Andreas Schindler

Fosmidomycin for malaria

Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.

Fosmidomycin, a Novel Chemotherapeutic Agent for Malaria

ABSTRACT In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated Plasmodium falciparum malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.

Short-Course Artesunate Treatment of Uncomplicated Plasmodium falciparum Malaria in Gabon

ABSTRACT Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within ≤72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.

Rivalry between afterimages and real images: The influence of the percept and the eye

In binocular rivalry, the conscious percept alternates stochastically between two images shown to the two eyes. Both suppressed and dominant images form afterimages (AIs) whose strength depends on the perceptual state during induction. Counterintuitively, when these two AIs rival, the AI of the previously suppressed percept gains initial dominance, even when it is weaker. Here, we examined rivalry between afterimages, between real images, and between both to examine eye-based and binocular contributions to this effect. In all experiments, we found that for both AIs and real images, the suppressed percept consistently gained initial dominance following a long suppression period. Dominance reversals failed to occur following short suppression periods and depended on an abrupt change (removal) of the stimulus. With real images, results were replicated also when eye channels were exchanged during the abrupt change. The initial dominance of the weaker, previously suppressed percept is thus not due to its weaker contrast, to it being an afterimage, or to monocular adaptation effects as previously suggested. Instead, it is due to binocular, higher level effects that favor a perceptual switch after prolonged dominance. We discuss a plausible neural account for these findings in terms of neural interactions between binocular and eye-related stages.

Knowing with Which Eye We See: Utrocular Discrimination and Eye-Specific Signals in Human Visual Cortex

Neurophysiological and behavioral reports converge to suggest that monocular neurons in the primary visual cortex are biased toward low spatial frequencies, while binocular neurons favor high spatial frequencies. Here we tested this hypothesis with functional magnetic resonance imaging (fMRI). Human participants viewed flickering gratings at one of two spatial frequencies presented to either the left or the right eye, and judged which of the two eyes was being stimulated (utrocular discrimination). Using multivoxel pattern analysis we found that local spatial patterns of signals in primary visual cortex (V1) allowed successful decoding of the eye-of-origin. Decoding was above chance for low but not high spatial frequencies, confirming the presence of a bias reported by animal studies in human visual cortex. Behaviorally, we found that reliable judgment of the eye-of-origin did not depend on spatial frequency. We further analyzed the mean response in visual cortex to our stimuli and revealed a weak difference between left and right eye stimulation. Our results are thus consistent with the interpretation that participants use overall levels of neural activity in visual cortex, perhaps arising due to local luminance differences, to judge the eye-of-origin. Taken together, we show that it is possible to decode eye-specific voxel pattern information in visual cortex but, at least in healthy participants with normal binocular vision, these patterns are unrelated to awareness of which eye is being stimulated.

Coding of Melodic Gestalt in Human Auditory Cortex

The perception of a melody is invariant to the absolute properties of its constituting notes, but depends on the relation between them—the melodys relative pitch profile. In fact, a melodys “Gestalt” is recognized regardless of the instrument or key used to play it. Pitch processing in general is assumed to occur at the level of the auditory cortex. However, it is unknown whether early auditory regions are able to encode pitch sequences integrated over time (i.e., melodies) and whether the resulting representations are invariant to specific keys. Here, we presented participants different melodies composed of the same 4 harmonic pitches during functional magnetic resonance imaging recordings. Additionally, we played the same melodies transposed in different keys and on different instruments. We found that melodies were invariantly represented by their blood oxygen level–dependent activation patterns in primary and secondary auditory cortices across instruments, and also across keys. Our findings extend common hierarchical models of auditory processing by showing that melodies are encoded independent of absolute pitch and based on their relative pitch profile as early as the primary auditory cortex.

Integration of visual and non-visual self-motion cues during voluntary head movements in the human brain

