphene shape. Overall, this work has the potential to drastically improve the utility of prosthetic vision for people blinded from retinal degenerative diseases.

Purpose In addition to motor cortex involvement, sensory abnormalities have been demonstrated in amyotrophic lateral sclerosis (ALS), including structural and metabolic alterations in the occipital cortex. The aim of this study was to examine occipital excitability changes in ALS. Methods Twenty-one patients with ALS and 16 healthy subjects were enrolled into the study. Phosphene experience and phosphene threshold were studied to assess occipital excitability. Cognitive function was evaluated in both groups by means of Montreal Cognitive Assessment and Addenbrooke's Cognitive Examination-Revised visuospatial score tests. Results Phosphene was experienced in 13 (81.3%) healthy subjects and 9 (42.9%) patients with ALS (P = 0.04). The mean phosphene threshold was not significantly different between the two groups. No correlation existed between phosphene threshold and motor cortical excitability parameters, ALS Functional Rating Scale Revised, Montreal Cognitive Assessment, and Addenbrooke's Cognitive Examination-Revised scores. Conclusions Visual cortex is affected, and the occipital excitability is reduced in ALS, without any relation to motor cortical excitability changes, providing another clue suggestive of sensory involvement in ALS.

Purpose. To assess the recognition pattern of dynamic action by visual prosthesis' wearers. Methods. Twenty volunteers (classified by gender and experience) were recruited to carried out action recognition test in simulated prosthetic vision. Twenty-three common dynamic actions video clips usually see in daily life were selected and formed the experimental action set which was divided into three parts including combined actions, simple actions and difficult actions in turn. The action animations made by 3D Studio Max were recorded by Banicam to convert to MP4 video format and processed to phosphene video clips by MATLAB in different resolutions (16 × 16, 24 × 24, 32 × 32, 48 × 48, 64 × 64, 128 × 128). Result. Comparing the recognition results, male group and female group had no significant difference. 48 × 48 resolution was the considerable latent capacity which subjects had stable performance. After a period of study, the performance of prosthesis wearers could be improved significantly.

Phosphene is a phenomenon that human can perceive a flash of light in the brain when the human’s visual pathway is stimulated electrically or magnetically. Therefore, blind people can also perceive phosphenes even though their crystalline lenses are not functioning. There are great hopes that phosphenes can be used as visual information for a walking support system for blind people. However, the phosphenes induction mechanism has not as yet been clarified since the mechanism of the conventional theory is inconsistent with real experimental results in terms of the perceived phosphenes position. In this paper, a new hypothesis on the phosphenes induction mechanism, which focuses on exposed visual retinae and the stimulated area by electrical current, is posited based on the anatomical characteristics of eyeball. Through experimental evaluation, our hypothesis is successfully verified.

ObjectiveTemporal resolution is a key challenge in artificial vision. Several prosthetic approaches are limited by the perceptual fading of evoked phosphenes upon repeated stimulation from the same electrode. Therefore, implanted patients are forced to perform active scanning, via head movements, to refresh the visual field viewed by the camera. However, active scanning is a draining task, and it is crucial to find compensatory strategies to reduce it.ApproachTo address this question, we implemented perceptual fading in simulated prosthetic vision using virtual reality. Then, we quantified the effect of fading on two indicators: the time to complete a reading task and the head rotation during the task. We also tested if stimulation strategies previously proposed to increase the persistence of responses in retinal ganglion cells to electrical stimulation could improve these indicators.Main resultsThis study shows that stimulation strategies based on interrupted pulse trains and randomisation of the pulse duration allows significant reduction of both the time to complete the task and the head rotation during the task.SignificanceThe stimulation strategy used in retinal implants is crucial to counteract perceptual fading and to reduce active head scanning during prosthetic vision. In turn, less active scanning might improve the patient’s comfort in artificial vision.

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 and demonstrate that perceived phosphene locations map veridically to eye position, although there are considerable individual differences in the reliability of this mapping. 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.

