Search

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

The amygdala is a medial temporal lobe structure known to be involved in processing emotional conflict. However, its role in processing non-emotional conflict is not well understood. Previous studies have utilized the Stroop Task to examine brain modulation of humans under the color-word conflict scenario, which is non-emotional conflict processing, and found hippocampal theta-band (4-7 Hz) modulation. This study aims to survey amygdaloid theta power changes during non-emotional conflict processing using intracranial depth electrodes in nine epileptic patients (3 female; age 20-62). All patients were asked to perform a modified Stroop task. During task performance, local field potential (LFP) data was recorded from macro contacts sampled at 2 K Hz and used for analysis. Mean theta power change from baseline was compared between the incongruent and congruent task condition groups using a paired sample t-test. Seven patients were available for analysis after artifact exclusion. In five out of seven patients, statistically significant increases in theta-band power from baseline were noted during the incongruent task condition (paired sample t-test p 0.001), including one patient exhibiting theta power increases in both task conditions. Average response time was 1.07 s (failure trials) and 1.04 s (success trials). No speed-accuracy tradeoff was noted in this analysis. These findings indicate that human amygdaloid theta-band modulation may play a role in processing non-emotional conflict. It builds directly upon work suggesting that the amygdala processes emotional conflict and provides a neurophysiological mechanism for non-emotional conflict processing as well.

Objective: Coherence between the hippocampus and other brain structures has been shown with the theta frequency (3–8 Hz). Cortical decreases in theta coherence are believed to reflect response accuracy efficiency. However, the role of theta coherence during conflict resolution is poorly understood in noncortical areas. In this study, coherence between the hippocampus and orbitofrontal cortex (OFC) was measured during a conflict resolution task. Although both brain areas have been previously implicated in the Stroop task, their interactions are not well understood. Methods: Nine patients were implanted with stereotactic electroencephalography contacts in the hippocampus and OFC. Local field potential data were sampled throughout discrete phases of a Stroop task. Coherence was calculated for hippocampal and OFC contact pairs, and coherence spectrograms were constructed for congruent and incongruent conditions. Coherence changes during cue processing were identified using a nonparametric cluster-permutation t test. Group analysis was conducted to compare overall theta coherence changes among conditions. Results: In 6 of 9 patients, decreased theta coherence was observed only during the incongruent condition (P < 0.05). Congruent theta coherence did not change from baseline. Group analysis showed lower theta coherence for the incongruent condition compared with the congruent condition (P < 0.05). Conclusions: Theta coherence between the hippocampus and OFC decreased during conflict. This finding supports existing theories that theta coherence desynchronization contributes to improved response accuracy and processing efficiency during conflict resolution. The underlying theta coherence observed between the hippocampus and OFC during conflict may be distinct from its previously observed role in memory.

Mesial temporal lobe epilepsy is a syndromic disorder presenting with seizures and cognitive comorbidities. The cellular mechanisms contributing to epilepsy progression are not well understood. Here we show that intelligence, verbal learning, and memory decline at a critical period when hippocampal neurogenesis becomes undetectable. Individual patient analysis revealed that the number of immature neurons, rather than total granule neurons, particularly benefit verbal learning. These results illustrate a functional role for adult human neurogenesis and reveal a therapeutic target accompanying cognitive decline.

Closed-loop brain-responsive neurostimulation via the RNS System is a treatment option for adults with medically refractory focal epilepsy. Using a novel technique, 2 RNS Systems (2 neurostimulators and 4 leads) were successfully implanted in a single patient with bilateral parietal epileptogenic zones. In patients with multiple epileptogenic zones, this technique allows for additional treatment options. Implantation can be done successfully, without telemetry interference, using proper surgical planning and neurostimulator positioning.Trajectories for the depth leads were planned using neuronavigation with CT and MR imaging. Stereotactic frames were used for coordinate targeting. Each neurostimulator was positioned with maximal spacing to avoid telemetry interference while minimizing patient discomfort. A separate J-shaped incision was used for each neurostimulator to allow for compartmentalization in case of infection. In order to minimize surgical time and risk of infection, the neurostimulators were implanted in 2 separate surgeries, approximately 3 weeks apart.The neurostimulators and leads were successfully implanted without adverse surgical outcomes. The patient recovered uneventfully, and the early therapy settings over several months resulted in preliminary decreases in aura and seizure frequency. Stimulation by one of the neurostimulators did not result in stimulation artifacts detected by the contralateral neurostimulator.

