Learning to See Again: Biological Constraints on Cortical Plasticity and the Implications for Sight Restoration Technologies

1. ABSTRACTThe “bionic eye” – so long a dream of the future – is finally becoming a reality with retinal prostheses available to patients in both the US and Europe. However, clinical experience with these implants has made it apparent that the vision provided by these devices differs substantially from normal sight. Consequently, the ability to learn to make use of this abnormal retinal input plays a critical role in whether or not some functional vision is successfully regained. The goal of the present review is to summarize the vast basic science literature on developmental and adult cortical plasticity with an emphasis on how this literature might relate to the field of prosthetic vision. We begin with describing the distortion and information loss likely to be experienced by visual prosthesis users. We then define cortical plasticity and perceptual learning, and describe what is known, and what is unknown, about visual plasticity across the hierarchy of brain regions involved in visual processing, and across different stages of life. We close by discussing what is known about brain plasticity in sight restoration patients and discuss biological mechanisms that might eventually be harnessed to improve visual learning in these patients.

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Glutamate in the pathophysiology of schizophrenia

Psychotic Disorders ◽

10.1093/med/9780190653279.003.0032 ◽

2020 ◽

pp. 287-296

Author(s):

Daniel C. Javitt

Keyword(s):

Visual System ◽

Visual Processing ◽

Negative Symptoms ◽

Glutamate Release ◽

Critical Role ◽

Brain Regions ◽

Long Term Memory ◽

Subcortical Structures ◽

Impaired Metabolism

Glutamate theories of schizophrenia were first proposed over 30 years ago and since that time have become increasingly accepted. Theories are supported by the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine to induce symptoms that closely resemble those of schizophrenia. Moreover, NMDAR antagonists uniquely reproduce the level of negative symptoms and cognitive deficits observed in schizophrenia, suggesting that such models may be particularly appropriate to poor outcome forms of the disorder. As opposed to dopamine, which is most prominent within frontostriatal brain regions, glutamate neurons are present throughout cortex and subcortical structures. Thus, NMDAR theories predict widespread disturbances across cortical and thalamic pathways, including sensory brain regions. In auditory cortex, NMDAR play a critical role in the generation of mismatch negativity (MMN), which may therefore serve as a translational marker of NMDAR dysfunction across species. In the visual system, NMDAR play a critical role in function of the magnocellular visual system. Deficits in both auditory and visual processing contribute to social and communication deficits, which, in turn, lead to poor functional outcome. By contrast, NMDAR dysfunction within the frontohippocampal system may contribute to well described deficits in working memory, executive processing and long-term memory formation. Deficits in NMDAR function may be driven by disturbances in presynaptic glutamate release, impaired metabolism of NMDAR modulators such as glycine or D-serine, or intrinsic abnormalities in NMDAR themselves.

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Biased M1 positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

10.1101/806943 ◽

2019 ◽

Author(s):

Sean P. Moran ◽

Zixiu Xiang ◽

Catherine A. Doyle ◽

James Maksymetz ◽

Xiaohui Lv ◽

...

Keyword(s):

Phospholipase D ◽

Cortical Plasticity ◽

Critical Role ◽

Muscarinic Acetylcholine Receptor ◽

Brain Regions ◽

Allosteric Modulators ◽

Diverse Range ◽

Positive Allosteric Modulators ◽

Potential Improvement

AbstractHighly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for the potential improvement of cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. M1 PAM discovery programs have produced a structurally diverse range of M1 PAMs with distinct pharmacological properties, including different levels of agonist activity and differences in signal bias. This includes the recent discovery of novel biased M1 PAMs that can potentiate coupling of M1 to activation of phospholipase C but not phospholipase D (PLD). However, little is known about the role of PLD in M1 signaling in native systems and it is not clear whether biased M1 PAMs will display differences in modulating M1-mediated responses in native tissue. We now report a series of studies using novel PLD inhibitors and PLD knockout mice to show that PLD is necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Importantly, biased M1 PAMs that do not couple to PLD not only fail to potentiate orthosteric agonist-induced LTD but also block M1-dependent LTD in the PFC. In contrast, biased and non-biased M1 PAMs act similarly in potentiating M1-dependent electrophysiological responses that are PLD-independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain CNS functions and that biased M1 PAMs function differently in brain regions implicated in cognition.SummaryWe demonstrate a novel role of phospholipase D in M1-dependent rodent cortical plasticity and M1 PAMs that do not couple to phospholipase D have functionally distinct effects on cortical plasticity than non-biased M1 PAMs.

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Biased M1 receptor–positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity

Science Signaling ◽

10.1126/scisignal.aax2057 ◽

2019 ◽

Vol 12 (610) ◽

pp. eaax2057 ◽

Cited By ~ 2

Author(s):

Sean P. Moran ◽

Zixiu Xiang ◽

Catherine A. Doyle ◽

James Maksymetz ◽

Xiaohui Lv ◽

...

