Ulf Theodor Eysel

Adult visual plasticity underlying local remodeling of the cortical circuitry in vivo appears to be associated with a spatiotemporal pattern of strongly increased spontaneous and evoked activity of populations of cells. Here we review and discuss pioneering work by us and others about principles of plasticity in the adult visual cortex, starting with our study which showed that a confined lesion in the cat retina causes increased excitability in the affected region in the primary visual cortex accompanied by fine-tuned restructuring of neuronal function. The underlying remodeling processes was further visualized with voltage-sensitive dye (VSD) imaging that allowed a direct tracking of retinal lesion-induced reorganization across horizontal cortical circuitries. Nowadays, application of noninvasive stimulation methods pursues the idea further of increased cortical excitability along with decreased inhibition as key factors for the induction of adult cortical plasticity. We used high-frequency transcranial magnetic stimulation (TMS), for the first time in combination with VSD optical imaging, and provided evidence that TMS-amplified excitability across large pools of neurons forms the basis for noninvasively targeting reorganization of orientation maps in the visual cortex. Our review has been compiled on the basis of these four own studies, which we discuss in the context of historical developments in the field of visual cortical plasticity and the current state of the literature. Overall, we suggest markers of LTP-like cortical changes at mesoscopic population level as a main driving force for the induction of visual plasticity in the adult. Elevations in excitability that predispose towards cortical plasticity are most likely a common property of all cortical modalities. Thus, interventions that increase cortical excitability are a promising starting point to drive perceptual and potentially motor learning in therapeutic applications.

Although by adulthood cortical structures and their capacity for processing sensory information have become established and stabilized, under conditions of cortical injury, or sensory deprivation, rapid reorganization occurs. Little is known as to the impact of this kind of adaptation on cellular processes related to memory encoding. However, imaging studies in humans suggest that following loss or impairment of a sensory modality, not only cortical but also subcortical structures begin to reorganize. It is likely that these processes are supported by neurotransmitter receptors that enable synaptic and cortical plasticity. Here, we explored to what extent the expression of plasticity-related proteins (GABA-A, GABA-B, GluN1, GluN2A, GluN2B) is altered following early vision loss, and whether this impacts on hippocampal function. We observed that in the period of 2–4 months postnatally in CBA/J-mice that experience hereditary postnatal retinal degeneration, systematic changes of GABA-receptor and NMDA-receptor subunit expression occurred that emerged first in the hippocampus and developed later in the cortex, compared to control mice that had normal vision. Changes were accompanied by significant impairments in hippocampal long-term potentiation and hippocampus-dependent learning. These data indicate that during cortical adaptation to early loss of vision, hippocampal information processing is compromised, and this status impacts on the acquisition of spatial representations.

Significance: Transcranial magnetic stimulation (TMS) holds promise as a tool for noninvasively facilitating plastic changes in cortical networks. However, highly resolved visualization of its modulatory effects remains elusive because current neuroimaging techniques applicable in humans are limited in spatiotemporal resolution. Here we used an imaging approach with voltage-sensitive dye and tracked, at submillimeter range, TMS-induced plastic changes across cat primary visual cortex. We show that high-frequency 10-Hz TMS induces a state where visual cortical maps are transiently “destabilized.” In turn, the cortex was sensitized to a bias in input—here imposed by prolonged exposure to a single visual orientation—and primed to relearn connectivity patterns. These findings implicate an early post-TMS time window for promising therapeutic interventions through TMS.

Induction of a central retinal lesion in both eyes of adult mammals is a model for macular degeneration and leads to retinotopic map reorganization in the primary visual cortex (V1). Here we characterized the spatiotemporal dynamics of molecular activity levels in the central and peripheral representation of five higher-order visual areas, V2/18, V3/19, V4/21a,V5/PMLS, area 7, and V1/17, in adult cats with central 10° retinal lesions (both sexes), by means of real-time PCR for the neuronal activity reporter genezif268.The lesions elicited a similar, permanent reduction in activity in the center of the lesion projection zone of area V1/17, V2/18, V3/19, and V4/21a, but not in the motion-driven V5/PMLS, which instead displayed an increase in molecular activity at 3 months postlesion, independent of visual field coordinates. Also area 7 only displayed decreased activity in its LPZ in the first weeks postlesion and increased activities in its periphery from 1 month onward. Therefore we examined the impact of central vision loss on motion perception using random dot kinematograms to test the capacity for form from motion detection based on direction and velocity cues. We revealed that the central retinal lesions either do not impair motion detection or even result in better performance, specifically when motion discrimination was based on velocity discrimination. In conclusion, we propose that central retinal damage leads to enhanced peripheral vision by sensitizing the visual system for motion processing relying on feedback from V5/PMLS and area 7.SIGNIFICANCE STATEMENTCentral retinal lesions, a model for macular degeneration, result in functional reorganization of the primary visual cortex. Examining the level of cortical reactivation with the molecular activity markerzif268revealed reorganization in visual areas outside V1. Retinotopic lesion projection zones typically display an initial depression inzif268expression, followed by partial recovery with postlesion time. Only the motion-sensitive area V5/PMLS shows no decrease, and even a significant activity increase at 3 months post-retinal lesion. Behavioral tests of motion perception found no impairment and even better sensitivity to higher random dot stimulus velocities. We demonstrate that the loss of central vision induces functional mobilization of motion-sensitive visual cortex, resulting in enhanced perception of moving stimuli.

