Preterm infants show an atypical processing of the mother's voice.

To understand the consequences of prematurity on language perception, it is fundamental to determine how atypical early sensory experience affects brain development. At term equivalent age, ten preterm and ten full-term newborns underwent high-density EEG during mother or stranger speech presentation, in the forward or backward order. A general group effect terms > preterms is evident in the theta frequency band, in the left temporal area, with preterms showing significant activation for strangers' and terms for the mother's voice. A significant group contrast in the low and high theta in the right temporal regions indicates higher activations for the stranger's voice in preterms. Finally, only full terms presented a late gamma band increase for the maternal voice, indicating a more mature brain response. EEG time-frequency analysis demonstrate that preterm infants are selectively responsive to stranger voices in both temporal hemispheres, and that they lack selective brain responses to their mother's forward voice.

Deficient Novelty Detection and Encoding in Early Alzheimer's Disease: An ERP Study.

Patients with early Alzheimer's disease (AD) have difficulty in learning new information and in detecting novel stimuli. The underlying physiological mechanisms are not well known. We investigated the electrophysiological correlates of the early (< 400 ms), automatic phase of novelty detection and encoding in AD. We used high-density EEG Queryin patients with early AD and healthy age-matched controls who performed a continuous recognition task (CRT) involving new stimuli (New), thought to provoke novelty detection and encoding, which were then repeated up to 4 consecutive times to produce over-familiarity with the stimuli. Stimuli then reappeared after 9-15 intervening items (N-back) to be re-encoded. AD patients had substantial difficulty in detecting novel stimuli and recognizing repeated ones. Main evoked potential differences between repeated and new stimuli emerged at 180-260 ms: neural source estimations in controls revealed more extended MTL activation for N-back stimuli and anterior temporal lobe activations for New stimuli compared to highly familiar repetitions. In contrast, AD patients exhibited no activation differences between the three stimulus types. In direct comparison, healthy subjects had significantly stronger MTL activation in response to New and N-back stimuli than AD patients. These results point to abnormally weak early MTL activity as a correlate of deficient novelty detection and encoding in early AD.

Shedding light on excessive crying in babies.

BACKGROUND: Excessive and inconsolable crying behavior in otherwise healthy infants (a condition called infant colic (IC)) is very distressing to parents, may lead to maternal depression, and in extreme cases, may result in shaken baby syndrome. Despite the high prevalence of this condition (20% of healthy infants), the underlying neural mechanisms of IC are still unknown. METHODS: By employing the latest magnetic resonance imaging (MRI) techniques in newborns, we prospectively investigated whether newborns' early brain responses to a sensory stimulus (smell) is associated with a subsequent crying behavior. RESULTS: In our sample population of 21 healthy breastfed newborns, those who developed IC at 6 weeks exhibited brain activation and functional connectivity in primary and secondary olfactory brain areas that were distinct from those in babies that did not develop IC. Different activation in brain regions known to be involved in sensory integration was also observed in colicky babies. These responses measured shortly after birth were highly correlated with the mean crying time at 6 weeks of age. CONCLUSIONS: Our results offer novel insights into IC pathophysiology by demonstrating that, shortly after birth, the central nervous system of babies developing IC has already greater reactivity to sensory stimuli than that of their noncolicky peers. IMPACT: Shortly after birth, the central nervous system of colicky infants has a greater sensitivity to olfactory stimuli than that of their noncolicky peers. This early sensitivity explains as much as 48% of their subsequent crying behavior at 6 weeks of life. Brain activation patterns to olfactory stimuli in colicky infants include not only primary olfactory areas but also brain regions involved in pain processing, emotional valence attribution, and self-regulation. This study links earlier findings in fields as diverse as gastroenterology and behavioral psychology and has the potential of helping healthcare professionals to define strategies to advise families.

Neural Correlates of Voice Perception in Newborns and the Influence of Preterm Birth.

Maternal voice is a highly relevant stimulus for newborns. Adult voice processing occurs in specific brain regions. Voice-specific brain areas in newborns and the relevance of an early vocal exposure on these networks have not been defined. This study investigates voice perception in newborns and the impact of prematurity on the cerebral processes. Functional magnetic resonance imaging (fMRI) and high-density electroencephalography (EEG) were used to explore the brain responses to maternal and stranger female voices in full-term newborns and preterm infants at term-equivalent age (TEA). fMRI results and the EEG oddball paradigm showed enhanced processing for voices in preterms at TEA than in full-term infants. Preterm infants showed additional cortical regions involved in voice processing in fMRI and a late mismatch response for maternal voice, considered as a first trace of a recognition process based on memory representation. Full-term newborns showed increased cerebral activity to the stranger voice. Results from fMRI, oddball, and standard auditory EEG paradigms highlighted important change detection responses to novelty after birth. These findings suggest that the main components of the adult voice-processing networks emerge early in development. Moreover, an early postnatal exposure to voices in premature infants might enhance their capacity to process voices.

Music enhances structural maturation of emotional processing neural pathways in very preterm infants.