Objectives Describe changes in clinical seizure frequency and electrophysiological data recorded in patients with medically-intractable seizures and periventricular nodular heterotopias (PVNH) treated with the RNS® System (NeuroPace, Inc., Mountain View, CA). Methods Clinical seizures from eight patients (mean follow-up of 10.1 years) were analyzed pre- and post-treatment. Chronic ambulatory electrocorticograms (ECoGs) recorded from PVNHs, hippocampus and neocortex were evaluated to identify the earliest electrographic seizure onset type, pattern of spread, and interictal characteristics. Results Mean reduction in disabling seizures was 85.7 % (n = 8); seven patients had >50% seizure reduction and two were seizure-free in the final year of analysis. Seizure rate showed a progressive reduction over the course of the study with the highest rate of improvement in the first two to three years after implantation. Four of seven patients with one PVNH lead and a second lead in the hippocampus or neocortex had some electrographic seizures first recorded at either lead location, suggesting two foci or seizure propagation patterns. Low voltage fast type activity was the prominent seizure onset pattern. Interictal ECoG power was lower in PVNH than hippocampus. Conclusions RNS® System treatment substantially reduced clinical seizure frequency in patients with PVNH. Analysis of ictal ECoG records suggests PVNH may be involved in seizure generation. Significance Chronic ECoG recordings suggest PVNH tissue can actively participate in epileptogenic networks. Direct brain-responsive neurostimulation is a safe and effective treatment option in such patients, progressively reducing seizure rate over a period of years.

Objective. This study aimed to characterize hippocampal neural signatures of uncertainty by measuring beta band power in the period prior to movement cue. Approach. Participants with epilepsy were implanted with hippocampal depth electrodes for stereo electroencephalographic (SEEG) monitoring. Hippocampal beta (13–30 Hz) power changes have been observed during motor tasks such as the direct reach (DR) and Go/No-Go (GNG) tasks. The primary difference between the tasks is the presence of uncertainty about whether movement should be executed. Previous research on cortical responses to uncertainty has found that baseline beta power changes with uncertainty. SEEG data were sampled throughout phases of the DR and GNG tasks. Beta-band power during the fixation phase was compared between the DR and GNG task using a Wilcoxon rank sum test. This unpaired test was also used to analyze response times from cue to task completion between tasks. Main results. Eight patients who performed both reaching tasks were analyzed in this study. Movement response times in the GNG task were on average 210 milliseconds slower than in the DR task. All patients exhibited a significantly increased response latency in the GNG task compared to the DR task (Wilcoxon rank-sum p-value < 0.001). Six out of eight patients demonstrated statistically significant differences in beta power in single hippocampal contacts between the fixation phases of the GNG and DR tasks. At the group level, baseline beta power was significantly lower in the GNG task than in the DR task (Wilcoxon rank-sum p-value < 0.001). Significance. This novel study found that, in the presence of task uncertainty, baseline beta power in the hippocampus is lower than in its absence. This finding implicates movement uncertainty as an important factor in baseline hippocampal beta power during movement preparation.

INTRODUCTION: The hippocampus is thought to be involved in movement, but its precise role in movement execution and inhibition has not been well studied. Previous work with direct neural recordings has found beta-band (13–30 Hz) modulation in both movement execution and inhibition throughout the motor system, but the role of beta-band modulation in the hippocampus during movement inhibition is not well understood. Here we perform a Go/No-Go reaching task in ten patients with medically-refractory epilepsy to study human hippocampal beta-power changes during movement. MATERIALS AND METHODS: Ten epilepsy patients (5 female; ages 21–46) were implanted with intracranial depth electrodes for seizure monitoring and localization. Local field potentials were sampled at 2000 Hz during a Go/No-Go movement task. Comparison of beta band power between Go and No-Go conditions was conducted using Wilcoxon signed-rank hypothesis testing for each patient. Sub-analyses were conducted to assess differences in the anterior versus posterior contacts, ipsilateral versus contralateral contacts, and male versus female beta power values. RESULTS: Eight out of ten patients showed significant beta power decreases during the Go movement response (p < 0.05) compared to baseline. Eight out of ten patients also showed significant beta power increases in the No-Go condition, occurring in the absence of movement. No significant differences were noted between ipsilateral versus contralateral contacts, nor in anterior versus posterior hippocampal contacts. Female participants had a higher task success rate than males and had significantly greater beta-power increases in the No-Go condition (p < 0.001). CONCLUSION: These findings indicate that increases in hippocampal beta power are associated with movement inhibition. To our knowledge, this study is the first to report this phenomenon in the human hippocampus. The beta band may represent a state-change signal involved in motor processing. Future focus on the beta band in understanding human motor and impulse control will be vital.

