Joseph F. Rizzo

Short-Wavelength Light Sensitivity of Circadian, Pupillary, and Visual Awareness in Humans Lacking an Outer Retina

Summary As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight [1–11]. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength (∼480 nm) blue light and remain functional in the absence of rods and cones [8–10]. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (λmax) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus (∼480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all “visual” responses to light.

Minimally Invasive Retinal Prosthesis

A wireless retinal implant with a low-power area-efficient stimulator chip features an ASK demodulator, single-ended-to-differential converter, low-power DLL and programmable current drivers. The chip dissipates 1.3mW from plusmn2.5V at a data rate of 100kb/s. The chip is powered and driven through a wireless inductive link separated by 15mm

Ocular implants for the blind

Now in early development, an ultra-thin array of electrodes, powered by a laser and placed directly on surviving neurons of the retina, could provide usable percepts of light for the visually impaired.

Risk of developing multiple sclerosis after uncomplicated optic neuritis A long‐term prospective study

We prospectively studied 60 white patients living in New England who presented with uncomplicated optic neuritis (ON) to determine the risk of developing multiple sclerosis (MS). The diagnoses of ON and MS were made solely on the basis of clinical criteria. Patients were followed for a mean of 14.9 years. Life table analysis indicated that 74% of the women and 34% of the men will have developed MS 15 years after their attack of ON. The risk of developing MS was 3. 4 times greater for women than for men. Onset of ON between the ages of 21 and 40 years may have had a modest effect in increasing the risk of developing MS. Recurrence of ON did not appear to affect the risk.

Axonal Sodium-Channel Bands Shape the Response to Electric Stimulation in Retinal Ganglion Cells

Electric stimulation of the retina reliably elicits light percepts in patients blinded by outer retinal diseases. However, individual percepts are highly variable and do not readily assemble into more complex visual images. As a result, the quality of visual information conveyed to patients has been quite limited. To develop more effective stimulation methods that will lead to improved psychophysical outcomes, we are studying how retinal neurons respond to electric stimulation. The situation in the retina is analogous to other neural prosthetic applications in which a better understanding of the underlying neural response may lead to improved clinical outcomes. Here, we determined which element in retinal ganglion cells has the lowest threshold for initiating action potentials. Previous studies suggest multiple possibilities, although all were within the soma/proximal axon region. To determine the actual site, we measured thresholds in a dense two-dimensional grid around the soma/proximal axon region of rabbit ganglion cells in the flat mount preparation. In directionally selective (DS) ganglion cells, the lowest thresholds were found along a small section of the axon, about 40 microm from the soma. Immunochemical staining revealed a dense band of voltage-gated sodium channels centered at the same location, suggesting that thresholds are lowest when the stimulating electrode is closest to the sodium-channel band. The size and location of the low-threshold region was consistent within DS cells, but varied for other ganglion cell types. Analogously, the length and location of sodium channel bands also varied by cell type. Consistent with the differences in band properties, we found that the absolute (lowest) thresholds were also different for different cell types. Taken together, our results suggest that the sodium-channel band is the site that is most responsive to electric stimulation and that differences in the bands underlie the threshold differences we observed.

What blindness can tell us about seeing again: merging neuroplasticity and neuroprostheses

Significant progress has been made in the development of visual neuroprostheses to restore vision in blind individuals. Appropriate delivery of electrical stimulation to intact visual structures can evoke patterned sensations of light in those who have been blind for many years. However, success in developing functional visual prostheses requires an understanding of how to communicate effectively with the visually deprived brain in order to merge what is perceived visually with what is generated electrically.

Photic Resetting of the Human Circadian Pacemaker in the Absence of Conscious Vision

Ocular light exposure patterns are the primary stimuli for entraining the human circadian system to the local 24-h day. Many totally blind persons cannot use these stimuli and, therefore, have circadian rhythms that are not entrained. However, a few otherwise totally blind persons retain the ability to suppress plasma melatonin concentrations after ocular light exposure, probably using a neural pathway that includes the site of the human circadian pacemaker, suggesting that light information is reaching this site. To test definitively whether ocular light exposure could affect the circadian pacemaker of some blind persons and whether melatonin suppression in response to bright light correlates with light-induced phase shifts of the circadian system, the authors performed experiments with 5 totally blind volunteers using a protocol known to induce phase shifts of the circadian pacemaker in sighted individuals. In the 2 blind individuals who maintained light-induced melatonin suppression, the circadian system was shifted by appropriately timed bright-light stimuli. These data demonstrate that light can affect the circadian pacemaker of some totally blind individuals— either by altering the phase of the circadian pacemaker or by affecting its amplitude. They are consistent with data from animal studies demonstrating that there are different neural pathways and retinal cells that relay photic information to the brain: one for conscious light perception and the other for non-image-forming functions.