ObjectiveRetinal stimulation in blind patients evokes the sensation of discrete points of light called phosphenes, which allows them performing visual guided tasks, such as orientation, navigation, object recognition, object manipulation and reading. However, the clinical benefit of artificial vision in profoundly blind patients is still tenuous, as several engineering and biophysical obstacles keep it away from natural perception. The relative preservation of the inner retinal neurons in hereditary degenerative retinal diseases, such as retinitis pigmentosa, supports artificial vision through the network-mediated stimulation of retinal ganglion cells. However, the response of retinal ganglion cells to repeated electrical stimulation rapidly declines, primarily because of the intrinsic desensitisation of their excitatory network. In patients, upon repetitive stimulation, phosphenes fade out in less than half of a second, which drastically limits the understanding of the percept.ApproachA more naturalistic stimulation strategy, based on spatiotemporal modulation of electric pulses, could overcome the desensitisation of retinal ganglion cells. To investigate this hypothesis, we performed network-mediated epiretinal stimulations paired to electrophysiological recordings in retinas explanted from both male and female retinal degeneration 10 mice.Main resultsThe results showed that the spatial and temporal modulation of the network-mediated epiretinal stimulation prolonged the responsivity of retinal ganglion cells from 400 ms up to 4.2 s.SignificanceA time-varied, non-stationary and interrupted stimulation of the retinal network, mimicking involuntary microsaccades, might reduce the fading of the visual percept and improve the clinical efficacy of retinal implants.

Background Restoring sight for the blind using electrical stimulation of the visual pathways is feasible but demands an understanding of the spatial mapping of the visual world at the site of targeted stimulation, whether in the retina, thalamus, or cortex. While a visual cortex stimulator can bypass the eye and create visual percepts, there is an inherent dissociation between this stimulation and eye movements. It is unknown whether and how robustly the brain maintains the oculomotor circuitry in patients with bare- or no-light perception. Objective To critically and quantitatively evaluate the effect of eye movements have on phosphene locations elicited by cortical stimulation that bypasses the eyes in order to restore sight in blind subjects. Methods The NeuroPace Responsive Neurostimulator (RNS) and the Orion visual cortical prosthesis devices were used to electrically stimulate the visual cortex of blind subjects with bare or no light perception. Eye positions were recorded synchronized with stimulation and the location of the percepts were measured using a handheld marker. Results The locations of cortical stimulation-evoked percepts are shifted based on the eye position at the time of stimulation. Measured responses can be remapped based on measured eye positions to determine the retinotopic locations associated with the implanted electrodes, with remapped responses having variance limited by pointing error. Conclusions Eye movements dominate the perceived location of cortical stimulation-evoked phosphenes, even after years of blindness. By accounting for eye positions, we can mimic retinal mapping as in natural sight.

Electrical stimulation of neural tissue is used in both clinical and experimental devices to evoke a desired spatiotemporal pattern of neural activity. These devices induce a local field that drives neural activation, referred to as an activating function or generator signal. In visual prostheses, the spread of generator signal from each electrode within the neural tissue results in a spread of visual perception, referred to as a phosphene. Objective. In cases where neighbouring phosphenes overlap, it is desirable to use current steering or neural activity shaping strategies to manipulate the generator signal between the electrodes to provide greater control over the total pattern of neural activity. Applying opposite generator signal polarities in neighbouring regions of the retina forces the generator signal to pass through zero at an intermediate point, thus inducing low neural activity that may be perceived as a high-contrast line. This approach provides a form of high contrast visual perception, but it requires partitioning of the target pattern into those regions that use positive or negative generator signals. This discrete optimization is an NP-hard problem that is subject to being trapped in detrimental local minima. Approach. This investigation proposes a new partitioning method using image segmentation to determine the most beneficial positive and negative generator signal regions. Utilizing a database of 1000 natural images, the method is compared to alternative approaches based upon the mean squared error of the outcome. Main results. Under nominal conditions and with a set computation limit, partitioning provided improvement for 32% of these images. This percentage increased to 89% when utilizing image pre-processing to emphasize perceptual features of the images. The percentage of images that were dealt with most effectively with image segmentation increased as lower computation limits were imposed on the algorithms. Significance. These results provide a new method to increase the resolution of neural stimulating arrays and thus improve the experience of visual prosthesis users.

Microwave-assisted annulation of cyclic imine dibenzo[b,f][1,4]oxazepines and diaryl(aryl)phosphenes generated from diazo(aryl)methyl(diaryl)phosphine oxides through the Wolff rearrangement accesse...

