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Purpose To identify sustained differences in intraocular pressure (IOP) after intravitreous injections of anti–vascular endothelial growth factor (VEGF) drugs. Design Database study. Participants Patients seeing an ophthalmic provider who contributes to the database. Methods We identified a total of 23 776 unique patients who received only a single type of anti-VEGF medication (bevacizumab, aflibercept, or ranibizumab) by injection in the right eye in the American Academy of Ophthalmology Intelligent Research in Sight Registry. Subgroups included patients with age-related macular degeneration only and patients who had not received an anti-VEGF injection for at least 1 year before the study. We examined those with at least 12, 18, and 25 injections for each of these 3 medications. For all groups, we used fellow, untreated eyes for comparison. Main Outcome Measures The mean change in IOP from baseline at a minimum of 1 year of follow-up and the proportion of eyes with a clinically significant IOP increase (defined as sustained rise of at least 6 mmHg to an IOP of more than 21 mmHg). Results All patients in all groups receiving all drugs showed a decrease in IOP from baseline, with a mean of 0.9 mmHg in treated eyes compared with an average decrease of 0.2 mmHg in fellow untreated eyes, a statistically significant difference. A generalized linear model accounting for confounders associated bevacizumab with slightly less lowering of IOP than aflibercept and ranibizumab in most subgroups. A clinically significant IOP increase was seen in 2.6% of eyes receiving injections compared with 1.5% in the associated untreated fellow eyes. Clinically significant IOP increases occurred at a rate of 1.9%, 2.8%, and 2.8% for aflibercept, ranibizumab, and bevacizumab, respectively, which was significantly higher than untreated fellow eyes for bevacizumab and ranibizumab, but not for aflibercept. Conclusions These analyses from real-world data indicate that anti-VEGF intravitreous injections are associated with a small but statistically significant decrease in IOP over time. A proportion of patients, on average 2.6%, experienced a sustained clinically significant IOP rise with these drugs overall compared with 1.5% in the fellow untreated eyes. However, such an increase was not seen with aflibercept.

The subcallosal cingulate (SCC) region, or its rodent homologue the medial prefrontal cortex (mPFC), and midbrain dorsal raphe (DR) are crucial nodes of the widespread network implicated in emotional regulation. Stimulation of the SCC is being explored as a potential treatment for depression. Because modulation of the 5-HT system is the most common pharmacological means of treating depression, we sought to establish 5-HT's role in the mPFC-DR projection. Using anaesthetized mice, we recorded neuronal activity in 49 neurons of the DR before, during, and after high frequency stimulation (HFS) of the mPFC. The majority of DR cells (74%) significantly decreased firing rate during HFS (p

Histamine plays a major role in the mediation of allergic reactions such as peripheral inflammation. This classical monoamine is also a neurotransmitter involved in the central nervous system but its role in this context is poorly understood. Studying histamine neurotransmission is important due to its implications in many neurological disorders. The sensitivity, selectivity and high temporal resolution of fast scan cyclic voltammetry (FSCV) offer many advantages for studying electroactive neurotransmitters. Histamine has previously been studied with FSCV; however, the lack of a robust Faradaic electrochemical signal makes it difficult to selectively identify histamine in complex media, as found in vivo. In this work, we optimize an electrochemical waveform that provides a stimulation-locked and unique electrochemical signal towards histamine. We describe in vitro waveform optimization and a novel in vivo physiological model for stimulating histamine release in the mouse premammillary nucleus via stimulation of the medial forebrain bundle. We demonstrate that a robust signal can be used to effectively identify histamine and characterize its in vivo kinetics.