Keyword(s):

Phospholipase D ◽

Cortical Plasticity ◽

Critical Role ◽

Muscarinic Acetylcholine Receptor ◽

Brain Regions ◽

Allosteric Modulators ◽

Diverse Range ◽

Electrophysiological Responses ◽

Positive Allosteric Modulators

Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M1 receptor signaling in native systems, and it is not clear whether biased M1 PAMs display differences in modulating M1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist–induced LTD but also blocked M1-dependent LTD in the PFC. In contrast, biased and nonbiased M1 PAMs acted similarly in potentiating M1-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain central nervous system (CNS) functions and that biased M1 PAMs function differently in brain regions implicated in cognition.

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How Learning to Read Changes the Listening Brain

Frontiers in Psychology ◽

10.3389/fpsyg.2021.726882 ◽

2021 ◽

Vol 12 ◽

Author(s):

Linda Romanovska ◽

Milene Bonte

Keyword(s):

Visual Processing ◽

Reading Skills ◽

Cortical Plasticity ◽

Visual Learning ◽

Structural Connectivity ◽

Skill Learning ◽

Behavioral Changes ◽

Functional Changes ◽

Reciprocal Interactions ◽

Child's Brain

Reading acquisition reorganizes existing brain networks for speech and visual processing to form novel audio-visual language representations. This requires substantial cortical plasticity that is reflected in changes in brain activation and functional as well as structural connectivity between brain areas. The extent to which a child’s brain can accommodate these changes may underlie the high variability in reading outcome in both typical and dyslexic readers. In this review, we focus on reading-induced functional changes of the dorsal speech network in particular and discuss how its reciprocal interactions with the ventral reading network contributes to reading outcome. We discuss how the dynamic and intertwined development of both reading networks may be best captured by approaching reading from a skill learning perspective, using audio-visual learning paradigms and longitudinal designs to follow neuro-behavioral changes while children’s reading skills unfold.

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Adaptive and Maladaptive Neural Plasticity Due to Facial Nerve Palsy

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000244 ◽

2016 ◽

Vol 224 (2) ◽

pp. 102-111 ◽

Cited By ~ 1

Author(s):

Carsten M. Klingner ◽

Stefan Brodoehl ◽

Gerd F. Volk ◽

Orlando Guntinas-Lichius ◽

Otto W. Witte

Keyword(s):

Facial Nerve ◽

Neural Plasticity ◽

Cortical Plasticity ◽

Brain Plasticity ◽

Motor Nerve ◽

Predictive Coding ◽

Theoretical Framework ◽

Cortical Reorganization ◽

Nerve Lesion ◽

Peripheral Facial Palsy

Abstract. This paper reviews adaptive and maladaptive mechanisms of cortical plasticity in patients suffering from peripheral facial palsy. As the peripheral facial nerve is a pure motor nerve, a facial nerve lesion is causing an exclusive deefferentation without deafferentation. We focus on the question of how the investigation of pure deefferentation adds to our current understanding of brain plasticity which derives from studies on learning and studies on brain lesions. The importance of efference and afference as drivers for cortical plasticity is discussed in addition to the crossmodal influence of different competitive sensory inputs. We make the attempt to integrate the experimental findings of the effects of pure deefferentation within the theoretical framework of cortical responses and predictive coding. We show that the available experimental data can be explained within this theoretical framework which also clarifies the necessity for maladaptive plasticity. Finally, we propose rehabilitation approaches for directing cortical reorganization in the appropriate direction and highlight some challenging questions that are yet unexplored in the field.

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The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

Science Translational Medicine ◽

10.1126/scitranslmed.abd6434 ◽

2021 ◽

Vol 13 (590) ◽

pp. eabd6434

Author(s):

Patrick Sweeney ◽

Michelle N. Bedenbaugh ◽

Jose Maldonado ◽

Pauline Pan ◽

Katelyn Fowler ◽

...

Keyword(s):

Sexual Dimorphism ◽

Feeding Behavior ◽

Critical Role ◽

Brain Regions ◽

Sexually Dimorphic ◽

Male And Female ◽

Female Mice ◽

Bidirectional Regulation ◽

Fear And Anxiety ◽

Agouti Related Protein

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

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Increased hypothalamic–pituitary–adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa

Acta Endocrinologica ◽

10.1530/eje-13-0433 ◽

2013 ◽

Vol 169 (5) ◽

pp. 639-647 ◽

Cited By ~ 36

Author(s):

Elizabeth A Lawson ◽

Laura M Holsen ◽

Rebecca DeSanti ◽

McKale Santin ◽

Erinne Meenaghan ◽

...