Transcranial alternating current stimulation, a non-invasive brain stimulation technique, has been used to increase alpha (8–12 Hz) power, the latter being associated with various brain functions and states. Heterogeneity among stimulation parameters across studies makes it difficult to implement reliable transcranial alternating current stimulation protocols, explaining the absence of consensus on optimal stimulation parameters to modulate the alpha rhythm. This project documents the differential impact of controlling for key transcranial alternating current stimulation parameters, namely the intensity, the frequency and the stimulation site (anterior versus posterior). Phase 1:20 healthy participants underwent 4 different stimulation conditions. In each experimental condition, stimulation via 2 electrodes was delivered for 20 min. Stimulation conditions were administered at PO7-PO8 or F3-F4 at individual’s alpha frequency, or at individual’s theta frequency or sham. Stimulation intensity was set according to each participant’s comfort following a standardized unpleasantness scale (≤ 40 out of 100) and could not exceed 6 mA. All conditions were counterbalanced. Phase 2: participants who tolerated higher intensity of stimulation (4–6 mA) underwent alpha-frequency stimulation applied over PO7–PO8 at 1 mA to investigate within-subject modulation of stimulation response according to stimulation intensity. Whether set over posterior or anterior cortical sites, alpha-frequency stimulation showed greater increase in alpha power relative to stimulation at theta frequency and sham stimulation. Posterior alpha-frequency stimulation showed a greater increase in alpha power relative to the adjacent frequency bands over frontal and occipito-parietal brain areas. Low intensity (1 mA) posterior alpha stimulation showed a similar increase in alpha power than at high (4–6 mA) intensity when measured immediately after stimulation. However, when tested at 60 min or 120 min, low intensity stimulation was associated with significantly superior alpha power increase relative to high intensity stimulation. This study shows that posterior individual’s alpha frequency stimulation at higher intensities is well tolerated but fails to increase stimulation aftereffects recorded within 2 h of stimulation on brain oscillations of the corresponding frequency band. In sharp contrast, stimulating at 1 mA (regardless of phosphene generation or sensory perception) effectively and selectively modulates alpha power within that 2-h time window, thus validating that it as a reliable stimulus intensity for future studies. This study also shows that posterior alpha-frequency stimulation preferentially modulates endogenous brain oscillations of the corresponding frequency band. Moreover, our data suggest that posterior alpha-frequency transcranial alternating current stimulation is a reliable and precise non-invasive brain stimulation technique for persistent modulation of both frontal and occipito-parietal alpha power., This study documents how key tACS parameters, namely the intensity, the frequency and the stimulation site, modulate alpha power via a within-subject paradigm involving four stimulation conditions. tACS after effects on alpha power were measured at fixed time points up to 120 minutes post-stimulation., Graphical Abstract Graphical Abstract

Cortical visual prostheses could one day help restore sight to the blind by targeting the visual cortex with electrical stimulation. However, power consumption and limited spatial resolution impose limits on performance, while large amounts of electrical charge sometimes necessary to evoke phosphenes can cause seizures. Here, we propose the use of the local field potential as a control signal for the timing of stimulation to reduce charge requirements. In Sprague-Dawley rats, visual cortex was electrically stimulated at random times, and neural responses recorded. Electrical stimulation at specific phases of the local field potential required smaller amounts of charge to elicit spikes than naïve stimulation. Incorporating this into prosthesis design could improve their safety and efficacy.

Retinal microprostheses strive to evoke a sense of vision in individuals blinded by outer retinal degenerative diseases, by electrically stimulating the surviving retina. It is widely suspected that a stimulation strategy that can selectively activate different retinal ganglion cell types will improve the quality of evoked phosphenes. Previous efforts towards this goal demonstrated the potential for selective ON and OFF brisk-transient cell activation using high-rate (2000 pulses per second, PPS) stimulation. Here, we build upon this earlier work by testing an additional rate of stimulation and additional cell populations. We find considerable variability in responses both within and across individual cell types, but show that the sensitivity of a ganglion cell to repetitive stimulation is highly correlated to its single-pulse threshold. Consistent with this, we found thresholds for both stimuli to be correlated to soma size, and thus likely mediated by the properties of the axon initial segment. The ultimate efficacy of high-rate stimulation will likely depend on several factors, chief among which are (a) the residual ganglion types, and (b) the stimulation frequency.

Background and purpose Nonketotic hyperglycemia often causes transient visual field defects, but only scattered anecdotes are available in the literature. Methods We report a patient with homonymous superior quadrantanopsia due to nonketotic hyperglycemia and provide a systematic literature review of the clinical features of 40 previously reported patients (41 in total, including our case) with homonymous visual field defects in association with nonketotic hyperglycemia. Results The typical visual field defect was congruous (84.6%), homonymous hemianopsia (87.8%) with macular splitting (61.5%) or sparing (38.5%). It was transient and repetitive in 54.5% of the patients, but it developed as a persistent form in the remainder. Positive visual symptoms such as hallucinations and phosphenes developed in 73.2% of patients. Brain MRI revealed corresponding abnormalities in most patients (84.8%), characterized by a low-intensity white-matter signal or a high-intensity gray-matter signal on T2-weighted or fluid-attenuated inversion recovery images with diffusion restriction or gadolinium enhancement. Most (97.0%) patients recovered completely, with 48.5% treated by glycemic control alone and the remainder also receiving antiepileptic agents. Conclusions Nonketotic hyperglycemia should be considered a possible cause of transient visual field defects, especially when it is associated with repetitive positive visual symptoms and typical MRI findings in hyperglycemic patients.

