Salmon patch-associated vitreous hemorrhage in non-proliferative sickle cell retinopathy masquerading as infectious uveitis.

PURPOSE: To report three cases of non-proliferative sickle cell retinopathy (NPSR) with vitreous hemorrhage masquerading as infectious uveitis. OBSERVATIONS: Three patients were referred from ophthalmologists to our practices with clinical findings suggestive of infectious uveitis. The first patient was referred for new-onset floaters in both eyes, bilateral vitritis and dome-shaped lesions on B-scan ultrasound. He was initially treated for tuberculosis uveitis due to a positive purified protein derivative test. The second patient was referred with floaters and hazy vision in the setting of recent fever and headache and was also reported to have vitritis and unilateral yellow vitreoretinal lesions on fundoscopy. She was initially treated for toxoplasmosis and endogenous endophthalmitis. The third patient presented with flashes, floaters, and decreased vision four months after a ring-enhancing lesion was found on brain imaging, and was found to have unilateral vitritis with yellow vitreoretinal lesions. He was initially started on topical steroids and cycloplegics empirically for uveitis. All patients were ultimately diagnosed as having manifestations of NPSR, including vitreous hemorrhage, and dehemoglobinized salmon patch hemorrhages. CONCLUSIONS AND IMPORTANCE: NPSR can occasionally masquerade as infectious uveitis. Obtaining a detailed history with relevant ancillary testing, along with performing a careful physical exam to recognize important clues, can help the physician arrive at the correct diagnosis in these equivocal cases.

Patient Concerns Regarding Suspended Ophthalmic Care Due to COVID-19.

PURPOSE: The temporary cessation and profound changes in ophthalmic care delivery that occurred as a result of the coronavirus disease 2019 (COVID-19) pandemic have yet to be fully understood. Our objective is to assess patients' self-reported impact of health care lockdown measures on their fears and anxieties during the crisis period of the COVID-19 pandemic in New York City. METHODS: We conducted a digital, self-reported, patient care survey distributed by an e-mail at Columbia University's Department of Ophthalmology outpatient faculty practice. Inclusion criteria were age greater than or equal to 18 years, a diagnosis of either retinal disease or glaucoma, and a canceled or rescheduled ophthalmology established patient appointment during the acute phase of the COVID-19 pandemic in New York City. Patients without an e-mail address listed in their electronic medical records were excluded. The survey occurred between March 2, 2020, to May 30, 2020. Primary measures were survey responses to assess key areas of patient anxiety or concern during the pandemic including the safety of care delivery in a COVID pandemic, difficulties contacting or being seen by their ophthalmologist, concern of vision loss or disease progression, and concern over missed or access to treatments. Secondary measures were correlating survey response to factors such as visual acuity, intraocular pressure, diagnosis, disease severity, follow-up urgency, recent treatments, and diagnostic testing data. RESULTS: Of the 2594 surveys sent out, 510 (19.66%) were completed. Over 95% of patients were at least as concerned as in normal circumstances about their ocular health during the peak of the pandemic. Overall, 76% of respondents were more concerned than normal that they could not be seen by their ophthalmologist soon enough. Increased concern over ocular health, disease progression, and access to care all showed positive correlations (P<0.05) with worse disease severity as measured with testing such as visual fields and optical coherence tomography. In addition, 55% of patients were afraid of contracting COVID-19 during an office visit. CONCLUSION AND RELEVANCE: We found a majority of our patients were concerned about limitations in access to ophthalmic care and were fearful of disease progression. In addition, we found a number of demographic and clinical factors that correlated with increased anxiety in our patients.

The Challenge of Managing Bilateral Acute Angle-closure Glaucoma in the Presence of Active SARS-CoV-2 Infection.

