Brittle cornea syndrome: recognition, molecular diagnosis and management.

Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.

Bihippocampal damage with emotional dysfunction: impaired auditory recognition of fear.

A right-handed man developed a sudden transient, amnestic syndrome associated with bilateral hemorrhage of the hippocampi, probably due to Urbach-Wiethe disease. In the 3rd month, despite significant hippocampal structural damage on imaging, only a milder degree of retrograde and anterograde amnesia persisted on detailed neuropsychological examination. On systematic testing of recognition of facial and vocal expression of emotion, we found an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger. Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces versus voices). This is consistent with the idea that there may be multiple emotion systems. The study of emotional perception in this unique case of bilateral involvement of hippocampus suggests that this structure may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions and from that of fear in facial expression. In regard of recent data suggesting that the amygdala is playing a role in the recognition of fear in the auditory as well as in the visual modality this could suggest that the hippocampus may be part of the auditory pathway of fear recognition.

Selective integration of auditory-visual looming cues by humans.

An object's motion relative to an observer can confer ethologically meaningful information. Approaching or looming stimuli can signal threats/collisions to be avoided or prey to be confronted, whereas receding stimuli can signal successful escape or failed pursuit. Using movement detection and subjective ratings, we investigated the multisensory integration of looming and receding auditory and visual information by humans. While prior research has demonstrated a perceptual bias for unisensory and more recently multisensory looming stimuli, none has investigated whether there is integration of looming signals between modalities. Our findings reveal selective integration of multisensory looming stimuli. Performance was significantly enhanced for looming stimuli over all other multisensory conditions. Contrasts with static multisensory conditions indicate that only multisensory looming stimuli resulted in facilitation beyond that induced by the sheer presence of auditory-visual stimuli. Controlling for variation in physical energy replicated the advantage for multisensory looming stimuli. Finally, only looming stimuli exhibited a negative linear relationship between enhancement indices for detection speed and for subjective ratings. Maximal detection speed was attained when motion perception was already robust under unisensory conditions. The preferential integration of multisensory looming stimuli highlights that complex ethologically salient stimuli likely require synergistic cooperation between existing principles of multisensory integration. A new conceptualization of the neurophysiologic mechanisms mediating real-world multisensory perceptions and action is therefore supported.

Preperceptual and stimulus-selective enhancement of low-level human visual cortex excitability by sounds.

Evidence of multisensory interactions within low-level cortices and at early post-stimulus latencies has prompted a paradigm shift in conceptualizations of sensory organization. However, the mechanisms of these interactions and their link to behavior remain largely unknown. One behaviorally salient stimulus is a rapidly approaching (looming) object, which can indicate potential threats. Based on findings from humans and nonhuman primates suggesting there to be selective multisensory (auditory-visual) integration of looming signals, we tested whether looming sounds would selectively modulate the excitability of visual cortex. We combined transcranial magnetic stimulation (TMS) over the occipital pole and psychophysics for "neurometric" and psychometric assays of changes in low-level visual cortex excitability (i.e., phosphene induction) and perception, respectively. Across three experiments we show that structured looming sounds considerably enhance visual cortex excitability relative to other sound categories and white-noise controls. The time course of this effect showed that modulation of visual cortex excitability started to differ between looming and stationary sounds for sound portions of very short duration (80 ms) that were significantly below (by 35 ms) perceptual discrimination threshold. Visual perceptions are thus rapidly and efficiently boosted by sounds through early, preperceptual and stimulus-selective modulation of neuronal excitability within low-level visual cortex.

Where sound position influences sound object representations: a 7-T fMRI study.

Evidence from human and non-human primate studies supports a dual-pathway model of audition, with partially segregated cortical networks for sound recognition and sound localisation, referred to as the What and Where processing streams. In normal subjects, these two networks overlap partially on the supra-temporal plane, suggesting that some early-stage auditory areas are involved in processing of either auditory feature alone or of both. Using high-resolution 7-T fMRI we have investigated the influence of positional information on sound object representations by comparing activation patterns to environmental sounds lateralised to the right or left ear. While unilaterally presented sounds induced bilateral activation, small clusters in specific non-primary auditory areas were significantly more activated by contra-laterally presented stimuli. Comparison of these data with histologically identified non-primary auditory areas suggests that the coding of sound objects within early-stage auditory areas lateral and posterior to primary auditory cortex AI is modulated by the position of the sound, while that within anterior areas is not.

Alpha-band suppression in the visual word form area as a functional bottleneck to consciousness.