Purpose The purpose of this study is to compare real-world visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) treated with a single anti–vascular endothelial growth factor (VEGF) drug monotherapy for 1 year from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry. Design Retrospective, nonrandomized, comparative study. Participants IRIS Registry patients with nAMD who received bevacizumab, ranibizumab, or aflibercept only for 1 year between 2013–2016. Methods Participants were divided into 3 groups based on monotherapy type. Multivariate analysis of covariance models (ANCOVA) was constructed in a stepwise fashion. Main Outcome Measures The logarithm of the minimum angle of resolution (logMAR) VA at 1 year and mean change in logMAR VA between baseline and 1 year were compared between drug types. Results Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year. A total of 84 828 injections were performed. The mean number of injections (standard deviation) at 1 year was higher in the ranibizumab (6.4 [±2.4]) and aflibercept groups (6.2 [±2.4]) compared to bevacizumab group (5.9 [±2.4]; P 0.0001). In the age-adjusted model, both ranibizumab and aflibercept achieved better logMAR VA at 1 year compared with bevacizumab (0.50 [±0.49], 0.49 [±0.44], 0.55 [±0.57]; P 0.0001). However, this difference was not significant after multivariate adjustment (age, baseline VA, diabetes, posterior vitreous detachment, number of injections, race, insurance). There was no statistical difference in the age-adjusted or multivariate-adjusted mean logMAR VA change (standard deviation) at 1 year among treatment groups (−0.048 [0.44] bevacizumab, −0.053 [0.46] ranibizumab, −0.040 [0.39] aflibercept; P = 0.46). A higher percentage of patients achieved a ≥3-line VA improvement at 1 year in the bevacizumab group (22.7%) compared with ranibizumab (20.1%; P = 0.0093) and aflibercept (17.8%; P 0.0001). However, after multivariate adjustment, aflibercept exhibited a greater log odds of a ≥3-line VA loss compared with bevacizumab only (1.25 log odds ratio; P 0.0016). Conclusions This study suggests that all 3 drugs improve VA similarly over 1 year of monotherapy.

To identify sustained differences in intraocular pressure (IOP) after intravitreous injections of anti-vascular endothelial growth factor (VEGF) drugs.Database study.Patients seeing an ophthalmic provider who contributes to the database.We identified a total of 23 776 unique patients who received only a single type of anti-VEGF medication (bevacizumab, aflibercept, or ranibizumab) by injection in the right eye in the American Academy of Ophthalmology Intelligent Research in Sight Registry. Subgroups included patients with age-related macular degeneration only and patients who had not received an anti-VEGF injection for at least 1 year before the study. We examined those with at least 12, 18, and 25 injections for each of these 3 medications. For all groups, we used fellow, untreated eyes for comparison.The mean change in IOP from baseline at a minimum of 1 year of follow-up and the proportion of eyes with a clinically significant IOP increase (defined as sustained rise of at least 6 mmHg to an IOP of more than 21 mmHg).All patients in all groups receiving all drugs showed a decrease in IOP from baseline, with a mean of 0.9 mmHg in treated eyes compared with an average decrease of 0.2 mmHg in fellow untreated eyes, a statistically significant difference. A generalized linear model accounting for confounders associated bevacizumab with slightly less lowering of IOP than aflibercept and ranibizumab in most subgroups. A clinically significant IOP increase was seen in 2.6% of eyes receiving injections compared with 1.5% in the associated untreated fellow eyes. Clinically significant IOP increases occurred at a rate of 1.9%, 2.8%, and 2.8% for aflibercept, ranibizumab, and bevacizumab, respectively, which was significantly higher than untreated fellow eyes for bevacizumab and ranibizumab, but not for aflibercept.These analyses from real-world data indicate that anti-VEGF intravitreous injections are associated with a small but statistically significant decrease in IOP over time. A proportion of patients, on average 2.6%, experienced a sustained clinically significant IOP rise with these drugs overall compared with 1.5% in the fellow untreated eyes. However, such an increase was not seen with aflibercept.

The distribution and density of neurons within the brain poses many challenges when making quantitative measurements of neurotransmission in the extracellular space. A volume neurotransmitter is released into the synapse during chemical communication and must diffuse through the extracellular space to an implanted sensor for real-time in situ detection. Fast-scan cyclic voltammetry is an excellent technique for measuring biologically relevant concentration changes in vivo; however, the sensitivity is limited by mass-transport-limited adsorption. Due to the resistance to mass transfer in the brain, the response time of voltammetric sensors is increased, which decreases the sensitivity and the temporal fidelity of the measurement. Here, experimental results reveal how the tortuosity of the extracellular space affects the response of the electrode. Additionally, a model of mass-transport-limited adsorption is utilized to account for both the strength of adsorption and the magnitude of the diffusion coefficie...