OBJECTIVEMotor brain-computer interface (BCI) represents a new frontier in neurological surgery that could provide significant benefits for patients living with motor deficits. Both the primary motor cortex and posterior parietal cortex have successfully been used as a neural source for human motor BCI, leading to interest in exploring other brain areas involved in motor control. The amygdala is one area that has been shown to have functional connectivity to the motor system; however, its role in movement execution is not well studied. Gamma oscillations (30–200 Hz) are known to be prokinetic in the human cortex, but their role is poorly understood in subcortical structures. Here, the authors use direct electrophysiological recordings and the classic “center-out” direct-reach experiment to study amygdaloid gamma-band modulation in 8 patients with medically refractory epilepsy.METHODSThe study population consisted of 8 epilepsy patients (2 men; age range 21–62 years) who underwent implantation of micro-macro depth electrodes for seizure localization and EEG monitoring. Data from the macro contacts sampled at 2000 Hz were used for analysis. The classic center-out direct-reach experiment was used, which consists of an intertrial interval phase, a fixation phase, and a response phase. The authors assessed the statistical significance of neural modulation by inspecting for nonoverlapping areas in the 95% confidence intervals of spectral power for the response and fixation phases.RESULTSIn 5 of the 8 patients, power spectral analysis showed a statistically significant increase in power within regions of the gamma band during the response phase compared with the fixation phase. In these 5 patients, the 95% bootstrapped confidence intervals of trial-averaged power in contiguous frequencies of the gamma band during the response phase were above, and did not overlap with, the confidence intervals of trial-averaged power during the fixation phase.CONCLUSIONSTo the authors’ knowledge, this is the first time that direct neural recordings have been used to show gamma-band modulation in the human amygdala during the execution of voluntary movement. This work indicates that gamma-band modulation in the amygdala could be a contributing source of neural signals for use in a motor BCI system.

Objective. The human orbitofrontal cortex (OFC) is involved in automatic response inhibition and conflict processing, but the mechanism of frequency-specific power changes that control these functions is unknown. Theta and gamma activity have been independently observed in the OFC during conflict processing, while theta–gamma interactions in other brain areas have been noted primarily in studies of memory. Within the OFC, it is possible that theta–gamma phase amplitude coupling (PAC) drives conflict processing. This study aims to characterize the coupled relationship between theta and gamma frequency bands in the OFC during conflict processing using a modified Stroop task. Approach. Eight epilepsy patients implanted with OFC stereotactic electroencephalography electrodes participated in a color-word modified Stroop task. PAC between theta phase and gamma amplitude was assessed to determine the timing and magnitude of neural oscillatory changes. Group analysis was conducted using a non-parametric cluster-permutation t-test on coherence values. Main results. Theta-low gamma (LG) PAC significantly increased in five out of eight patients during successful trials of the incongruent condition compared with the congruent condition. Significant increases in theta-LG PAC were most prominent during cue processing 200–800 ms after cue presentation. On group analysis, trial-averaged mean theta-LG PAC was statistically significantly greater in the incongruent condition compared to the congruent condition (p < 0.001, Cohen’s d = 0.51). Significance. For the first time, we report that OFC theta phase and LG amplitude coupling increases during conflict resolution. Given the delayed onset after cue presentation, OFC theta-LG PAC may contribute to conflict processing after conflict detection and before motor response. This explanation follows the hypothesis that global theta waves modulate local gamma signals. Understanding this relationship within the OFC will help further elucidate the neural mechanisms of human conflict resolution.

Previous work in directional tuning for brain machine interfaces has primarily relied on algorithm sorted neuronal action potentials in primary motor cortex. However, local field potential has been utilized to show directional tuning in macaque studies, and inferior parietal cortex has shown increased neuronal activity in reaching tasks that relied on MRI imaging. In this study we utilized local field potential recordings from a human subject performing a delayed reach task and show that high frequency band (76–100 Hz) spectral power is directionally tuned to different reaching target locations during an active reach. We also show that during the delay phase of the task, directional tuning is present in areas of the inferior parietal cortex, in particular, the supramarginal gyrus.