Responses of rabbit retinal ganglion cells to electrical stimulation with an epiretinal electrode

Rational selection of electrical stimulus parameters for an electronic retinal prosthesis requires knowledge of the electrophysiological responses of retinal neurons to electrical stimuli. In this study, we examined the effects of cathodal and anodal current pulses on the extracellularly recorded responses of OFF and ON rabbit retinal ganglion cells (RGCs) in an in vitro preparation. Current pulses (1 msec duration), delivered by a 125 microm electrode placed on the inner retinal surface within the receptive field of a RGC, produced both short-latency (< or =5 msec) and long-latency (8-60 msec) responses. The long-latency responses, but not the short-latency responses, were abolished upon application of the glutamate receptor antagonists CNQX and NBQX, thus indicating that the long-latency responses of RGCs are due to activation of presynaptic neurons in the retina. The latency of the long-latency response depended upon the polarity of the stimulus. For OFF RGCs, the average latency was 11 msec for a cathodal stimulus and 24 msec for an anodal stimulus. For ON RGCs, the average latency was 25 msec for a cathodal stimulus and 16 msec for an anodal stimulus. The threshold current also depended upon the polarity of the stimulus, at least for OFF RGCs. The average threshold current for evoking a long-latency response in OFF RGCs was 10 microA for a cathodal stimulus and 21 microA for an anodal stimulus. In ON RGCs, the average threshold current was 13 microA for a cathodal stimulus and 15 microA for an anodal stimulus.

REVIEW ■ : Prospects for a Visual Prosthesis

Diseases of the retina and optic nerve are common causes of irreversible blindness. Given the lack of effective treatments, several laboratories are utilizing microelectronic technology to develop either a cortical or retinal prosthesis. Each strategy offers certain advantages, but both face numerous and formidable chal lenges. Consequently, a clinically useful device of either type is still conceptual. The technological means to build prostheses are available, but the ultimate obstacle is the integration of the technology with the brain. This article reviews achievements of the ongoing efforts and focuses on our project to develop a retinal prosthesis. NEUROSCIENTIST 3:251-262, 1997

Use of magnetic resonance imaging to differentiate optic neuritis and nonarteritic anterior ischemic optic neuropathy

OBJECTIVE To determine if magnetic resonance imaging (MRI) of the optic nerves obtained during the acute phase can distinguish patients with optic neuritis (ON) from those with nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN Retrospective, neuroradiologic, observational study. PARTICIPANTS Sixty-four patients diagnosed as having either ON or NAION who were diagnosed by clinical criteria and imaged by MRI. METHODS Demographic information on the MRI scans was masked and the patients were presented randomly and in a blinded fashion to a neuroradiologist (JDR) for determination of abnormalities. Reproducibility was assessed by presenting 10 of the scans a second time to the same neuroradiologist. MAIN OUTCOME MEASURES The presence or absence and location of abnormal MRI signals of the optic nerve. RESULTS Evaluation of reproducibility revealed identical interpretations of the ten scans submitted a second time. The optic nerve was abnormal in the clinically affected eye in 31 of the 32 ON patients but in only 5 of the 32 NAION patients. Thirty of the 31 ON patients who received gadolinium had enhancement, and 27 of the 32 ON patients had increased short T(1) inversion recovery signal in the clinically affected optic nerve. The five NAION patients with abnormal scans in the clinically affected eye had increased short T(1) inversion recovery signal, and in two of these, there also was enhancement of the optic nerve. For the ON patients, enhancement involved the entire length of the intraorbital optic nerve in 18 cases and the intracranial segment of the optic nerve in 19 cases. CONCLUSIONS Our study shows that MRI scanning of the optic nerve shows significantly different results between patients clinically diagnosed with either ON or NAION.