The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants.

The treatment of depression with selective serotonin reuptake inhibitors, SSRIs, is important to study on a neurochemical level because of the therapeutic variability experienced by many depressed patients. We employed the rapid temporal capabilities of fast scan cyclic voltammetry at carbon fiber microelectrodes to study the effects of a popular SSRI, escitalopram (ESCIT), marketed as Lexapro, on serotonin in mice. We report novel, dynamic serotonin behavior after acute ESCIT doses, characterized by a rapid increase in stimulated serotonin release and a gradual rise in serotonin clearance over 120 min. Dynamic changes after acute SSRI doses may be clinically relevant to the pathology of increased depression or suicidality after onset of antidepressant treatment. Due to the short-term variability of serotonin responses after acute ESCIT, we outline difficulties in creating dose response curves and we suggest effective means to visualize dynamic serotonin changes after SSRIs. Correlating chemical serotonin patterns to clinical findings will allow a finer understanding of SSRI mechanisms, ultimately providing a platform for reducing therapeutic variability.

It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed invivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density, which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests.

Dopamine and serotonin (5-hydroxytryptamine or 5-HT) are neurotransmitters that are implicated in many psychological disorders. Although dopamine transmission in the brain has been studied extensively in vivo with fast scan cyclic voltammetry, detection of 5-HT using in vivo voltammetric methods has only recently been established. In this work we use two carbon-fiber microelectrodes to simultaneously measure dopamine release in the nucleus accumbens and 5-HT release in the substantia nigra pars reticulata, using a common stimulation in a single rat. We find that 5-HT release is profoundly restricted in comparison with dopamine release despite comparable tissue content levels. Using physiological and pharmacological analysis, we find that 5-HT transmission is mostly sensitive to uptake and metabolic degradation mechanisms. In contrast, dopamine transmission is constrained by synthesis and repackaging. Finally, we show that disruption of serotonergic regulatory mechanisms by simultaneous inhibition of uptake and metabolic degradation can have severe physiological consequences that mimic serotonin syndrome.

J. Neurochem. (2011) 118, 749–759. Abstract Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.

Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.

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This study examined 30 children with hyperlexic reading patterns and average intelligence to determine if established learning disability subtypes could be applied to these children with hyperlexia. Two groups emerged. One type showed language learning disorder patterns with good visual memory. This group also showed a high percentage of phonetic word errors. A second hyperlexic group showed signs of nonverbal learning disorder with visual spatial deficits and impaired visual memory. This latter subgroup showed few phonetic errors with more sight word errors. These findings suggest subtypes of high functioning hyperlexia, one showing language deficits characteristic of dysphasia and one showing patterns similar to visual spatial dyslexia.

This study examined immediate memory processes in specific reading disability subtypes. Three subgroups (n = 15 in each subgroup) of reading disabled children were examined: (a) perceptual-motor disorder, (b) verbal disorder-general, and (c) verbal disorder-specific (memory). The three groups were matched for age and full scale IQ. All children received a memory-for-colors task (Color Span Test) designed to evaluate intra- and intermodal serial memory functioning. Comparison of memory profiles for the three reading disability subtypes revealed that patterns varied depending on mode of stimulus presentation or response. Although all three groups performed considerably below normative levels on each of the four subtests of the Color Span Test, all subjects performed significantly better on verbally presented items than on visually presented items. The findings were interpreted to suggest that these reading disabled children may not consistently utilize verbal strategies for coding or retrieval of information when stimuli are visually presented.

This study examined memory patterns of children from three memory‐deficient reading‐disability (RD) groups that differed according to patterns of abstract reasoning and perceptuomotor functions. The investigation examined differences on a verbal learning task among four different age groups and among different neuropsychological subtypes. Results suggested that performances of the subtypes varied across trials and that each group benefited from repeated trials of the task. Developmental trends were also noted. Findings suggest that some RD children may not consistently utilize verbal strategies for coding/retrieval of information. Furthermore, remedial interventions need to consider both developmental and neuropsychological factors.