Somatosensory feedback is the next step in brain computer interface (BCI). Here, we compare three cortical stimulating array modalities for generating somatosensory percepts in BCI. We compared human subjects with either a 64-channel “mini”-electrocorticography grid (mECoG; 1.2-mm diameter exposed contacts with 3-mm spacing, N = 1) over the hand area of primary somatosensory cortex (S1), or a standard grid (sECoG; 1.5-mm diameter exposed contacts with 1-cm spacing, N = 1), to generate artificial somatosensation through direct electrical cortical stimulation. Finally, we reference data in the literature from a patient implanted with microelectrode arrays (MEA) placed in the S1 hand area. We compare stimulation results to assess coverage and specificity of the artificial percepts in the hand. Using the mECoG array, hand mapping revealed coverage of 41.7% of the hand area versus 100% for the sECoG array, and 18.8% for the MEA. On average, stimulation of a single electrode corresponded to sensation reported in 4.42 boxes (range 1–11 boxes) for the mECoG array, 19.11 boxes (range 4–48 boxes) for the sECoG grid, and 2.3 boxes (range 1–5 boxes) for the MEA. Sensation in any box, on average, corresponded to stimulation from 2.65 electrodes (range 1–5 electrodes) for the mECoG grid, 3.58 electrodes for the sECoG grid (range 2–4 electrodes), and 11.22 electrodes (range 2–17 electrodes) for the MEA. Based on these findings, we conclude that mECoG grids provide an excellent balance between spatial cortical coverage of the hand area of S1 and high-density resolution.

Objective. Identify the role of beta-band (13–30 Hz) power modulation in the human hippocampus during conflict processing. Approach. We investigated changes in the spectral power of the beta band (13–30 Hz) as measured by depth electrode leads in the hippocampus during a modified Stroop task in six patients with medically refractory epilepsy. Previous work done with direct electrophysiological recordings in humans has shown hippocampal theta-band (3–8 Hz) modulation during conflict processing. Local field potentials sampled at 2 k Hz were used for analysis and a non-parametric cluster-permutation t-test was used to identify the time period and frequency ranges of significant power change during cue processing (i.e. post-stimulus, pre-response). Main results. In five of the six patients, we observe a statistically significant increase in hippocampal beta-band power during successful conflict processing in the incongruent trial condition (cluster-based correction for multiple comparisons, p < 0.05). There was no significant beta-band power change observed during the cue-processing period of the congruent condition in the hippocampus of these patients. Significance. The beta-power changes during conflict processing represented here are consistent with previous studies suggesting that the hippocampus plays a role in conflict processing, but it is the first time that the beta band has been shown to be involved in humans with direct electrophysiological evidence. We propose that beta-band modulation plays a role in successful conflict detection and automatic response inhibition in the human hippocampus as studied during a conflict response task.

Objective: Restoration of somatosensory deficits in humans requires a clear understanding of the neural representations of percepts. To characterize the cortical response to naturalistic somatosensation, we examined field potentials in the primary somatosensory cortex of humans. Methods: Four patients with intractable epilepsy were implanted with subdural electrocorticography (ECoG) electrodes over the hand area of S1. Three types of stimuli were applied, soft-repetitive touch, light touch, and deep touch. Power in the alpha (8–15 Hz), beta (15–30 Hz), low-gamma (30–50 Hz), and high-gamma (50–125 Hz) frequency bands were evaluated for significance. Results: Seventy-seven percent of electrodes over the hand area of somatosensory cortex exhibited changes in these bands. High-gamma band power increased for all stimuli, with concurrent alpha and beta band power decreases. Earlier activity was seen in these bands in deep touch and light touch compared to soft touch. Conclusions: These findings are consistent with prior literature and suggest a widespread response to focal touch, and a different encoding of deeper pressure touch than soft touch.

Objective The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains. Methods Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21–71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE-31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test–retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed. Results The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0–4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE-31. Conclusion The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change.