PURPOSE: To report a case of bilateral acute angle-closure glaucoma associated with hyponatremia in the setting of chlorthalidone use and SARS-CoV-2 infection, and to demonstrate the challenges of managing this patient given her infectious status. METHODS: This was a case report. CASE: A 65-year-old woman taking chlorthalidone for hypertension presented to the emergency room with headache, pain, and blurry vision in both eyes and was found to be in bilateral acute angle closure. On laboratory investigation, she was severely hyponatremic and also tested positive for SARS-CoV-2. B-scan ultrasound demonstrated an apparent supraciliary effusion in the right eye. Following stabilization of her intraocular pressures with medical management, she ultimately underwent cataract extraction with iridectomies and goniosynechiolysis in both eyes. CONCLUSIONS: We report a rare case of bilateral acute angle-closure glaucoma associated with hyponatremia. Chlorthalidone use and perhaps SARS-CoV-2 infection may have contributed to this electrolyte abnormality and unique clinical presentation. In addition, we discuss the challenges of managing this complex patient with active SARS-CoV-2 infection during the pandemic.

Late-onset angle closure in pseudophakic eyes with posterior chamber intraocular lenses.

Two patients presented with angle closure many years after cataract extraction. The first patient presented with acute intraocular pressure (IOP) elevation and closed iridocorneal angle that resolved with a laser iridotomy. The second patient presented with an insidious course of high IOP and progressive narrowing of the iridocorneal angle, ultimately requiring a pars plana vitrectomy and glaucoma valve implant, with subsequent normalization of pressure and angle anatomy. Although rare, angle closure in eyes with posterior chamber intraocular lenses is a dangerous complication that can occur many years after cataract extraction. Retained lens fragments, and perhaps repeated intravitreal injections, might place susceptible patients at risk.

Renal Medullary Carcinoma With Metastasis to the Temporal Fossa and Orbit.

A 22-year-old Hispanic man with sickle cell trait presented with blurred vision, double vision, and pain with OD movement. MRI demonstrated an extra-axial mass centered around the temporal bone with extension into the middle cranial fossa and lateral aspect of the extra-conal right orbit, and mass effect on the lateral rectus muscle. Biopsy of the lesion was consistent with renal medullary carcinoma. CT chest/abdomen/pelvis confirmed a primary tumor in the right kidney. No additional metastases were found. Renal medullary carcinoma is a rare, highly aggressive malignancy, which almost exclusively affects young men of African descent with sickle cell trait or sickle cell disease. The authors present the second confirmed case of renal medullary carcinoma metastatic to the orbit, with ocular symptoms prior the typical presenting symptoms of flank pain and hematuria.Renal medullary carcinoma is a highly aggressive malignancy, most commonly seen in African American patients with sickle cell disease. Involvement of the orbit is rare and visual symptoms may precede systemic diagnosis.

Earliest Evidence of Preclinical Diabetic Retinopathy Revealed Using Optical Coherence Tomography Angiography Perfused Capillary Density.

PURPOSE: To compare perfused capillary density (PCD) in diabetic patients and healthy controls using optical coherence tomography angiography (OCTA). METHODS: Forty controls, 36 diabetic subjects without clinical retinopathy (NoDR), 38 with nonproliferative retinopathy (NPDR), and 38 with proliferative retinopathy (PDR) were imaged using spectral-domain optical coherence tomography. A 3 × 3-mm full-thickness parafoveal OCTA scan was obtained from each participant. Following manual delineation of the foveal avascular zone (FAZ), FAZ area, perimeter, and acircularity index were determined. Seven consecutive equidistant 200-µm-wide annular segments were drawn at increasing eccentricities from the FAZ margin. Annular PCD (%) was defined as perfused capillary area divided by the corresponding annulus area after subtraction of noncapillary blood vessel areas. Nonparametric Kruskal-Wallis testing with Bonferroni correction was performed in pairwise comparisons of group PCD values. RESULTS: The NoDR group demonstrated consistently higher PCD compared to the control group in all 7 annuli, reaching statistical significance (36.6% ± 3.30% vs 33.6% ± 3.98%, P = .034) at the innermost annulus (FAZ margin to 200 µm out). The NPDR and PDR groups demonstrated progressively decreasing PCD. Differences in FAZ metrics between the NoDR and control groups did not reach statistical significance. CONCLUSIONS: Relative to healthy controls, increased PCD values in the NoDR group likely represent an autoregulatory response to increased metabolic demand, while the decrease in PCD that follows in NPDR and PDR results largely from an incremental loss of capillary segments. These findings, consistent with previous studies, demonstrate the potential of OCTA as a clinical tool for earlier objective detection of preclinical diabetic retinopathy. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Parafoveal Nonperfusion Analysis in Diabetic Retinopathy Using Optical Coherence Tomography Angiography.

