Chromatic Full-Field Stimulus Threshold and Pupillography as Functional Markers for Late-Stage, Early-Onset Retinitis Pigmentosa Caused by CRB1 Mutations.

PURPOSE: Mutations in the CRB1 gene cause early-onset retinal degeneration (EORD). Clinical disease progression markers, such as visual fields or electrophysiology, are not reliably measurable in most patients to follow the retinal function in patients with CRB1-mutations. METHODS: Ten patients (five females, five males; age 22-56 years) with EORD caused by CRB1 mutations were examined in a cross-sectional manner using best corrected visual acuity (BCVA), perimetry, full-field and multifocal electroretinography, full-field stimulus threshold (FST), and pupillography to red and blue light. Disease duration was defined as the difference between the age at the first symptoms to the age at examination in years. RESULTS: BCVA was quantifiable in six patients and ranged from light perception to 20/50. The visual field was measurable only in three patients who had the shortest disease duration. Full-field and multifocal electroretinography were not measurable in any patient. FST to blue and red light were measurable in all patients except the one with the longest disease duration; the thresholds ranged from -16.7 to 1.5 dB for red light and from -40.2 to 2.5 dB for blue light (0 dB = 0.01 cd.s/m2) and showed correlations with disease duration (r = 0.87 for blue, r = 0.65 for red, r = 0.8 for blue-red difference). The maximal relative pupil constriction amplitude (MRA) showed low or no correlations with disease duration (r = -0.55 for blue, r = -0.3 for red light); the blue-red difference in the post-illumination pupil responses (PIPR) showed no correlation with disease duration (r = -0.05). Compared to healthy eyes, the MRA to red and blue light was significantly decreased (P < 0.001) and the blue-red PIPR difference was significantly increased (P = 0.003). CONCLUSIONS: FST features a valid clinical marker in late-stage early-onset retinitis pigmentosa caused by CRB1 mutations correlating with disease duration. This indicates the potential as a progression marker of disease. The pupil responses to full-field chromatic stimuli show significant differences from the normal population: the remaining responses, although reduced, indicate a partially preserved inner retinal function despite severe photoreceptor dysfunction. TRANSLATIONAL RELEVANCE: The functional measurements presented in this study present a valid clinical progression marker in late-stage early onset retinitis pigmentosa caused by biallelic CRB1 mutations. Additionally, they can be used as outcome measures for safety and efficacy in clinical therapy trials.

Modulation of attentional networks by food-related disinhibition.

The risk of weight gain is especially related to disinhibition, which indicates the responsiveness to external food stimuli with associated disruptions in eating control. We adapted a food-related version of the attention network task and used functional magnetic resonance imaging to study the effects of disinhibition on attentional networks in 19 normal-weight participants. High disinhibition scores were associated with a rapid reorienting response to food pictures after invalid cueing and with an enhanced alerting effect of a warning cue signalizing the upcoming appearance of a food picture. Imaging data revealed activation of a right-lateralized ventral attention network during reorienting. The faster the reorienting and the higher the disinhibition score, the less activation of this network was observed. The alerting contrast showed activation in visual, temporo-parietal and anterior sites. These modulations of attentional networks by food-related disinhibition might be related to an attentional bias to energy dense and palatable food and increased intake of food in disinhibited individuals.

Magnetoencephalographic signatures of right prefrontal cortex involvement in response inhibition.

The prefrontal cortex has a pivotal role in top-down control of cognitive and sensory functions. In complex go-nogo tasks, the right dorsolateral prefrontal cortex is considered to be important for guiding the response inhibition. However, little is known about the temporal dynamics and neurophysiological nature of this activity. To address this issue, we recorded magnetoencephalographic brain activity in 20 women during a visual go-nogo task. The right dorsolateral prefrontal cortex showed an increase for the amplitude of the event-related fields and an increase in induced alpha frequency band activity for nogo in comparison to go trials. The peak of this prefrontal activity preceded the mean reaction time of around 360 ms for go trials, and thus supports the proposed role of right dorsolateral prefrontal cortex in gating the response inhibition and further suggests that right prefrontal alpha band activity might be involved in this gating. However, the results in right dorsolateral prefrontal cortex were similar for both successful and unsuccessful response inhibition. In these conditions, we instead observed pre- and poststimulus differences in alpha band activity in occipital and central areas. Thus, successful response inhibition seemed to additionally depend on prestimulus anticipatory alpha desynchronization in sensory areas as it was reduced prior to unsuccessful response inhibition. In conclusion, we suggest a role for functional inhibition by alpha synchronization not only in sensory, but also in prefrontal areas.

Auditory habituation to simple tones: reduced evidence for habituation in children compared to adults.