In Deutschland leiden etwa 30 000–40 000 Menschen an der Krankheit Retinitis pigmentosa (RP), die im Endstadium zur Erblindung führt. Die bisher einzige Hilfe für an RP erblindete Patienten sind Netzhautimplantate, die seit mehreren Jahren entwickelt werden und nunmehr als Medizinprodukt zugelassen sind. Netzhautimplantate erzeugen durch elektrische Stimulation der degenerierten Netzhaut Sehwahrnehmungen, die im Alltag blinder Menschen hilfreich sind. Allerdings ist die gegenwärtig erreichbare Sehqualität noch so, dass die Menschen auch mit Implantat gesetzlich blind sind. Die Sehqualität, die mit epi- und subretinalen Implantaten erreicht werden kann, hängt zum einen von patientenindividuellen Faktoren ab, wie etwa dem individuellen Verlauf und Status der Netzhautdegeneration, zum anderen von der Schnittstelle zwischen Implantat und Netzhaut und der Qualität der mit elektrischer Stimulation erzielbaren neuronalen Aktivierung. Biophysikalische Ansatzpunkte zur funktionellen Weiterentwicklung der Implantate, die sich an der Physiologie der Netzhaut (Zelldichte, intraretinale Verschaltungen) orientieren, bieten die technische Seite der Schnittstelle (Elektrodenmaterialien, -größe und -dichte) sowie die Stimulationsprotokolle (Zeitverläufe der elektrischen Reize, räumlich-zeitliche Stimulationsmuster), mit denen visuelle Informationen in die degenerierte Netzhaut eingespeist werden. Die Optimierung der Reizparameter kann durch eine detaillierte Analyse kortikaler Antworten mit geeigneten elektrophysiologischen und optischen Methoden unterstützt werden. Dieser Artikel beschreibt die physiologischen und biophysikalischen Grundlagen der elektrischen Netzhautstimulation und die daraus resultierende retinale und kortikale Aktivierung. In Germany, about 30,000 to 40,000 people suffer from retinitis pigmentosa (RP), which ultimately results in blindness. The only aid to blind RP patients are retinal implants: These have been under development for several years and have now been approved as a medical product. Retinal implants produce visual perceptions in response to electrical stimulation of the degenerated retina and are useful in the everyday life of blind people. However, the currently achievable quality of vision is such that people with a retinal implant are still legally blind. The visual quality that can be achieved with epi- and subretinal implants depends not only on patient-specific factors such as individual history and status of retinal degeneration, but especially on the interface between implant and retina and the quality of the achievable neuronal activation. Biophysical approaches to functional improvements of the implants are founded on the physiology of the retina (cell density, intraretinal interconnections), are based on technical optimisation of the interface (electrode materials, size and density), and exploit the stimulation protocols with which visual information is fed into the degenerated retina (time courses of electrical stimuli, spatiotemporal stimulation pattern). Optimisation of stimulation parameters can be supported by a detailed analysis of cortical responses, with appropriate electrophysiological and optical methods. This article looks at both the physiological and biophysical fundamentals of electrical retinal stimulation, as well as the resulting retinal and cortical activation.

Optical illusions have broadened our understanding of the brains role in visual perception 13. A modern day optical illusion emerged from a posted photo of a striped dress, which some perceived as white and gold and others as blue and black. Theories on the differences have been proposed and included e.g. colour constancy, contextual integration, and the principle of ambiguous forms4, however no consensus has yet been reached. The fact that one group sees a white/gold dress, instead of the actual blue/black dress, provides a control and therefore a unique opportunity in vision research, where two groups perceive the same object differently. Using functional magnetic resonance imaging (fMRI) we can identify human brain regions that are involved in this optical illusion concerning colour perception and investigate the neural correlates that underlie the observed differences. Furthermore open questions in visual neuroscience concerning the computation of complex visual scenes can be addressed. Here we show, using fMRI, that those who perceive The Dress as white/gold (n=14) have higher activation in response to The Dress in brain regions critically involved in visual processing and conflict management (V2, V4, as well as frontal and parietal brain areas), as compared to those who perceive The Dress as blue/black (n=14). These results are consistent with the theory of top-down modulation5 and extend the Retinex theory6 to include differing strategies the brain uses to form a coherent representation of the world around us. This provides a fundamental building block to study interindividual differences in visual processing. Meeting presented at VSS 2016

Neuronal activity plays an important role in the development and structural–functional maintenance of the brain as well as in its life‐long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post‐lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy‐based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region‐ and cell‐type‐specific contributions to functional recovery, up to microcircuit level.