PURPOSE: To describe a new technique for mapping parafoveal intercapillary areas (PICAs) using optical coherence tomography angiography (OCTA), and demonstrate its utility for quantifying parafoveal nonperfusion in diabetic retinopathy (DR). METHODS: Nineteen controls, 15 diabetics with no retinopathy (noDR), 15 with nonproliferative diabetic retinopathy (NPDR), and 15 with proliferative diabetic retinopathy (PDR) were imaged with 10 macular OCTA scans. PICAs were automatically delineated on the averaged superficial OCTA images. Following creation of an eccentricity-specific reference database from the controls, all PICAs greater than 2 SD above the reference means for PICA area and minor axis length were identified as nonperfused areas. Regions of interest (ROI) at 300 µm and 1000 µm from the foveal avascular zone (FAZ) margin were analyzed. Percent nonperfused area was defined as summed nonperfused areas divided by ROI area. Values were compared using Kruskal-Wallis and post-hoc Mann-Whitney U tests. RESULTS: Median values for total percent nonperfused area at the 300-µm ROI were 2.09, 2.44, 18.08, and 27.55 in the control, noDR, NPDR, and PDR groups, respectively. Median values at the 1000-µm ROI were 3.10, 3.31, 13.42, and 23.00. While there were no significant differences between the control and noDR groups, significant differences were observed between all other groups at both ROIs. CONCLUSIONS: Percent nonperfused area can quantify parafoveal nonperfusion in DR and can be calculated through automatic delineation of PICAs in an eccentricity-specific manner using a standard deviation mapping approach. TRANSLATIONAL RELEVANCE: Percent nonperfused area shows promise as a metric to measure disease severity in diabetic retinopathy.

Noninvasive Detection of Mitochondrial Dysfunction in Ocular Hypertension and Primary Open-angle Glaucoma.

PURPOSE: To assess mitochondrial dysfunction in vivo in ocular hypertension (OHT) and primary open-angle glaucoma (POAG) using retinal metabolic analysis. PATIENTS AND METHODS: This was an observational, cross-sectional study performed from November 2015 to October 2016 at the New York Eye and Ear Infirmary of Mount Sinai. Thirty-eight eyes with varying stages of POAG, 16 eyes with OHT, and 32 control eyes were imaged on a custom fundus camera modified to measure full retinal thickness fluorescence at a wavelength optimized to detect flavoprotein fluorescence (FPF). Optical coherence tomography was used to measure the retinal ganglion cell-plus layer (RGC+) thickness. Macular FPF and the ratio of macular FPF to RGC+ thickness were the primary outcome variables and were compared among the three groups using an age-adjusted linear regression model. A mixed-effects model was used to assess correlations between FPF variables and clinical characteristics. RESULTS: Both macular FPF and the macular FPF/RGC+ thickness ratio were significantly increased in OHT compared with control eyes (P<0.05 and <0.01, respectively). In POAG eyes, macular FPF was not significantly increased compared with controls (P=0.24). However, the macular FPF/RGC+ thickness ratio in POAG eyes was significantly increased compared with controls (P<0.001). FPF was significantly correlated to age in POAG eyes. CONCLUSIONS: Despite lacking clinical evidence of glaucomatous deterioration, OHT eyes displayed significantly elevated macular FPF, suggesting that mitochondrial dysfunction may be detected before structural changes visible on current clinical imaging. Our preliminary results suggest that macular FPF analysis may prove to be a useful tool in assessing and evaluating OHT and POAG eyes.

