Long-term persistence of viral RNA and inflammation in the CNS of macaques exposed to aerosolized Venezuelan equine encephalitis virus.

Venezuelan equine encephalitis virus (VEEV) is a positively-stranded RNA arbovirus of the genus Alphavirus that causes encephalitis in humans. Cynomolgus macaques are a relevant model of the human disease caused by VEEV and are useful in exploring pathogenic mechanisms and the host response to VEEV infection. Macaques were exposed to small-particle aerosols containing virus derived from an infectious clone of VEEV strain INH-9813, a subtype IC strain isolated from a human infection. VEEV-exposed macaques developed a biphasic fever after infection similar to that seen in humans. Maximum temperature deviation correlated with the inhaled dose, but fever duration did not. Neurological signs, suggestive of virus penetration into the central nervous system (CNS), were predominantly seen in the second febrile period. Electroencephalography data indicated a statistically significant decrease in all power bands and circadian index during the second febrile period that returned to normal after fever resolved. Intracranial pressure increased late in the second febrile period. On day 6 post-infection macaques had high levels of MCP-1 and IP-10 chemokines in the CNS, as well as a marked increase of T lymphocytes and activated microglia. More than four weeks after infection, VEEV genomic RNA was found in the brain, cerebrospinal fluid and cervical lymph nodes. Pro-inflammatory cytokines & chemokines, infiltrating leukocytes and pathological changes were seen in the CNS tissues of macaques euthanized at these times. These data are consistent with persistence of virus replication and/or genomic RNA and potentially, inflammatory sequelae in the central nervous system after resolution of acute VEEV disease.

Physiological and immunological changes in the brain associated with lethal eastern equine encephalitis virus in macaques.

Aerosol exposure to eastern equine encephalitis virus (EEEV) can trigger a lethal viral encephalitis in cynomolgus macaques which resembles severe human disease. Biomarkers indicative of central nervous system (CNS) infection by the virus and lethal outcome of disease would be useful in evaluating potential medical countermeasures, especially for therapeutic compounds. To meet requirements of the Animal Rule, a better understanding of the pathophysiology of EEEV-mediated disease in cynomolgus macaques is needed. In this study, macaques given a lethal dose of clone-derived EEEV strain V105 developed a fever between 2-3 days post infection (dpi) and succumbed to the disease by 6 dpi. At the peak of the febrile phase, there was a significant increase in the delta electroencephalography (EEG) power band associated with deep sleep as well as a sharp rise in intracranial pressure (ICP). Viremia peaked early after infection and was largely absent by the onset of fever. Granulocytosis and elevated plasma levels of IP-10 were found early after infection. At necropsy, there was a one hundred- to one thousand-fold increase in expression of traumatic brain injury genes (LIF, MMP-9) as well as inflammatory cytokines and chemokines (IFN-γ, IP-10, MCP-1, IL-8, IL-6) in the brain tissues. Phenotypic analysis of leukocytes entering the brain identified cells as primarily lymphoid (T, B, NK cells) with lower levels of infiltrating macrophages and activated microglia. Massive amounts of infectious virus were found in the brains of lethally-infected macaques. While no infectious virus was found in surviving macaques, quantitative PCR did find evidence of viral genomes in the brains of several survivors. These data are consistent with an overwhelming viral infection in the CNS coupled with a tremendous inflammatory response to the infection that may contribute to the disease outcome. Physiological monitoring of EEG and ICP represent novel methods for assessing efficacy of vaccines or therapeutics in the cynomolgus macaque model of EEEV encephalitis.

Cross-population coupling of neural activity based on Gaussian process current source densities.

