LIGHTSITE II Randomized Multicenter Trial: Evaluation of Multiwavelength Photobiomodulation in Non-exudative Age-Related Macular Degeneration.

INTRODUCTION Photobiomodulation (PBM) represents a potential treatment for non-exudative age-related macular degeneration (AMD). PBM uses wavelengths of light to target components of the mitochondrial respiratory chain to improve cellular bioenergetic outputs. The aim of this study was to further investigate the effects of PBM on clinical, quality of life (QoL) and anatomical outcomes in subjects with intermediate stage non-exudative AMD. METHODS The multicenter LIGHTSITE II study was a randomized clinical trial evaluating safety and efficacy of PBM in intermediate non-exudative AMD. The LumiThera Valeda® Light Delivery System delivered multiwavelength PBM (590, 660 and 850 nm) or sham treatment 3 × per week over 3-4 weeks (9 treatments per series) with repeated treatments at baseline (BL), 4 and 8 months. Subjects were enrolled with 20/32 to 20/100 best-corrected visual acuity (BCVA) and no central geographic atrophy (GA) within the central fovea (500 μm). RESULTS LIGHTSITE II enrolled 44 non-exudative AMD subjects (53 eyes). PBM-treated eyes showed statistically significant improvement in BCVA at 9 months (n = 32 eyes, p = 0.02) with a 4-letter gain in the PBM-treated group versus a 0.5-letter gain in the sham-treated group (ns, p < 0.1) for patients that received all 27 PBM treatments (n = 29 eyes). Approximately 35.3% of PBM-treated eyes showed ≥ 5-letter improvement at 9 months. Macular drusen volume was not increased over time in the PBM-treated group but did show increases in the sham-treated group. While PBM and sham groups both showed GA lesion growth in the trial period, there was 20% less growth in the PBM group over 10 months, suggesting potential disease-modifying effects. No safety concerns or signs of phototoxicity were observed. CONCLUSION These results confirm previous clinical testing of multiwavelength PBM and support treatment with Valeda as a novel therapy with a unique mechanism of action as a potential treatment for non-exudative AMD. TRIAL REGISTRATION Clinicaltrial.Gov Registration Identifier: NCT03878420

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the LumiThera Valeda Light Delivery System.

PURPOSE The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) AMD using the LumiThera Valeda® Light Delivery System. METHODS LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were treated with multiwavelength PBM (590, 660 and 850 nm) or Sham treatment delivered 9 treatments over 3-5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy BCVA endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 - -0.1, p = 0.02)(PBM alone: 5.4 letters (SE 0.96), CI: 3.5 - 7.3, p < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7 - 5.2, p < 0.0001). The PBM group showed a significant decrease in new onset GA (p = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSIONS LIGHTSITE III provides a prospective, randomized controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM

Role of Kv1 Potassium Channels in Regulating Dopamine Release and Presynaptic D2 Receptor Function

Dopamine (DA) release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK) have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK) and ATP-gated (KATP) potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum

Non-Invasive Treatment of Early Diabetic Macular Edema by Multiwavelength Photobiomodulation with the Valeda Light Delivery System.

PURPOSE Diabetes is associated with ocular complications including diabetic macular edema (DME). Current therapies are invasive and include repeated intravitreal injections and laser therapy. Photobiomodulation (PBM) is a treatment (Tx) that utilizes selected wavelengths of light to induce cellular benefits including reduction of inflammation and edema. This single-center, open-label, post-hoc analysis explored the utility of multiwavelength PBM in subjects with DME. METHODS Analysis included review of data from patients undergoing standard clinical care with an approved and marketed PBM medical device, the Valeda® Light Delivery System. Subjects with early-stage DME with good vision (Best-corrected visual acuity (BCVA) > 20/25, logMAR > 0.1) were evaluated in clinic and treated with one series of multiwavelength PBM (Tx delivered 3x/week over 3-4 weeks; total of 9 Tx sessions). Clinical, anatomical, and safety parameters were assessed in addition to subjective quality of life. RESULTS A total of 30 eyes (19 subjects) were analyzed. Subjects were predominately male (68.4%) with a mean age of 56 ± 14 years. Reductions in central retinal thickness (CRT), resolution of intraretinal fluid (IRF) and improvement in diabetic retinopathy severity scale scores were observed following PBM treatment in select patients. Baseline BCVA remained stable over the follow-up observation period of 3 months post-PBM. Approximately 64% of patients reported subjective improvements in their ocular condition and decreased influence in everyday life. Detailed OCT evaluations confirmed no safety issues related to phototoxicity up to 16 months. CONCLUSION Early-stage DME subjects treated with Valeda multiwavelength PBM showed improvements in clinical and anatomical parameters. The Valeda multiwavelength PBM approach demonstrates a favorable safety profile with no signs of phototoxicity following an independent OCT review. PBM therapy may offer an alternative, non-invasive treatment strategy with a unique mechanism and modality for patients with early-stage DME