OBJECTIVEStimulation of the primary somatosensory cortex (S1) has been successful in evoking artificial somatosensation in both humans and animals, but much is unknown about the optimal stimulation parameters needed to generate robust percepts of somatosensation. In this study, the authors investigated frequency as an adjustable stimulation parameter for artificial somatosensation in a closed-loop brain-computer interface (BCI) system.METHODSThree epilepsy patients with subdural mini-electrocorticography grids over the hand area of S1 were asked to compare the percepts elicited with different stimulation frequencies. Amplitude, pulse width, and duration were held constant across all trials. In each trial, subjects experienced 2 stimuli and reported which they thought was given at a higher stimulation frequency. Two paradigms were used: first, 50 versus 100 Hz to establish the utility of comparing frequencies, and then 2, 5, 10, 20, 50, or 100 Hz were pseudorandomly compared.RESULTSAs the magnitude of the stimulation frequency was increased, subjects described percepts that were “more intense” or “faster.” Cumulatively, the participants achieved 98.0% accuracy when comparing stimulation at 50 and 100 Hz. In the second paradigm, the corresponding overall accuracy was 73.3%. If both tested frequencies were less than or equal to 10 Hz, accuracy was 41.7% and increased to 79.4% when one frequency was greater than 10 Hz (p = 0.01). When both stimulation frequencies were 20 Hz or less, accuracy was 40.7% compared with 91.7% when one frequency was greater than 20 Hz (p < 0.001). Accuracy was 85% in trials in which 50 Hz was the higher stimulation frequency. Therefore, the lower limit of detection occurred at 20 Hz, and accuracy decreased significantly when lower frequencies were tested. In trials testing 10 Hz versus 20 Hz, accuracy was 16.7% compared with 85.7% in trials testing 20 Hz versus 50 Hz (p < 0.05). Accuracy was greater than chance at frequency differences greater than or equal to 30 Hz.CONCLUSIONSFrequencies greater than 20 Hz may be used as an adjustable parameter to elicit distinguishable percepts. These findings may be useful in informing the settings and the degrees of freedom achievable in future BCI systems.

SUMMARY Dual-sided subdural electrodes are used in the localization and lateralization of seizure-onset zones when the area of interest is within the interhemispheric fissure. We designed the current study to test the validity of the assumption that each side of the dual-sided electrodes records from the hemisphere it faces. We recorded with dual-sided strip and grid electrodes implanted in the occipital interhemispheric space in two patients with nonoccipital epilepsy during two visual stimulation tasks in which subjects were presented with visual stimuli in the ipsilateral or contralateral visual hemifields. Our findings show substantial contamination of recordings from the opposite hemisphere. Although, as expected, electrodes recording through the falx record faintly from the contralateral cortical surface, they unexpectedly pick up strong signals from the cortex behind them. Therefore, we conclude that these electrodes should not be used for lateralization of the origin of epileptic activity or evoked responses.

Neuromodulation devices are used in the treatment of medically refractory epilepsy. This has been defined as epilepsy with persistent seizures despite adequate trials of at least two anti-epileptic drugs (AEDs). In most cases of medically refractory partial epilepsy, the first choice of treatment is resective surgery if the seizure focus can be definitively localized and if surgery can be safely performed without causing intolerable neurologic deficits. Patients with medically refractory epilepsy who are not candidates for potentially curative surgery may benefit from the implantation of a neuromodulation device. While most of these devices require surgical implantation, they provide a significant added seizure reduction without typical medication side effects. Furthermore, the efficacy of these devices continues to improve over years. There are currently no head-to-head trials comparing the different neuromodulation devices but efficacy appears to be roughly similar. The choice of device therefore depends on the type of epilepsy, whether the seizure focus can be identified, and other clinical factors. Vagal Nerve Stimulation (VNS) does not require identification of the seizure focus and also carries an FDA indication for depression. While in the United States VNS is only approved for use in partial epilepsy, it is commonly used off-label to treat generalized seizures as well. VNS delivers stimulation on a scheduled basis, in response to patient activation, or in response to heart rate increases serving as a proxy for seizures. Responsive Neurostimulation (RNS) requires the identification of up to two seizure foci and delivers stimulation only in response to the detection of epileptiform activity. While it requires intracranial placement of electrodes, it allows for long-term monitoring of electrographic seizures and may be effective where VNS has not produced an optimal response. Deep brain stimulation of the anterior nucleus of the thalamus is not FDA approved at this time but is available in Europe and many other parts of the world. While it also carries an indication only for partial epilepsy, it does not require identification of the seizure focus and may be particularly helpful for temporal lobe epilepsy. It also appears effective in cases where VNS has not been sufficiently helpful. The Trigeminal Nerve Stimulation (TNS) system is another treatment modality which is not yet FDA approved but is available in Europe and other countries. Its mechanism of action is similar to the VNS system and it also appears to have anti-depression effects in addition to anti-epileptic benefits. However, the most compelling feature of TNS is that it is not implanted but rather applied to the skin with transdermal electrodes, typically at night.