Because local field potentials (LFPs) arise from multiple sources in different spatial locations, they do not easily reveal coordinated activity across neural populations on a trial-to-trial basis. As we show here, however, once disparate source signals are decoupled, their trial-to-trial fluctuations become more accessible, and cross-population correlations become more apparent. To decouple sources we introduce a general framework for estimation of current source densities (CSDs). In this framework, the set of LFPs result from noise being added to the transform of the CSD by a biophysical forward model, while the CSD is considered to be the sum of a zero-mean, stationary, spatiotemporal Gaussian process, having fast and slow components, and a mean function, which is the sum of multiple time-varying functions distributed across space, each varying across trials. We derived biophysical forward models relevant to the data we analyzed. In simulation studies this approach improved identification of source signals compared to existing CSD estimation methods. Using data recorded from primate auditory cortex, we analyzed trial-to-trial fluctuations in both steady-state and task-evoked signals. We found cortical layer-specific phase coupling between two probes and showed that the same analysis applied directly to LFPs did not recover these patterns. We also found task-evoked CSDs to be correlated across probes, at specific cortical depths. Using data from Neuropixels probes in mouse visual areas, we again found evidence for depth-specific phase coupling of primary visual cortex and lateromedial area based on the CSDs.

Formation and decay of auditory short-term memory in the macaque monkey.

Echoic memory (EM) is a short-lived, precategorical, and passive form of auditory short-term memory (STM). A key hallmark of EM is its rapid exponential decay with a time constant between 1 and 2 s. It is not clear whether auditory STM in the rhesus, an important model system, shares this rapid exponential decay. To resolve this shortcoming, two rhesus macaques were trained to perform a delayed frequency discrimination task. Discriminability of delayed tones was measured as a function of retention duration and the number of times the standard had been repeated before the target. Like in the human, our results show a rapid decline of discriminability with retention duration. In addition, the results suggest a gradual strengthening of discriminability with repetition number. Model-based analyses suggest the presence of two components of auditory STM: a short-lived component with a time constant on the order of 550 ms that most likely corresponds to EM and a more stable memory trace with time constants on the order of 10 s that strengthens with repetition and most likely corresponds to auditory recognition memory. NEW & NOTEWORTHY This is the first detailed quantification of the rapid temporal dynamics of auditory short-term memory in the rhesus. Much of the auditory information in short-term memory is lost within the first couple of seconds. Repeated presentations of a tone strengthen its encoding into short-term memory. Model-based analyses suggest two distinct components: an echoic memory homolog that mediates the rapid decay and a more stable but less detail-rich component that mediates strengthening of the trace with repetition.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-ᴅ-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-d-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

The Role of Response Inhibition in Medicated and Unmedicated Obsessive-Compulsive Disorder Patients: Evidence from the Stop-Signal Task.

BACKGROUND: Numerous studies have investigated response inhibition (RI) in obsessive-compulsive disorder (OCD), with many reporting that OCD patients demonstrate deficits in RI as compared to controls. However, reported effect sizes tend to be modest and results have been inconsistent, with some studies finding intact RI in OCD. To date, no study has examined the effect of medications on RI in OCD patients. METHODS: We analyzed results from a stop-signal task to probe RI in 65 OCD patients (32 of whom were medicated) and 58 healthy controls (HCs). RESULTS: There was no statistically significant difference in stop-signal reaction time between the OCD group and the HC group, or between the medicated and unmedicated OCD patients. However, variability was significantly greater in the medicated OCD group compared to the unmedicated group. CONCLUSIONS: These results indicate that some samples of OCD patients do not have deficits in RI, making it unlikely that deficient RI underlies repetitive behaviors in all OCD patients. Future research is needed to fully elucidate the impact of medication use on stop-signal performance. Implications for future research on the cognitive processes underlying repetitive thoughts and behaviors are discussed.

The importance of decision onset.

