Week in Review: Number 29

Corneal Confocal Microscopy Identifies Corneal Nerve Fiber Loss in Patients with Long COVID
Long COVID is defined as "signs and symptoms that develop during or following an infection consistent with COVID-19 and which continue for more than 4 weeks and are not explained by an alternative diagnosis," according to the National Institute for Health and Care Excellence (NICE) in England. Long COVID affects at least 10% of individuals who have recovered from acute SARS-CoV-2 infection, with symptoms ranging from headaches and "brain fog" to numbness and neuropathic pain. The presence of neurologic symptoms prompted researchers to investigate whether an imaging technique called corneal confocal microscopy (CCM) can be used to identify underlying nerve damage in patients with long COVID. A quick and non-invasive technique for real-time imaging of corneal nerve fibers, corneal confocal microscopy is useful in identifying tell-tale signs of corneal nerve damage in neurodegenerative diseases such as diabetic neuropathy and multiple sclerosis, and now long COVID, as indicators of nerve damage elsewhere in the body. The present study examined 40 patients who had recovered from COVID-19 three to four months previously, and compared them with 30 healthy control participants who never had the disease. They found evidence of both nerve damage and increased dendritic cells (a type of immune cell) in the corneas of individuals with long COVID, with the severity of nerve damage correlated with the severity of disease at presentation. Based on their findings, the authors argue that CCM has the potential to be a valuable diagnostic tool to diagnose and assess cases of long COVID. One of the researchers adds, "The identification of underlying nerve damage also allows us to think about this condition as a neurodegenerative disease, which may be amenable to treatment.”

CaMKII Gene Therapy Preserves RGC Axons & Somas
Some conditions, such as excitotoxicity and retinal ischemia, injure the retinal ganglion cell (RGC) soma, while damage to the retinal ganglion cell axon can result from optic nerve transection, compression, intracranial hypertension, and glaucoma. A neuroprotective therapy that preserves both RGC axons and somas would therefore have wide-ranging benefit. Researchers are investigating the potential of calcium / calmodulin-dependent protein kinase II (CaMKII) as a target for gene therapy to protect RGCs from diverse pathological insults and ultimately preserve vision. Studies in small animal models indicate that damage to RGC somas or optic nerve axons led to inactivation of CaMKII and its downstream signaling target, cAMP response element binding protein (CREB). However, reactivation of CaMKII and CREB provided robust protection for retinal ganglion cells. For example, experiments wherein CaMKII was delivered via adeno-associated viral vector to mice just prior to the toxic insult or just after optic nerve crush led to increased CaMKII activity and robust protection of retinal ganglion cells. In particular, the gene therapy introduced a more active version of CaMKII with a modified amino acid to boost their activity in RGCs. The researchers then tested the modified enzyme in a range of injury and disease animal models, including two models of glaucoma for both high and normal intraocular pressure. The results indicated that among gene therapy-treated mice, 77% of retinal ganglion cells survived 12 months after the toxic insult compared with 8% in control mice, and six months following optic nerve crush, 77% of retinal ganglion cells had survived versus 7% in controls. The mice treated with CaMKII gene therapy also showed preserved function for visually-guided behavior such as finding a submerged platform, depth perception, and avoiding overhead shadows (simulated predators). Further research in larger animal models is warranted to better characterize the precise role of CaMKII, which might vary depending on different conditions, before starting clinical trials. Nonetheless, as one of the researchers highlights, the fact that gene therapy with CaMKII would involve a one-time transfer of a single gene adds to its vast potential to treat many retinal and optic nerve conditions.