The current state of empirical investigations refers to consciousness as an all-or-none phenomenon. However, a recent theoretical account opens up this perspective by proposing a partial level (between nil and full) of conscious perception. In the well-studied case of single-word reading, short-lived exposure can trigger incomplete word-form recognition wherein letters fall short of forming a whole word in one's conscious perception thereby hindering word-meaning access and report. Hence, the processing from incomplete to complete word-form recognition straightforwardly mirrors a transition from partial to full-blown consciousness. We therefore hypothesized that this putative functional bottleneck to consciousness (i.e. the perceptual boundary between partial and full conscious perception) would emerge at a major key hub region for word-form recognition during reading, namely the left occipito-temporal junction. We applied a real-time staircase procedure and titrated subjective reports at the threshold between partial (letters) and full (whole word) conscious perception. This experimental approach allowed us to collect trials with identical physical stimulation, yet reflecting distinct perceptual experience levels. Oscillatory brain activity was monitored with magnetoencephalography and revealed that the transition from partial-to-full word-form perception was accompanied by alpha-band (7-11 Hz) power suppression in the posterior left occipito-temporal cortex. This modulation of rhythmic activity extended anteriorly towards the visual word form area (VWFA), a region whose selectivity for word-forms in perception is highly debated. The current findings provide electrophysiological evidence for a functional bottleneck to consciousness thereby empirically instantiating a recently proposed partial perspective on consciousness. Moreover, the findings provide an entirely new outlook on the functioning of the VWFA as a late bottleneck to full-blown conscious word-form perception.

Auditory localisation and recognition after left inferior collicular lesion: effects of work load on cortical activation patterns (fMRI study)

Evidence from neuropsychological and activation studies (Clarke et al., 2oo0, Maeder et al., 2000) suggests that sound recognitionand localisation are processed by two anatomically and functionally distinct cortical networks. We report here on a case of a patientthat had an interruption of auditory information and we show: i) the effects of this interruption on cortical auditory processing; ii)the effect of the workload on activation pattern.A 36 year old man suffered from a small left mesencephalic haemotrhage, due to cavernous angioma; the let% inferior colliculuswas resected in the surgical approach of the vascular malformation. In the acute stage, the patient complained of auditoryhallucinations and of auditory loss in right ear, while tonal audiometry was normal. At 12 months, auditory recognition, auditorylocalisation (assessed by lTD and IID cues) and auditory motion perception were normal (Clarke et al., 2000), while verbal dichoticlistening was deficient on the right side.Sound recognition and sound localisation activation patterns were investigated with fMRI, using a passive and an activeparadigm. In normal subjects, distinct cortical networks were involved in sound recognition and localisation, both in passive andactive paradigm (Maeder et al., 2OOOa, 2000b).Passive listening of environmental and spatial stimuli as compared to rest strongly activated right auditory cortex, but failed toactivate left primary auditory cortex. The specialised networks for sound recognition and localisation could not be visual&d onthe right and only minimally on the left convexity. A very different activation pattern was obtained in the active condition wherea motor response was required. Workload not only increased the activation of the right auditory cortex, but also allowed theactivation of the left primary auditory cortex. The specialised networks for sound recognition and localisation were almostcompletely present in both hemispheres.These results show that increasing the workload can i) help to recruit cortical region in the auditory deafferented hemisphere;and ii) lead to processing auditory information within specific cortical networks.References:Clarke et al. (2000). Neuropsychologia 38: 797-807.Mae.der et al. (2OOOa), Neuroimage 11: S52.Maeder et al. (2OOOb), Neuroimage 11: S33

Working memory load improves early stages of independent visual processing.

Increasing evidence suggests that working memory and perceptual processes are dynamically interrelated due to modulating activity in overlapping brain networks. However, the direct influence of working memory on the spatio-temporal brain dynamics of behaviorally relevant intervening information remains unclear. To investigate this issue, subjects performed a visual proximity grid perception task under three different visual-spatial working memory (VSWM) load conditions. VSWM load was manipulated by asking subjects to memorize the spatial locations of 6 or 3 disks. The grid was always presented between the encoding and recognition of the disk pattern. As a baseline condition, grid stimuli were presented without a VSWM context. VSWM load altered both perceptual performance and neural networks active during intervening grid encoding. Participants performed faster and more accurately on a challenging perceptual task under high VSWM load as compared to the low load and the baseline condition. Visual evoked potential (VEP) analyses identified changes in the configuration of the underlying sources in one particular period occurring 160-190 ms post-stimulus onset. Source analyses further showed an occipito-parietal down-regulation concurrent to the increased involvement of temporal and frontal resources in the high VSWM context. Together, these data suggest that cognitive control mechanisms supporting working memory may selectively enhance concurrent visual processing related to an independent goal. More broadly, our findings are in line with theoretical models implicating the engagement of frontal regions in synchronizing and optimizing mnemonic and perceptual resources towards multiple goals.