Transcranial magnetic stimulation (TMS) of the visual cortex can induce phosphenes as participants look at a visual target. So can non-diagnostic ultrasound (nDU), delivered in a transcranial fashion, while participants have closed their eyes during stimulation. Here, we sought to determine if DU, aimed at the visual cortex, could alter the perception of a visual target. We applied a randomized series of actual or sham DU, transcranially and towards the visual cortex of healthy participants while they stared at a visual target (a white crosshair on a light-blue background), with the ultrasound device placed where TMS elicited phosphenes. These participants observed percepts seven out of ten times, which consisted of extra or extensions of lines relative to the original crosshair, and additional colors, an average of 53.7 ± 2.6% of the time over the course of the experiment. Seven out of ten different participants exposed to sham-only DU observed comparable percepts, but only an average of 36.3 ± 1.9% of the time, a statistically significant difference (p < 0.00001). Moreover, on average, participants exposed to a combination of sham and actual ultrasound reported a net increase of 47.9 percentage points in the likelihood that they would report a percept by the end of the experiment. Our results are consistent with the hypothesis that a random combination of sham-only and actual DU, applied directly over the visual cortex of participants, increased the likelihood that they would observe visual effects, but not the type of effects, with that likelihood increasing over the course of the experiment. From this, we conclude that repeated exposures by DU may make the visual cortex more responsive to stimulation of their visual cortex by the visual target itself. Future studies should identify the biophysical mechanism(s) and neural pathways by which DU, in our hands and others, can generate its observed effects on brain function. These observations, consistent with other’s observation of effects of DU stimulation of the human motor cortex and amygdala, as well as the FDA approved nature of DU, may lead to increased use of DU as a means of altering brain function.

Altered cortical visuomotor integration has been involved in the pathophysiology of freezing of gait (FoG) in parkinsonism. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas with a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique in patients with FoG.Twelve Parkinson's disease (PD) patients suffering from levodopa-responsive-FoG (off-FoG) were compared with 12 PD patients without FoG and 12 healthy subjects of similar age/sex. In the "off" condition, visuomotor connections (VMCs) were assessed bilaterally. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle.Significant (P0.01), bilateral effects due to VMCs were detected in all three groups, consisting of a MEP suppression at ISI 18 and 40ms. However, in PD patients with FoG, the MEP suppression was significantly (P0.05) enhanced, both at ISI 18-40ms, in comparison with the other two groups. The phenomenon was limited to the right hemisphere.PD patients with FoG showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs. Right-sided alterations of the cortical visuomotor integration may contribute to the pathophysiology of FoG.

Objective. All of the human prosthetic visual systems implanted so far have been achromatic. Schmidt et al (1996 Brain 119 507–22) reported that at low stimulation intensities their subject reported that phosphenes usually had a specific hue, but when the stimulus intensity was increased, they desaturated to white. We speculate here that previous B/W prosthetic systems were unnecessarily over-stimulating the visual cortex to obtain white phosphenes, which may be why unexpected alterations in phosphenes and seizures were not an uncommon occurrence. A color prosthesis would have the advantage of being elicited by lower levels of stimulation, reducing the probability of causing epileptogenic responses. Approach. A ‘hybrid’ mode of stimulation is suggested, involving a combination of B/W and color stimulation, which could provide color information without reducing spatial resolution. Main results. Colors in the real world are spread along intensity and chromatic gradients. Significance. Software implementation strategies are discussed, as are the advantages and challenges for possible color prosthetic systems.

The advanced technology of ultrashort pulse laser has given many useful biomedical applications such as micro- and nanosurgery on a cellular and subcellular level, excimer laser refractive surgery (LASIK), protein or cell organelles activation or inactivation, and optogenetics. Here, we argue that the same technology can also be applied to stimulate the neurons in the retina mechanically with the pressure (pressure stimulation) generated from Laser Induced Breakdown (LIB) regime using femtosecond laser. Stimulating retinal cell with pressure is rarely discussed because of considerable difficulties to invoke pressure waves precisely, effectively, and safely into the eye. We investigated these problems theoretically to show that the generated pressure waves could be used to stimulate the neurons in the retina. This new technique might provide a way to understand deeper the roles of mechanical cues in the human visual system and to create an alternative phosphene-based retinal prosthetic.