Wearable Collision-Warning Device for Blind and Visually Impaired People
For individuals with visual impairment or blindness, collisions and falls are a common risk in independent daily life. The use of mobility aids such long canes and guide dogs can offer benefits, but also come with limitations. For example, a long cane primarily detects hazards on the ground, often missing hazards above ground level. The range of long cane sweeping is also limited and not always appropriate in busy settings with many pedestrians. Guide dogs are highly effective but can be cost-prohibitive, as training a guide dog typically costs $45,000-$60,000. Vision rehabilitation researchers at Harvard developed and tested a wearable collision-warning device as an added safety measure to reduce collisions, for use along with the conventional long cane. The device uses a chest-mounted wide-angle camera connected to a processing unit that records video and analyzes collision risk based on the relative movement of incoming and surrounding objects in the camera’s field of view. This information is relayed to two Bluetooth-connected wristbands worn by the user, which vibrate on either or both wrists depending on the location of the imminent object, with both wristbands vibrating to indicate an object directly ahead. Notably, this device analyzes relative motion, warning only of approaching obstacles that pose a collision risk and ignoring objects that are not on a collision course. The researchers then conducted a randomized-controlled trial involving 31 blind or severely visually impaired adults who, after training, were instructed to use the device at home for 4 weeks, in conjunction with their existing mobility aids. The device was randomized (double-masked) to switch between active and silent modes, with silent mode replicating the placebo condition, only recording but not alerting the user. The results showed that the collision frequency in active mode was 37% less than that in silent mode, demonstrating the potential benefit of the device, especially as a more affordable option than a guide dog. One of the authors adds that the video recordings from the device can also provide rich data about daily mobility life and challenges for people with visual impairment to improve mobility aid training. The researchers plan on ongoing technical improvements in device processing power and cosmesis.

Progress in SD-OCT Algorithms to Detect Early Biomarkers of Diabetic Retinopathy
Researchers conducted a study of spectral-domain ocular coherence tomography (SD-OCT) algorithms to detect early biomarkers in diabetic retinas. One of the study authors argues, "Many algorithms use any image information that differs between diabetic patients and controls, which can identify which individuals might have diabetes, but these can be nonspecific... Our method can be combined with the other AI methods to provide early information localized to specific retinal layers or types of tissues, which allows inclusion of information not analyzed in the other algorithms." In particular, they compared the SD-OCT images of 33 diabetic patients (without diabetic macular edema) with 33 age-matched control participants. According to their results, "Diabetic retinas, although not thicker than controls, had subtle but quantifiable pattern changes in SD-OCT images particularly in deeper fundus layers. The size range and distribution of this pattern in diabetic eyes were consistent with small blood vessel abnormalities and leakage of lipid and fluid. Feature-based biomarkers may augment retinal thickness criteria for management of diabetic eye complications, and may detect early changes."

Hippocampus Needed to Recognize Image Sequences
While the mammalian brain stores images in the visual cortex, new research shows that the ability to recognize a sequence of images depends on the hippocampus, a brain structure associated with memory. The hippocampus essentially influences how the images are stored in the cortex if they have a sequential relationship, but does not affect the encoding of simple visual stimuli in the cortex. In their experiments, the researchers trained mice with two forms of visual recognition memory: (1) stimulus selective response plasticity (SRP), which involves learning to recognize a non-rewarding, non-threatening single visual stimulus after it has been presented over and over, eventually leading to disinterest, and (2) visual sequence plasticity, which involves learning to recognize and predict a sequence of images. Visual sequence plasticity also evokes an elevated electrical response if the stimulus is novel. This response is much greater than what is observed if the same stimuli are presented in reverse order or at a different speed. To test the role of the hippocampus, the researchers chemically removed large portions of the structure in mice and examined the tell-tale electrical response each kind of recognition memory should evoke. Mice with or without a hippocampus performed equally well in learning SRP, suggesting that the hippocampus was not needed to form that kind of memory. However, mice lacking an intact hippocampus did not perform well in visual sequence plasticity, showing no elevated electrical response to the sequences, no ability to recognize them in reverse or when delayed and no inclination to "fill in the blank" when one was missing. The experiments reveal there is a "division of labor" for many different forms of memory, in this case between simple recognition of images and the more complex recognition of image sequence, only the latter of which involves the hippocampus. Because SRP and visual sequence plasticity involve different brain circuits, the researchers next plan to explore whether those differences can help to diagnose neurodegenerative diseases such as dementia.

In Other News
(1) Motor control and eye tracking in autism spectrum disorder
(2) A patient's story about his experience with low vision
(3) More to pictures than meets the eye