A method for age-matched OCT angiography deviation mapping in the assessment of disease- related changes to the radial peripapillary capillaries.

PURPOSE: To present a method for age-matched deviation mapping in the assessment of disease-related changes to the radial peripapillary capillaries (RPCs). METHODS: We reviewed 4.5x4.5mm en face peripapillary OCT-A scans of 133 healthy control eyes (133 subjects, mean 41.5 yrs, range 11-82 yrs) and 4 eyes with distinct retinal pathologies, obtained using spectral-domain optical coherence tomography angiography. Statistical analysis was performed to evaluate the impact of age on RPC perfusion densities. RPC density group mean and standard deviation maps were generated for each decade of life. Deviation maps were created for the diseased eyes based on these maps. Large peripapillary vessel (LPV; noncapillary vessel) perfusion density was also studied for impact of age. RESULTS: Average healthy RPC density was 42.5±1.47%. ANOVA and pairwise Tukey-Kramer tests showed that RPC density in the ≥60yr group was significantly lower compared to RPC density in all younger decades of life (p<0.01). Average healthy LPV density was 21.5±3.07%. Linear regression models indicated that LPV density decreased with age, however ANOVA and pairwise Tukey-Kramer tests did not reach statistical significance. Deviation mapping enabled us to quantitatively and visually elucidate the significance of RPC density changes in disease. CONCLUSIONS: It is important to consider changes that occur with aging when analyzing RPC and LPV density changes in disease. RPC density, coupled with age-matched deviation mapping techniques, represents a potentially clinically useful method in detecting changes to peripapillary perfusion in disease.

Within-subject assessment of foveal avascular zone enlargement in different stages of diabetic retinopathy using en face OCT reflectance and OCT angiography.

Enlargement of the foveal avascular zone (FAZ) due to progressive capillary nonperfusion is associated with visual deterioration in patients with diabetic retinopathy. The FAZ area has long been considered an important clinical marker of advancing retinopathy. However, a large body of literature shows that the FAZ area varies considerably in healthy eyes, resulting in substantial overlap between controls and diabetics, thus reducing its discriminatory value. In this study, within-subject FAZ area enlargement was obtained by the comparison of the structural FAZ area to the functional FAZ area using simultaneously-acquired, corresponding en face OCT reflectance and OCT angiography images. Our study suggests that en face OCT reflectance images provide useful anatomic baselines of structural FAZ morphology prior to the onset of disease. Measurements of within-subject FAZ area enlargement appear to be a more sensitive method for identifying the onset of diabetic retinopathy as compared to using OCT angiographic measurements of FAZ alone.

Peripapillary perfused capillary density in primary open-angle glaucoma across disease stage: an optical coherence tomography angiography study.

AIMS: To assess peripapillary perfused capillary density (PCD) in primary open-angle glaucoma (POAG) across stage of disease. METHODS: In this observational, cross-sectional study, 60 eyes with varying stages of POAG and 24 control eyes were imaged on a spectral domain optical coherence tomography angiography system (AngioVue, Optovue, Fremont, California, USA) generating images centred on the optic nerve head. Major blood vessels were removed using custom automated software. PCD was calculated as a percentage as the ratio of pixels associated with perfused capillaries to the total number of pixels in the corresponding region-of-interest (ROI). Analysis of covariance was used to compare PCD among the subject groups and control for possible covariates. Area under the receiver operating characteristic curve (AROC) and sensitivity at 95% specificity were calculated to assess the capability of PCD to distinguish mild glaucoma from control. The Pearson's product-moment correlation coefficient was used to assess correlations between PCD and circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and visual field mean deviation (MD). RESULTS: PCD demonstrated a progressive stepwise decrease from control eyes throughout worsening POAG stage at all ROIs. PCD demonstrated AROC and sensitivity values comparable to cpRNFLT and visual field parameters and exhibited significant correlations with cpRNFLT and MD at all corresponding ROIs. CONCLUSIONS: PCD displayed significant correlations with morphological and functional indices and exhibited diagnostic capabilities comparable to currently employed clinical variables. Our preliminary results suggest that PCD analysis may prove to be a useful tool in monitoring POAG across stage and identifying early POAG.