Data from: Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task

Dysregulated dopamine transmission in striatal circuitry is associated with impulsivity. The current study evaluated the influence of dopaminergic inputs to the dorsolateral striatum on impulsive choice, one aspect of impulsive behavior. We implemented an operant task that measures impulsive choice in rats via delay discounting wherein intracranial self-stimulation (ICSS) was used as the positive reinforcer. To do so, rats were anesthetized to allow implanting of a stimulating electrode within the lateral hypothalamus of one hemisphere and bilateral dorsal striatal injections of the dopaminergic toxin, 6-OHDA (lesioned) or its vehicle (sham). Following recovery, rats were trained in a delay discounting task wherein they selected between a small ICSS current presented immediately after lever pressing, and a large ICSS current presented following a 0 to 15s delay upon pressing the alternate lever. Task acquisition and reinforcer discrimination were similar for lesioned and sham rats. All rats exhibited an initial preference for the large reinforcer, and as the delay was increased, preference for the large reinforcer was decreased indicating that the subjective value of the large reinforcer was discounted as a function of delay time. However, this discounting effect was significantly enhanced in lesioned rats for the longer delays. These data reveal a contribution of dopaminergic inputs to the dorsolateral striatum on impulsive choice behavior, and provide new insights into neural substrates underlying discounting behaviors

Rats lever press in a fixed ratio-1 reinforcement test at increased rates for the large reinforcer (LR; 160Hz) over the small reinforcer (SR; 50Hz).

<p>Rats lever pressed for current stimulation frequencies at 50Hz and 160Hz. Both frequencies met our criteria for stable responding (8< lever presses/ min). These data demonstrate that 50Hz is sufficient to elicit moderate lever press responding and furthermore, 160Hz is more reinforcing than 50Hz as shown in the number of lever presses per session. These frequencies were used for the small (50Hz) and large reinforcer (160Hz) in the discounting task (Student’s <i>t</i>-test, p<0.05).</p

Electrode tip placement for intracranial self-stimulation.

<p>Illustration of electrode tip locations targeted at the medial forebrain bundle at the level of the LH. Neuroanatomical illustrations were modified from Paxinos and Watson (1998) and numbers indicate distance from bregma (mm). The bottom right panel shows a high magnification photomicrograph of a LH coronal section stained with cresyl violet. This section represents an electrode that was implanted for 90 days. Circles indicate sham controls whereas diamonds indicate lesioned rats. LH, Lateral hypothalamus.</p

Lesioned rats show increased discounting behavior in the delay discounting task.

<p>Sham control (n = 9) and lesioned (n = 6) rats were tested once-daily in single session delays until stable behavior was observed (< 20% variability) upon which they were incremented to the next delay in ascending order. These rats include those which completed the entire task with the same history of delay presentation. Shown is the free-choice ratio (i.e., the number of selections made for LR/SR divided by total selections x 100). <b>(A)</b> Both groups exhibited preference for the LR when the imposed delay was small but lesioned rats progressively decreased preference for the LR when the delay was increased. <b>(B)</b> Choice of the SR increased as delay length was increased. <b>(C)</b> Rats exhibited low omissions throughout the delays tested in the discounting paradigm. Shown are the percent omissions (# omissions averaged for free-choice trials divided by total trial # x 100). Data are presented as mean + SEM (two way rmANOVA; <i>post hoc</i> Newman-Keuls, * p<0.05).</p

Lesion extent following intra-striatal injections of 6-OHDA.

<p><b>(A)</b> Representative photomicrographs of tyrosine hydroxylase immunoreactivity (TH-ir) at the level of the DLS (~1.0mm AP from bregma) in one hemisphere. Compared with sham (vehicle-injected; left), 6-OHDA reduced staining in the DLS at 90 days (right) after treatment. <b>(B)</b> DLS lesions were targeted at +1.0mm from bregma. Tissue sections were outlined by two observers and the lesion extent was mapped to standard neuroanatomical plates. Lesion extent remained within 0.3mm of the target location. <b>(C)</b> Quantification of TH-ir in the SNpc. The left panels show low magnification photomicrographs of a SNpc coronal section in a sham (left) rat. This unilateral representation of the lesion was collapsed onto a neuroanatamoical plates (~5.80mm from bregma). The outlined box represents the location of the photomicrographs for the adjacent high magnification photomicrographs taken from a sham (middle) and lesioned (right) rat. <b>(D)</b> DLS lesions decreased cell counts in the ventrolateral region of the SNpc. Group means + SEM of stereological cell counts of TH-ir+ cells in the SNpc, (Student’s <i>t</i>-test, * p < 0.05) compared with sham controls. Neuroanatomical plates were provided by Paxinos and Watson (1998). SNR, Substantia nigra pars reticulata; SNpc, Substantia nigra pars compacta.</p

Flow chart showing contingencies for the delay discounting task.

<p>Definitions: LR, large reinforcer; SR, small reinforcer; BrS; brain stimulation. Rats are trained in forced trials (only one lever extended) to learn the contingencies of each lever, i.e., which lever delivers the small reinforcer (SR; 50Hz) presented immediately after a lever press, and which lever delivers the large reinforcer (LR; 160Hz) after various time intervals following a lever press. Free-choice trials allow the rat to make a selection between levers based on their individual preference. If no selection is made within 10s, the lever(s) are withdrawn and a 10s inter-trial timeout begins.</p