Transmission of visual signals at the first retinal synapse is associated with changes in calcium concentration in photoreceptors and bipolar cells. We investigated how loss of plasma membrane Ca2+ATPase isoform 2 (PMCA2), the calcium transporter isoform with the highest affinity for Ca2+/calmodulin, affects transmission of rod- and cone-mediated responses. PMCA2 expression in the neuroblast layer was observed soon after birth; in the adult, PMCA2 was expressed in inner segments and synaptic terminals of rod photoreceptors, in rod bipolar cells, and in most inner retinal neurons but was absent from cones. To determine the role of PMCA2 in retinal signaling, we compared morphology and light responses of retinas from control mice and deafwaddlerdfw2Jmice, which lack functional PMCA2 protein. The cytoarchitecture of retinas from control anddfw2Jmice was indistinguishable at the light microscope level. Suction electrode recordings revealed no difference in the sensitivity or amplitude of outer segment light responses of control anddfw2Jrods. However, rod-mediated ERG b-wave responses indfw2Jmice were ∼45% smaller and significantly slower than those of control mice. Furthermore, recordings from individual rod bipolar cells showed that the sensitivity of transmission at the rod output synapse was reduced by ∼50%. No changes in the amplitude or timing of cone-mediated ERG responses were observed. These results suggest that PMCA2-mediated Ca2+extrusion modulates the amplitude and timing of the high-sensitivity rod pathway to a much greater extent than that of the cone pathway.

Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.

Purpose To investigate the mechanism of bilateral central vision loss in a patient with graft-versus-host disease. Design Observational case report. Methods A 43-year-old man with graft-versus-host disease developed acute painless progressive central vision loss, first in the left eye and then in the right. The patient underwent slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography, visual field testing, full-field electroretinography, multifocal electroretinography, and testing for paraneoplastic antibodies. Results Fundus examination and fluorescein angiography were unremarkable. Goldmann perimetry revealed enlarged blind spots with central scotomas bilaterally. An electroretinogram testing showed asymmetric retinal dysfunction, consistent with acute zonal occult outer retinopathy. No paraneoplastic autoantibodies were detected. The patient continued to have asymmetric progressive vision loss that stabilized over the next 6 months. Conclusions Graft-versus-host disease should be included in the autoimmune conditions associated with AZOOR.

BDNF signaling through its TrkB receptor plays a pivotal role in activity-dependent refinement of synaptic connectivity of retinal ganglion cells. Additionally, studies using TrkB knockout mice have suggested that BDNF/TrkB signaling is essential for the development of photoreceptors and for synaptic communication between photoreceptors and second order retinal neurons. Thus the action of BDNF on refinement of synaptic connectivity of retinal ganglion cells could be a direct effect in the inner retina, or it could be secondary to its proposed role in rod maturation and in the formation of rod to bipolar cell synaptic transmission. To address this matter we have conditionally eliminated TrkB within the retina. We find that rod function and synaptic transmission to bipolar cells is not compromised in these conditional knockout mice. Consistent with previous work, we find that inner retina neural development is regulated by retinal BDNF/TrkB signaling. Specifically we show here also that the complexity of neuronal processes of dopaminergic cells is reduced in conditional TrkB knockout mice. We conclude that retinal BDNF/TrkB signaling has its primary role in the development of inner retinal neuronal circuits, and that this action is not a secondary effect due to the loss of visual signaling in the outer retina.