Acircularity index and axis ratio of the foveal avascular zone in diabetic eyes and healthy controls measured by optical coherence tomography angiography.

Given the complexity of the current system used to stage diabetic retinopathy (DR) and the risks and limitations associated with intravenous fluorescein angiography (IVFA), noninvasive quantification of DR severity is desirable. We examined the utility of acircularity index and axis ratio of the foveal avascular zone (FAZ), metrics that can noninvasively quantify the severity of diabetic retinopathy without the need for axial length to correct for individual retinal magnification. A retrospective review was performed of type 2 diabetics and age-matched controls imaged with optical coherence tomography angiography (OCTA). Diabetic eyes were divided into three groups according to clinical features: No clinically observable diabetic retinopathy (NoDR), nonproliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). OCTAs of the superficial and deep vascular layers centered at the fovea were superimposed to form a full vascular layer on which the FAZ was manually traced. Acircularity index and axis ratio were calculated for each FAZ. Significant differences in acircularity index were observed between all groups except for controls vs. NoDR. Similar results were found for axis ratio, although there was no significant difference observed between NPDR and PDR. We demonstrate that acircularity index and axis ratio can be used to help noninvasively stage DR using OCTA, and show promise as methods to monitor disease progression and detect response to treatment.

Visualization of Radial Peripapillary Capillaries Using Optical Coherence Tomography Angiography: The Effect of Image Averaging.

OBJECTIVES: To assess the effect of image registration and averaging on the visualization and quantification of the radial peripapillary capillary (RPC) network on optical coherence tomography angiography (OCTA). METHODS: Twenty-two healthy controls were imaged with a commercial OCTA system (AngioVue, Optovue, Inc.). Ten 10x10° scans of the optic disc were obtained, and the most superficial layer (50-µm slab extending from the inner limiting membrane) was extracted for analysis. Rigid registration was achieved using ImageJ, and averaging of each 2 to 10 frames was performed in five ~2x2° regions of interest (ROI) located 1° from the optic disc margin. The ROI were automatically skeletonized. Signal-to-noise ratio (SNR), number of endpoints and mean capillary length from the skeleton, capillary density, and mean intercapillary distance (ICD) were measured for the reference and each averaged ROI. Repeated measures analysis of variance was used to assess statistical significance. Three patients with primary open angle glaucoma were also imaged to compare RPC density to controls. RESULTS: Qualitatively, vessels appeared smoother and closer to histologic descriptions with increasing number of averaged frames. Quantitatively, number of endpoints decreased by 51%, and SNR, mean capillary length, capillary density, and ICD increased by 44%, 91%, 11%, and 4.5% from single frame to 10-frame averaged, respectively. The 10-frame averaged images from the glaucomatous eyes revealed decreased density correlating to visual field defects and retinal nerve fiber layer thinning. CONCLUSIONS: OCTA image registration and averaging is a viable and accessible method to enhance the visualization of RPCs, with significant improvements in image quality and RPC quantitative parameters. With this technique, we will be able to non-invasively and reliably study RPC involvement in diseases such as glaucoma.

Human retinal microvascular imaging using adaptive optics scanning light ophthalmoscopy.

BACKGROUND: Retinal microvascular imaging is an especially promising application of high resolution imaging since there are increasing options for therapeutic intervention and need for better structural and functional biomarkers to characterize ocular and systemic vascular diseases. MAIN BODY: Adaptive optics scanning light ophthalmoscopy (AOSLO) is an emerging technology for improving in vivo imaging of the human retinal microvasculature, allowing unprecedented visualization of retinal microvascular structure, measurements of blood flow velocity, and microvascular network mapping. This high resolution imaging technique shows significant potential for studying physiological and pathological conditions of the retinal microvasculature noninvasively. CONCLUSION: This review will briefly summarize the abilities of in vivo human retinal microvasculature imaging in healthy controls, as well as patients with diabetic retinopathy, retinal vein occlusion, and sickle cell retinopathy using AOSLO and discuss its potential contribution to scientific research and clinical applications.