&NA; Our phenomenological experience of the stable world is maintained by continuous integration of visual self‐motion with extra‐retinal signals. However, due to conventional constraints of fMRI acquisition in humans, neural responses to visuo‐vestibular integration have only been studied using artificial stimuli, in the absence of voluntary head‐motion. We here circumvented these limitations and let participants to move their heads during scanning. The slow dynamics of the BOLD signal allowed us to acquire neural signal related to head motion after the observers head was stabilized by inflatable aircushions. Visual stimuli were presented on head‐fixed display goggles and updated in real time as a function of head‐motion that was tracked using an external camera. Two conditions simulated forward translation of the participant. During physical head rotation, the congruent condition simulated a stable world, whereas the incongruent condition added arbitrary lateral motion. Importantly, both conditions were precisely matched in visual properties and head‐rotation. By comparing congruent with incongruent conditions we found evidence consistent with the multi‐modal integration of visual cues with head motion into a coherent “stable world” percept in the parietal operculum and in an anterior part of parieto‐insular cortex (aPIC). In the visual motion network, human regions MST, a dorsal part of VIP, the cingulate sulcus visual area (CSv) and a region in precuneus (Pc) showed differential responses to the same contrast. The results demonstrate for the first time neural multimodal interactions between precisely matched congruent versus incongruent visual and non‐visual cues during physical head‐movement in the human brain. The methodological approach opens the path to a new class of fMRI studies with unprecedented temporal and spatial control over visuo‐vestibular stimulation. HighlightsFirst fMRI study integrating voluntary head motion with visual selfmotion.BOLD dynamics allowed to acquire neural responses to head motion after offset.Evidence for multi‐modal integration in insular and visual motion regions.Allows future fMRI with high spatio‐temporal control over vestibular stimulation.

Visual high-level regions respond to high-level stimulus content in the absence of low-level confounds

High-level regions of the ventral stream exhibit strong category selectivity to stimuli such as faces, houses, or objects. However, recent studies suggest that at least part of this selectivity stems from low-level differences inherent to images of the different categories. For example, visual outdoor and indoor scenes as well as houses differ in spatial frequency, rectilinearity and obliqueness when compared to face or object images. Correspondingly, scene responsive para-hippocampal place area (PPA) showed strong preference to low-level properties of visual scenes also in the absence of high-level scene content. This raises the question whether all high-level responses in PPA, the fusiform face area (FFA), or the object-responsive lateral occipital compex (LOC) may actually be explained by systematic differences in low-level features. In the present study we contrasted two classes of simple stimuli consisting of ten rectangles each. While both were matched in visual low-level features only one class of rectangle arrangements gave rise to a percept compatible with a high-level 3D layout such as a scene or an object. We found that areas PPA, transverse occipital sulcus (TOS, also referred to as occipital place area, OPA), as well as FFA and LOC showed robust responses to the visual scene class compared to the low-level matched control. Our results suggest that visual category responsive regions are not purely driven by low-level visual features but also by the high-level perceptual stimulus interpretation.

Motion parallax links visual motion areas and scene regions

When we move, the retinal velocities of objects in our surrounding differ according to their relative distances and give rise to a powerful three-dimensional visual cue referred to as motion parallax. Motion parallax allows us to infer our surroundings 3D structure as well as self-motion based on 2D retinal information. However, the neural substrates mediating the link between visual motion and scene processing are largely unexplored. We used fMRI in human observers to study motion parallax by means of an ecologically relevant yet highly controlled stimulus that mimicked the observers lateral motion past a depth-layered scene. We found parallax selective responses in parietal regions IPS3 and IPS4, and in a region lateral to scene selective occipital place area (OPA). The traditionally defined scene responsive regions OPA, the para-hippocampal place area (PPA) and the retrosplenial cortex (RSC) did not respond to parallax. During parallax processing, the occipital parallax selective region entertained highly specific functional connectivity with IPS3 and with scene selective PPA. These results establish a network linking dorsal motion and ventral scene processing regions specifically during parallax processing, which may underlie the brains ability to derive 3D scene information from motion parallax.

Real-motion signals in human early visual cortex

&NA; Eye movements induce visual motion that can complicate the stable perception of the world. The visual system compensates for such self‐induced visual motion by integrating visual input with efference copies of eye movement commands. This mechanism is central as it does not only support perceptual stability but also mediates reliable perception of world‐centered objective motion. In humans, it remains elusive whether visual motion responses in early retinotopic cortex are driven by objective motion or by retinal motion associated with it. To address this question, we used fMRI to examine functional responses of sixteen visual areas to combinations of planar objective motion and pursuit eye movements. Observers were exposed to objective motion that was faster, matched or slower relative to pursuit, allowing us to compare conditions that differed in objective motion velocity while retinal motion and eye movement signals were matched. Our results show that not only higher level motion regions such as V3A and V6, but also early visual areas signaled the velocity of objective motion, hence the product of integrating retinal with non‐retinal signals. These results shed new light on mechanisms that mediate perceptual stability and real‐motion perception, and show that extra‐retinal signals related to pursuit eye movements influence processing in human early visual cortex. HighlightsWe quantified objective (world‐centered) motion responses in sixteen visual areas.Objective motion responses were present already in areas V1 and V2.Motion areas V3A and V6 had very strong real motion responses.Responses were also present in IPS0, IPS4 and in motion areas VIP, Pc, CSv.