Habituation-the response decrement to repetitively presented stimulation-is a basic cognitive capability and suited to investigate development and integrity of the human brain. To evaluate the developmental process of auditory habituation, the current study used magnetoencephalography (MEG) to investigate auditory habituation, dishabituation and stimulus specificity in children and adults and compared the results between age groups. Twenty-nine children (M age = 9.69 years, SD ± 0.47) and 14 adults (M age = 29.29 years, SD ± 3.47) participated in the study and passively listened to a habituation paradigm consisting of 100 trains of tones which were composed of five 500 Hz tones, one 750 Hz tone (dishabituator) and another two 500 Hz tones, respectively while focusing their attention on a silent movie. Adults showed the expected habituation and stimulus specificity within-trains while no response decrement was found between trains. Sensory adaptation or fatigue as a source for response decrement in adults is unlikely due to the strong reaction to the dishabituator (stimulus specificity) and strong mismatch negativity (MMN) responses. However, in children neither habituation nor dishabituation or stimulus specificity could be found within-trains, response decrement was found across trains. It can be speculated that the differences between children and adults are linked to differences in stimulus processing due to attentional processes. This study shows developmental differences in task-related brain activation and discusses the possible influence of broader concepts such as attention, which should be taken into account when comparing performance in an identical task between age groups.

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS.

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm(2) chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s(-1)), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037° or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant's power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Neuronal correlates of reduced memory performance in overweight subjects.

There is growing evidence that excessive body weight correlates with impaired cognitive performance like executive function, attention and memory. In our study, we applied a visual working memory task to quantify associations between body weight and executive function. In total, 34 lean (BMI 22±2.1 kg/m(2)) and 34 obese (BMI 30.4±3.2 kg/m(2)) subjects were included. Magnetic brain activity and behavioral responses were recorded during a one-back visual memory task with food and non-food pictures, which were matched for color, size and complexity. Behavioral responses (reaction time and accuracy) were reduced in obese subjects independent of the stimulus category. Neuronal activity at the source level showed a positive correlation between the right dorsolateral prefrontal cortex (DLPFC) activity and BMI only for the food category. In addition, a negative correlation between BMI and neuronal activity was observed in the occipital area for both categories. Therefore we conclude that increased body weight is associated with reduced task performance and specific neuronal changes. This altered activity is probably related to executive function as well as encoding and retrieval of information.

The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects.

BACKGROUND: Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named "cerebral insulin resistance", is responsible for overeating and the development of obesity. METHODOLOGY/PRINCIPAL FINDINGS: To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. CONCLUSIONS/SIGNIFICANCE: We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a "cerebral insulin resistance" in obese subjects and might be relevant in the pathogenesis of obesity.

Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects.

Lean and obese subjects can exhibit differences in neuronal activity during resting state and tasks. Changes in hormonal status and their action related to increased body weight may be the determining factor for these differences. One prime candidate is insulin, which until recently was mainly related to its metabolic function for the transport and regulation of glucose in the periphery. However insulin also acts as an anorexic signal in the central nervous system contributing to the termination of food intake in the postprandial state. In our study, we examined with whole-head magnetoencephalography the effect of intranasal insulin on the dynamics of the resting state network in a placebo controlled study. Weighted clustering coefficient C, which describes local interconnectedness, and weighted path length L, a measure of global interconnectedness, were computed. These parameters showed high intraindividual reliability. However, no difference for the network dynamics was found between lean and obese subjects in the basal state. The application of insulin led to subject specific changes and we found a statistically significant positive correlation between the insulin induced change in path length in the theta band (4-8 Hz) and body mass index. The change in pathway length after insulin administration indicates a strong insulin modulation on global communication efficiency, which is probably related to the signaling between different regions involved in satiation and homeostatic control.

The temporal sequence of magnetic brain activity for food categorization and memorization--an exploratory study.

The importance of food stimuli for all living organisms is defined by their relevance for survival. Therefore, visual processing of food stimuli is influenced by many factors, such as cultural and societal background. In this magnetoencephalography (MEG) study, we examined the categorization and memorization of visual food and non-food stimuli in lean subjects, using a one-back working memory task. We found an increase in neural activity in several different regions of the brain elicited by food stimuli in comparison to non-food stimuli. The first observed significant difference was found in low-level visual areas as early as 120 ms after stimulus onset. The stimulus category of the previous picture did not influence this effect. However, preceding stimuli modulated behavioral measures (reaction time and accuracy of responses) and later components of the evoked responses around 350 ms. The evoked magnetic field of this late component showed a significant increase inactivity in the temporal cortex for food versus non-food objects. This late component exhibited a significant correlation with the reaction time. The difference of category-specific effects in the early components and the behavioral modulation of late components could be useful for further investigations of the cortical activity in response to food stimuli, e.g. in subjects with eating disorders or obesity.