Keyword(s):

Anorexia Nervosa ◽

Visual Processing ◽

Serum Cortisol ◽

Brain Regions ◽

Cross Sectional Study ◽

Food Motivation ◽

Cross Sectional ◽

Hypothalamic Pituitary Adrenal ◽

Cortisol Levels ◽

The Relationship

ObjectiveCorticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic–pituitary–adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN.DesignCross-sectional study of 36 women (13 AN, ten weight-recovered AN (ANWR), and 13 healthy controls (HC)).MethodsPeripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal.ResultsIn each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min post-meal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula).ConclusionsHPA activation may contribute to the maintenance of AN by the suppression of appetitive drive.

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Multiple overlapping dynamic patterns of the visual sensory network in schizophrenia

10.1101/2020.12.21.423535 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mohammad S.E Sendi ◽

Godfrey D Pearlson ◽

Daniel H Mathalon ◽

Judith M Ford ◽

Adrian Preda ◽

...

Keyword(s):

Functional Connectivity ◽

Visual Processing ◽

Information Transfer ◽

Pearson Correlation ◽

Visual Learning ◽

Network Connectivity ◽

Resting State Fmri ◽

Connectivity Pattern ◽

Middle Temporal Gyrus ◽

Middle Temporal

Although visual processing impairments have been explored in schizophrenia (SZ), their underlying neurobiology of the visual processing impairments has not been widely studied. Also, while some research has hinted at differences in information transfer and flow in SZ, there are few investigations of the dynamics of functional connectivity within visual networks. In this study, we analyzed resting-state fMRI data of the visual sensory network (VSN) in 160 healthy control (HC) subjects and 151 SZ subjects. We estimated 9 independent components within the VSN. Then, we calculated the dynamic functional network connectivity (dFNC) using the Pearson correlation. Next, using k-means clustering, we partitioned the dFNCs into five distinct states, and then we calculated the portion of time each subject spent in each state, that we termed the occupancy rate (OCR). Using OCR, we compared HC with SZ subjects and investigated the link between OCR and visual learning in SZ subjects. Besides, we compared the VSN functional connectivity of SZ and HC subjects in each state. We found that this network is indeed highly dynamic. Each state represents a unique connectivity pattern of fluctuations in VSN FNC, and all states showed significant disruption in SZ. Overall, HC showed stronger connectivity within the VSN in states. SZ subjects spent more time in a state in which the connectivity between the middle temporal gyrus and other regions of VNS is highly negative. Besides, OCR in a state with strong positive connectivity between middle temporal gyrus and other regions correlated significantly with visual learning scores in SZ.

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Subanesthetic ketamine reactivates adult cortical plasticity to restore vision from amblyopia

10.1101/2020.03.16.994475 ◽

2020 ◽

Author(s):

Steven F. Grieco ◽

Xin Qiao ◽

Xiaoting Zheng ◽

Yongjun Liu ◽

Lujia Chen ◽

...

Keyword(s):

Functional Recovery ◽

Neural Plasticity ◽

Cortical Plasticity ◽

Brain Plasticity ◽

Excitatory Input ◽

Inhibitory Neurons ◽

List Type ◽

Visual Cortical

SummarySubanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine’s effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces down-regulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.Highlights○ Disinhibition of excitatory cells by ketamine occurs in a fast and sustained manner○ Ketamine evokes NRG1 downregulation and excitatory input loss to PV cells○ Ketamine induced plasticity is blocked by exogenous NRG1 or its receptor knockout○ PV inhibitory cells are the initial functional locus underlying ketamine’s effects

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C-19 An fMRI Study of Age-Associated Changes in Basic Visual Discrimination

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acz034.181 ◽

2019 ◽

Vol 34 (6) ◽

pp. 1048-1048

Author(s):

T Seider ◽

E Porges ◽

A Woods ◽

R Cohen

Keyword(s):

Visual Processing ◽

Visual Discrimination ◽

Community Sample ◽

Visual Assessment ◽

Brain Regions ◽

Brain Response ◽

Match To Sample ◽

Fmri Study ◽

Perceptual Skill ◽

Cluster Level

Abstract Objective The study was conducted to determine age-associated changes in functional brain response, measured with fMRI, during visual discrimination with regard to three elementary components of visual perception: shape, location, and velocity. A secondary aim was to validate the method used to isolate the hypothesized brain regions associated with these perceptual functions. Method Items from the Visual Assessment Battery (VAB), a simultaneous match-to-sample task, assessed visual discrimination in 40 healthy adults during fMRI. Participants were aged 51-91 and recruited from a larger community sample for a study on normal aging. The tasks were designed to isolate neural recruitment during discrimination of either location, shape, or velocity by using tasks that were identical aside from the perceptual skill required to complete them. Results The Location task uniquely activated the dorsal visual processing stream, the Shape task the ventral stream, and the Velocity task V5/MT. Greater age was associated with greater neural recruitment, particularly in frontal areas (uncorrected voxel-level p < .001, family-wise error cluster-level p□.05). Conclusions Results validated the specialization of brain regions for spatial, perceptual, and movement discriminations and the use of the VAB to assess functioning localized to these regions. Anterior neural recruitment during visual discrimination increases with age.

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