The neural mechanisms of decision making are thought to require the integration of evidence over time until a response threshold is reached. Much work suggests that response threshold can be adjusted via top-down control as a function of speed or accuracy requirements. In contrast, the time of integration onset has received less attention and is believed to be determined mostly by afferent or preprocessing delays. However, a number of influential studies over the past decade challenge this assumption and begin to paint a multifaceted view of the phenomenology of decision onset. This review highlights the challenges involved in initiating the integration of evidence at the optimal time and the potential benefits of adjusting integration onset to task demands. The review outlines behavioral and electrophysiolgical studies suggesting that the onset of the integration process may depend on properties of the stimulus, the task, attention, and response strategy. Most importantly, the aggregate findings in the literature suggest that integration onset may be amenable to top-down regulation, and may be adjusted much like response threshold to exert cognitive control and strategically optimize the decision process to fit immediate behavioral requirements.

Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus.

Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ∼65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions.

Performance monitoring in monkey frontal eye field.

The frontal eye fields (FEF) are thought to mediate response selection during oculomotor decision tasks. In addition, many FEF neurons have robust postsaccadic responses, but their role in postchoice evaluative processes (online performance monitoring) is only beginning to become apparent. Here we report error-related neural activity in FEF while monkeys performed a biased speed-categorization task that enticed the animals to make impulsive errors. Twenty-three percent of cells in macaque FEF coded an internally generated error-related signal, and many of the same cells also coded task difficulty. The observed responses are primarily consistent with three related concepts that have been associated with performance monitoring: (1) response conflict; (2) uncertainty; and (3) reward prediction. Overall, our findings suggest a novel role for the FEF as part of the neural network that evaluates the preceding choice to optimize behavior in the future.

Volumetric mesoscopic electrophysiology: a new imaging modality for the non-human primate.

The primate brain is a densely interconnected organ whose function is best understood by recording from the entire structure in parallel, rather than parts of it in sequence. However, available methods either have limited temporal resolution (functional magnetic resonance imaging), limited spatial resolution (macroscopic electroencephalography), or a limited field of view (microscopic electrophysiology). To address this need, we developed a volumetric, mesoscopic recording approach ( MePhys ) by tessellating the volume of a monkey hemisphere with 992 electrode contacts that were distributed across 62 chronically implanted multi-electrode shafts. We showcase the scientific promise of MePhys by describing the functional interactions of local field potentials between the more than 300,000 simultaneously recorded pairs of electrodes. We find that a subanesthetic dose of ketamine -believed to mimic certain aspects of psychosis- can create a pronounced state of functional disconnection and prevent the formation of stable large-scale intrinsic states. We conclude that MePhys provides a new and fundamentally distinct window into brain function whose unique profile of strengths and weaknesses complements existing approaches in synergistic ways.

Intensity and inter-stimulus-interval effects on human middle- and long-latency auditory evoked potentials in an unpredictable auditory context.

It is not known how Auditory-Evoked Responses (AERs) comprising Middle Latency Responses (MLRs) and Long Latency Responses (LLRs) are modulated by stimulus intensity and inter-stimulus interval (ISI) in an unpredictable auditory context. Further, intensity and ISI effects on MLR and LLR have never been assessed simultaneously in the same humans. To address this important question, thirty participants passively listened to a random sequence of auditory clicks of three possible intensities (65, 75, and 85 dB) at five possible ISI ranges (0.25 to 0.5 s, 0.5 to 1 s, 1 to 2 s, 2 to 4 s, 4 to 8 s) over four to seven one-hour sessions while EEG was recorded. P0, Na, Pa, Nb, and Pb MLR peaks and N1 and P2 LLR peaks were measured. MLRs P0 (p = .005), Pa (p = .021), and Pb (p = <.001) were modulated by intensity, while only MLR Pb (p = <.001) was modulated by ISI. LLR N1 and P2 were modulated by both intensity and ISI (all p values < .001). Intensity and ISI interacted at Pb, N1, and P2 (all p values < .001), with greater intensity effects at longer ISIs and greater ISI effects at louder intensities. Together, these results provide a comprehensive picture of intensity and ISI effects on AER across the entire thalamocortical auditory pathway, while controlling for stimulus predictability. Moreover, they highlight P0 as the earliest MLR response sensitive to stimulus intensity and Pb (~50 ms) as the earliest cortical response coding for ISIs above 250 ms and showing an interdependence between intensity and ISI effects.