Optical Coherence Tomography Angiography Analysis of Perfused Peripapillary Capillaries in Primary Open-Angle Glaucoma and Normal-Tension Glaucoma.

Purpose: To compare perfused peripapillary capillary density in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and normal patients using optical coherence tomography angiography (OCT-A). Methods: A retrospective review of POAG, NTG, and normal patients imaged with OCT-A was performed. En face OCT angiograms identifying peripapillary vessels were obtained using a spectral-domain OCT system (Avanti RTVue-XR). A custom image analysis approach identified perfused peripapillary capillaries, quantified perfused capillary density (PCD), and generated color-coded PCD maps for 3.5- and 4.5-mm-diameter scans. We compared PCD values, PCD maps, standard automated perimetry (Humphrey visual field [HVF]) parameters, and OCT retinal nerve fiber layer (RNFL) thickness analyses across all groups. Results: Forty POAG, 26 NTG, and 26 normal patients were included. Annular PCD in POAG (34.24 ± 6.76%) and NTG (37.75 ± 3.52%) patients was significantly decreased compared to normal patients (42.99 ± 1.81%) in 4.5-mm scans (P < 0.01 and P < 0.01, respectively). Similar trends and statistical significances were seen in 3.5-mm scans. Linear regression analysis resulted in moderate correlations between annular PCD values and other glaucomatous parameters. Pearson coefficients comparing annular PCD from 4.5-mm scans in POAG and NTG groups to HVF mean deviation, HVF pattern standard deviation, and average RNFL thickness all showed statistical significance (P < 0.05). Color maps showed that POAG and NTG patients had a reduction of perfused capillaries that progressed in size when comparing early, moderate, and severe glaucoma groups. Conclusions: Optical coherence tomography angiography can uniquely identify changes in peripapillary PCD in glaucoma patients. Optical coherence tomography angiography may offer insights into the pathophysiology of glaucomatous damage and risk factors for disease progression.

Imaging Foveal Microvasculature: Optical Coherence Tomography Angiography Versus Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography.

PURPOSE: To compare the use of optical coherence tomography angiography (OCTA) and adaptive optics scanning light ophthalmoscope fluorescein angiography (AOSLO FA) for characterizing the foveal microvasculature in healthy and vasculopathic eyes. METHODS: Four healthy controls and 11 vasculopathic patients (4 diabetic retinopathy, 4 retinal vein occlusion, and 3 sickle cell retinopathy) were imaged with OCTA and AOSLO FA. Foveal perfusion maps were semiautomatically skeletonized for quantitative analysis, which included foveal avascular zone (FAZ) metrics (area, perimeter, acircularity index) and vessel density in three concentric annular regions of interest. On each set of OCTA and AOSLO FA images, matching vessel segments were used for lumen diameter measurement. Qualitative image comparisons were performed by visual identification of microaneurysms, vessel loops, leakage, and vessel segments. RESULTS: Adaptive optics scanning light ophthalmoscope FA and OCTA showed no statistically significant differences in FAZ perimeter, acircularity index, and vessel densities. Foveal avascular zone area, however, showed a small but statistically significant difference of 1.8% (P = 0.004). Lumen diameter was significantly larger on OCTA (mean difference 5.7 µm, P < 0.001). Microaneurysms, fine structure of vessel loops, leakage, and some vessel segments were visible on AOSLO FA but not OCTA, while blood vessels obscured by leakage were visible only on OCTA. CONCLUSIONS: Optical coherence tomography angiography is comparable to AOSLO FA at imaging the foveal microvasculature except for differences in FAZ area, lumen diameter, and some qualitative features. These results, together with its ease of use, short acquisition time, and avoidance of potentially phototoxic blue light, support OCTA as a tool for monitoring ocular pathology and detecting early disease.

Basal forebrain projections to the lateral habenula modulate aggression reward.

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.