Age related macular degeneration (AMD) is the leading cause of blindness among the elderly in the United States (Klein et al., 1992; Klein et al., 2002), and choroidal neovascularization (CNV) accounts for the majority of severe vision loss (Ferris et al., 1984). The current standard treatment for CNV is verteporfin photodynamic therapy (PDT) (Landy and Brown, 2003), which uses a laser to activate a photosensitizing dye accumulated within the CNV. Although PDT causes less damage to the retina overlying CNV than thermal laser, in normal primate (Husain et al., 1996; Kramer et al., 1996; Reinke et al., 1999; Peyman et al., 2000), rabbit (Peyman et al., 2000) and rat (Zacks et al., 2002) models, PDT damages photoreceptors and retinal pigment epithelial (RPE) cells. Although there has been no histologic evidence of damage to normal human retinal cells after PDT (Schlotzer-Schrehardt et al., 2002), patients treated with PDT experience visual disturbances and acute severe vision loss significantly more often than patients receiving placebo (Arnold et al., 2004; Azab et al., 2004). Because neurotrophic agents, such as brain-derived neurotrophic factor (BDNF) have been proven effective in reducing retinal damage in rodents after exposure to constant light (LaVail et al., 1992; Okoye et al., 2003), we hypothesized that BDNF treatment prior to PDT might reduce collateral damage to retinal and RPE cells in normal rats.

Purpose A prior study showed that brain-derived neurotrophic factor (BDNF) rescues photoreceptors from collateral retinal damage caused by photodynamic therapy (PDT). This study was conducted to determine whether ciliary neurotrophic factor (CNTF), a combination of BDNF and CNTF, or pigment epithelial cell-derived growth factor (PEDF) might protect photoreceptors and retinal function more effectively than BDNF. Also investigated was whether protection would be observed after a second round of PDT with adjunctive BDNF treatment. Methods Normal rats received intravitreal injections of BDNF, CNTF, a combination of BDNF and CNTF, or PEDF in one eye and PBS in the other 2 days before PDT. Retinal function and photoreceptor survival were assessed with multifocal ERG (mfERG) and histology 1 week after PDT. Another group of rats received two courses of PDT 3 months apart, with injection of BDNF 2 days before each treatment. Results All factors significantly increased photoreceptor survival. The combination of BDNF and CNTF rescued more photoreceptors than either factor alone. Only BDNF improved retinal function 1 week after PDT, with CNTF and the combination of BDNF and CNTF reducing mfERG responses. BDNF injection before a second round of PDT improved mfERG responses and retinal structure. Conclusions BDNF is the most effective single factor among those tested for neuroprotection and improvement of retinal function after PDT, although a combination of BDNF and CNTF rescues more photoreceptors. Adjunctive treatment with BDNF also protects retinal structure and function through two rounds of PDT, suggesting its potential value for patients who require multiple treatments.

PURPOSE. Verteporfin photodynamic therapy (PDT) is the most effective treatment for age-related macular degeneration, using laser activation of a photosensitizing dye to achieve closure of choroidal neovascularization. Although PDT preferentially affects pathologic vessels, it can also cause collateral damage to the overlying retina. In the current study, it was found that the neuroprotective agent brain-derived neurotrophic factor (BDNF) reduces this retinal damage. METHODS. Normal adult rats received intravitreal BDNF in one eye and PBS or no injection in the other eye 2 days before PDT. RESULTS. Control eyes exhibited choroidal hypofluorescence, moderate to severe photoreceptor loss, and depression of local retinal function measured using multifocal ERG in the laser-treated area. BDNF-injected eyes had more surviving photoreceptors and improved multifocal ERG responses 1 week after PDT. BDNF did not diminish the effect of PDT on the choroidal circulation as assessed by fluorescein angiography, and there was no evidence of retinal toxicity due to BDNF treatment. CONCLUSIONS. These results suggest that adjunctive neuroprotective therapy may reduce collateral damage to photoreceptors and improve visual outcome after PDT.

Purpose To investigate severe unilateral vision loss in a choroideremia carrier. Design Case report. Methods Ocular examination, genetic testing, Humphrey visual fields, full-field and multifocal (mf) electroretinogram (ERG) tests were used to study a family with choroideremia. Results In a carrier with unilateral central vision loss, mfERG showed severely reduced amplitudes which correlated with a band of retinal pigment epithelial and choroidal atrophy in the macula, a dense central scotoma on Humphrey visual fields testing, and decreased ERG amplitudes. Conclusions Multifocal ERG may be a sensitive tool to measure functional abnormalities in choroideremia carriers. Mosaic inactivation of the normal gene may cause expression of the mutation with severe vision loss in choroideremia carriers.

Purpose CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function. Methods Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically. Results In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses. Conclusions Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.