A Linear Superposition Model of Envelope and Frequency Following Responses May Help Identify Generators Based on Latency.

Envelope and frequency-following responses (FFRENV and FFRTFS) are scalp-recorded electrophysiological potentials that closely follow the periodicity of complex sounds such as speech. These signals have been established as important biomarkers in speech and learning disorders. However, despite important advances, it has remained challenging to map altered FFRENV and FFRTFS to altered processing in specific brain regions. Here we explore the utility of a deconvolution approach based on the assumption that FFRENV and FFRTFS reflect the linear superposition of responses that are triggered by the glottal pulse in each cycle of the fundamental frequency (F0 responses). We tested the deconvolution method by applying it to FFRENV and FFRTFS of rhesus monkeys to human speech and click trains with time-varying pitch patterns. Our analyses show that F0ENV responses could be measured with high signal-to-noise ratio and featured several spectro-temporally and topographically distinct components that likely reflect the activation of brainstem (<5 ms; 200-1000 Hz), midbrain (5-15 ms; 100-250 Hz), and cortex (15-35 ms; ~90 Hz). In contrast, F0TFS responses contained only one spectro-temporal component that likely reflected activity in the midbrain. In summary, our results support the notion that the latency of F0 components map meaningfully onto successive processing stages. This opens the possibility that pathologically altered FFRENV or FFRTFS may be linked to altered F0ENV or F0TFS and from there to specific processing stages and ultimately spatially targeted interventions.

The dorsal medial frontal cortex is sensitive to time on task, not response conflict or error likelihood.

The dorsal medial frontal cortex (dMFC) is highly active during choice behavior. Though many models have been proposed to explain dMFC function, the conflict monitoring model is the most influential. It posits that dMFC is primarily involved in detecting interference between competing responses thus signaling the need for control. It accurately predicts increased neural activity and response time (RT) for incompatible (high-interference) vs. compatible (low-interference) decisions. However, it has been shown that neural activity can increase with time on task, even when no decisions are made. Thus, the greater dMFC activity on incompatible trials may stem from longer RTs rather than response conflict. This study shows that (1) the conflict monitoring model fails to predict the relationship between error likelihood and RT, and (2) the dMFC activity is not sensitive to congruency, error likelihood, or response conflict, but is monotonically related to time on task.

Frequency-Following Responses to Speech Sounds Are Highly Conserved across Species and Contain Cortical Contributions.

Time-varying pitch is a vital cue for human speech perception. Neural processing of time-varying pitch has been extensively assayed using scalp-recorded frequency-following responses (FFRs), an electrophysiological signal thought to reflect integrated phase-locked neural ensemble activity from subcortical auditory areas. Emerging evidence increasingly points to a putative contribution of auditory cortical ensembles to the scalp-recorded FFRs. However, the properties of cortical FFRs and precise characterization of laminar sources are still unclear. Here we used direct human intracortical recordings as well as extracranial and intracranial recordings from macaques and guinea pigs to characterize the properties of cortical sources of FFRs to time-varying pitch patterns. We found robust FFRs in the auditory cortex across all species. We leveraged representational similarity analysis as a translational bridge to characterize similarities between the human and animal models. Laminar recordings in animal models showed FFRs emerging primarily from the thalamorecipient layers of the auditory cortex. FFRs arising from these cortical sources significantly contributed to the scalp-recorded FFRs via volume conduction. Our research paves the way for a wide array of studies to investigate the role of cortical FFRs in auditory perception and plasticity.

Perisaccadic mislocalization as optimal percept.