Non-invasive brain stimulation to target specific network activity patterns, e.g. transcranial alternating current stimulation (tACS), has become an essential tool to understand the causal role of neuronal oscillations in cognition and behavior. However, conventional sinusoidal tACS limits the ability to record neuronal activity during stimulation and lacks spatial focality. One particularly promising new tACS stimulation paradigm uses amplitude-modulated (AM) high-frequency waveforms (AM-tACS) with a slow signal envelope that may overcome the limitations. Moreover. AM-tACS using high-frequency carrier signals is more tolerable than conventional tACS, e.g. in terms of skin irritation and occurrence of phosphenes, when applied at the same current intensities (e.g. 1–2 mA). Yet, the fundamental mechanism of neuronal target-engagement by AM-tACS waveforms has remained unknown. We used a computational model of cortex to investigate how AM-tACS modulates endogenous oscillations and compared the target engagement mechanism to the case of conventional (unmodulated) low-frequency tACS. Analysis of stimulation amplitude and frequency indicated that cortical oscillations were phase-locked to the envelope of the AM stimulation signal, which thus exhibits the same target engagement mechanism as conventional (unmodulated) low frequency tACS. However, in the computational model substantially higher current intensities were needed for AM-tACS than for low-frequency (unmodulated) tACS waveforms to achieve pronounced phase synchronization. Our analysis of the carrier frequency suggests that there might be a trade-off between the use of high-frequency carriers and the stimulation amplitude required for successful entrainment. Together, our computational simulations support the use of slow-envelope high frequency carrier AM waveforms as a tool for noninvasive modulation of brain oscillations. More empirical data will be needed to identify the optimal stimulation parameters and to evaluate tolerability and safety of both, AM- and conventional tACS.

Background Transcranial magnetic stimulation (TMS) is a non-invasive method to stimulate localized brain regions. Despite widespread use in motor cortex, TMS is seldom performed in sensory areas due to variable, qualitative metrics. Objective Assess the reliability and validity of tracing phosphenes, and to investigate the stimulation parameters necessary to elicit decreased visual cortex excitability with paired-pulse TMS at short inter-stimulus intervals. Methods Across two sessions, single and paired-pulse recruitment curves were derived by having participants outline elicited phosphenes and calculating resulting average phosphene sizes. Results Phosphene size scaled with stimulus intensity, similar to motor cortex. Paired-pulse recruitment curves demonstrated inhibition at lower conditioning stimulus intensities than observed in motor cortex. Reliability was high across sessions. Conclusions TMS-induced phosphenes are a valid and reliable tool for measuring cortical excitability and inhibition in early visual areas. Our results also provide appropriate stimulation parameters for measuring short-latency intracortical inhibition in visual cortex.

The premise of neuro-rehabilitation after injury is to access the residual capacity of the nervous system to improve function. We describe a patient who developed a quadrantopsia and drug-resistant focal epilepsy after an arteriovenous malformation hemorrhage. Thirty years later, he underwent placement of subdural electrodes for seizure mapping. Phosphenes were elicited in the blind right visual field with stimulation of occipital cortex. This case demonstrates that visual cortex may retain functional organization after a partial subcortical visual pathway injury. This persistent conscious mapping suggests that disconnected visual cortex could serve as a region for interfacing with neural prosthetic devices for acquired blindness., Highlights • Stimulation of occipital cortex elicited phosphenes in a blind visual field. • Conscious visual perception can be preserved after visual pathway injury. • Disconnected visual cortex could serve to interface with neural prosthetic devices.

Transcranial magnetic stimulation (TMS) transports a short (about 100 µs) high intensity (∼ 2 Tesla) magnetic field painless through the skull into the brain and induces an electric current flow. This in turn excites neurons or fiber tracts. TMS can only induce tangential current flow. Its intensity declines exponentially; thus mainly cortical areas closed to the surface are targeted. The best available data are those obtained at the motor cortex (M1). M1 stimulation allows easy quantification of effects by recording electromyographic muscle activity. When stimulating the visual cortex phosphenes can be induced. Computational models allocate the lowest threshold elements into terminals of the axon collaterals. The dependence of threshold and polarization on spatial and temporal stimulation parameters are strongly affected by morphological features of the axonal arbor, including myelination, diameter, and branching. The thresholds for current flow are directionally sensitive, with lower threshold from the back to the front as vice versa. Intensity dependent a D-wave and several I-waves with 1.5 ms intervals are induced, which can be recorded in man invasively at the cervical spinal cord. In psychology it allows to induce short virtual lesions which provide data on cortical functions arising in the area stimulated. TMS is clinically used to quantify central motor conduction time in particular in patients with multiple sclerosis. Reliable information on amplitude changes e.g. in cervical myelopathy can be obtained by the triple stimulation technique.