The spatially uniform mislocalization of stimuli flashed around the onset of fast eye-movements (perisaccadic shift) has previously been explained by an inaccurate internal representation of current eye position. However, this hypothesis does not account for the observation that continuously presented stimuli are correctly localized during saccades. Here we show that the two findings are not mutually exclusive. The novelty of our approach lies in our interpretation of the extraretinal signal which, in contrast to other models, is not considered an (erroneous) estimate of current eye-position. Based on the reafference principle, our model assumes that the extraretinal signal is optimal in that it accurately predicts the neural representation of the retinal position of a continuously present stimulus. Perisaccadic shift arises as a consequence of maintaining stable perisaccadic position estimates for continuously present stimuli under the physiologically plausible assumption of temporal low-pass filtering in the afferent visual pathway. Consequently, our model reconciles the reafference principle with the finding of perisaccadic shift.

A surface metric and software toolbox for EEG electrode grids in the macaque.

BACKGROUND: The past years have seen increased appreciation of electroencephalographic (EEG) recordings in non-human primates (NHP) as a tool for translational research. In humans, even large EEG electrode grids can easily and quickly be placed on standardized positions using commercially available EEG caps. In the NHP, the identification of standardized EEG electrode positions is more complicated and time-consuming. NEW METHOD: Here we introduce a surface metric and software package (NHP1020) that automates the planning of large, approximately evenly spaced electrode grids for EEG recordings in the NHP. RESULTS: Based on one CT and one MRI image as well as two intracranial markers, the NHP1020 software defines electrode positions on the brain surface using a surface-based spherical metric similar to the one used by the international 10-20 system. Standardized electrode grids can be shared, imported or defined with few high-level commands. EXISTING METHODS: NHP EEG electrodes can be placed relative to extracranial markers and measurements or relative to underlying neural structures of interest. Both approaches are time-consuming and require manual intervention. Furthermore, the use of extracranial markers in this species may be more problematic than in humans, because cranial muscles and ridges are larger and keep maturing long into adulthood. CONCLUSION: The presented surface metric and the NHP1020 toolbox provide fast and automated identification of entire electrode grids in the non-human primate based on a two-dimensional metric on the brain surface.

A roadmap for development of neuro-oscillations as translational biomarkers for treatment development in neuropsychopharmacology.

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development.

Applications of minimally invasive multimodal telemetry for continuous monitoring of brain function and intracranial pressure in macaques with acute viral encephalitis.

Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics can mitigate CNS infection or disease in this model. The documentation of alphavirus encephalitis in animals relies on traditional physiological biomarkers and behavioral/neurological observations by veterinary staff; quantitative measurements such as electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naïve macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-infection in a cohort of twelve adult cynomolgus macaques. Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 - 4Hz); theta: [4 - 8Hz); alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to alphavirus infection. This novel enhancement of the cynomolgus macaque model offers utility for timely determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and therapeutic candidates.

Depth perception during saccades.

A number of studies have investigated the localization of briefly flashed targets during saccades to understand how the brain perceptually compensates for changes in gaze direction. Typical version saccades, i.e., saccades between two points of the horopter, are not only associated with changes in gaze direction, but also with large transient changes of ocular vergence. These transient changes in vergence have to be compensated for just as changes in gaze direction. We investigated depth judgments of perisaccadically flashed stimuli relative to continuously present references and report several novel findings. First, disparity thresholds increased around saccade onset. Second, for horizontal saccades, depth judgments were prone to systematic errors: Stimuli flashed around saccade onset were perceived in a closer depth plane than persistently shown references with the same retinal disparity. Briefly before and after this period, flashed stimuli tended to be perceived in a farther depth plane. Third, depth judgments for upward and downward saccades differed substantially: For upward, but not for downward saccades we observed the same pattern of mislocalization as for horizontal saccades. Finally, unlike localization in the fronto-parallel plane, depth judgments did not critically depend on the presence of visual references. Current models fail to account for the observed pattern of mislocalization in depth.