Prematurity disrupts brain maturation by exposing the developing brain to different noxious stimuli present in the neonatal intensive care unit (NICU) and depriving it from meaningful sensory inputs during a critical period of brain development, leading to later neurodevelopmental impairments. Musicotherapy in the NICU environment has been proposed to promote sensory stimulation, relevant for activity-dependent brain plasticity, but its impact on brain structural maturation is unknown. Neuroimaging studies have demonstrated that music listening triggers neural substrates implied in socio-emotional processing and, thus, it might influence networks formed early in development and known to be affected by prematurity. Using multi-modal MRI, we aimed to evaluate the impact of a specially composed music intervention during NICU stay on preterm infant's brain structure maturation. 30 preterm newborns (out of which 15 were exposed to music during NICU stay and 15 without music intervention) and 15 full-term newborns underwent an MRI examination at term-equivalent age, comprising diffusion tensor imaging (DTI), used to evaluate white matter maturation using both region-of-interest and seed-based tractography approaches, as well as a T2-weighted image, used to perform amygdala volumetric analysis. Overall, WM microstructural maturity measured through DTI metrics was reduced in preterm infants receiving the standard-of-care in comparison to full-term newborns, whereas preterm infants exposed to the music intervention demonstrated significantly improved white matter maturation in acoustic radiations, external capsule/claustrum/extreme capsule and uncinate fasciculus, as well as larger amygdala volumes, in comparison to preterm infants with standard-of-care. These results suggest a structural maturational effect of the proposed music intervention on premature infants' auditory and emotional processing neural pathways during a key period of brain development.

Early vocal contact and music in the NICU: new insights into preventive interventions.

It is now clearly established that the environment and the sensory stimuli, particularly during the perinatal period, have an impact on infant's development. During the last trimester of gestation, activity-dependent plasticity shapes the fetal brain, and prematurity has been shown to alter the typical developmental trajectories. In this delicate period, preventive interventions aiming at modulating these developmental trajectories through activity-inducing interventions are currently underway to be tested. The purpose of this review paper is to describe the potentialities of early vocal contact and music on the preterm infant's brain development, and their potential beneficial effect on early development. Scientific evidence supports a behavioral orientation of the newborn to organized sounds, such as those of voice and music, and recent neuroimaging studies further confirm full cerebral processing of music as multisensory stimuli. However, the impact of long-term effects of music exposure and early vocal contact on preterm infants' long-term neurodevelopment needs be further investigated. To conclude, it is necessary to establish the neuroscientific bases of the early perception and the long-term effects of music and early vocal contact on the premature newborns' development. Scientific projects are currently on the way to fill this gap in knowledge.

Absence of an early hippocampal encoding signal after medial temporal lesions: No consequence for the spacing effect.

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200-300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)-the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL-mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200-300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's.

fMRI-based Neuronal Response to New Odorants in the Newborn Brain.

The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

IMPORTANCE: Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. OBJECTIVE: To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. DESIGN, SETTING, AND PARTICIPANTS: A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. INTERVENTIONS: Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES: The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. RESULTS: At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). CONCLUSIONS AND RELEVANCE: In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00413946.

Anatomical and functional predictors of disorientation after first-ever brain damage.

BACKGROUND AND OBJECTIVES: Disorientation is a frequent consequence of acute brain injury or diffuse disorders, such as confusional states or dementia. Its anatomical correlates are debated. Impaired memory as its commonly assumed mechanism predicts that disorientation is associated with medial temporal damage. The alternative is that disorientation reflects defective orbitofrontal reality filtering (ORFi) - a specific failure to identify whether thoughts or memories refer to present reality or not. The latter is a function of the posterior orbitofrontal cortex and connected structures. This study examined the mechanisms and anatomical basis of disorientation in an unselected group of patients with first-ever subacute brain injury. METHODS: Participants hospitalized for neurorehabilitation were asked to participate in this observational cohort study if they had first-ever organic hemispheric brain dysfunction as evident in a localizable brain lesion or verbal amnesia (often without localizable brain damage). Orientation to time, place, situation and person was tested with a 20-items questionnaire. To identify the mechanisms of disorientation, we determined its correlations with executive tasks, verbal episodic memory, and ORFi in all patients. ORFi was examined with a continuous recognition task, which measures learning and item recognition in the first run, and ORFi as reflected in the increase of false positive responses in the second run (temporal context confusion). Lesions of patients having localizable brain damage were manually delineated and normalized before entering multivariate lesion-symptom-mapping (LSM) to determine anatomical predictors of orientation. RESULTS: Eighty-four patients (61.1 ± 14.4 years, 29 women) were included. Among measures of memory and executive functioning, a step-wise regression retained temporal context confusion (R = -0.71, p < 0.0001), item recognition (R = 0.67, p < 0.0001) and delayed free recall (R = 0.63, p < 0.0001) as significant predictors of orientation. LSM was possible in 67 participants; it revealed an association of disorientation with damage of the right OFC and the bilateral head of the caudate nucleus. CONCLUSION: Disorientation in non-confused, non-demented patients with first-ever brain damage is associated with impaired orbitofrontal reality filtering and memory dysfunction, but not with executive dysfunction. Its main anatomical determinant is damage to the orbitofrontal cortex and its subcortical relay, the head of the caudate.

Attentional modulation of early ERP components in response to faces: evidence from the attentional blink paradigm.

The attentional blink (AB) is a transient attentional deficit that occurs when two stimuli that must both be detected are presented within an interval of less than 500 ms. Event-related potential (ERP) investigations have suggested that the AB affects a specific component, the P3, which is suppressed when targets are blinked. In view of the link between the P3 and working memory, it has been suggested that the AB might be due to the inability of the blinked target to access working memory. Interestingly, it seems that faces, due to their saliency, might escape the AB effect when cross-category detection is required (i.e., when the targets are composed of faces versus other categories of stimuli). In the present study we investigated this phenomenon in an event-related potential (ERP) study using upright and inverted faces as targets. In a first task, the participants were asked to identify two successive targets, the first composed of geometric shapes and the second of upright or inverted faces. A second control task, identical to the first was also performed, in which only the second targets had to be identified in order to compare ERPs. ERPs and scalp topographies of physically identical sequences of events, differing only by the attentional involvement, were thus compared. Behavioural results showed that faces indeed escape the AB while inverted faces do not. However, the electrophysiological findings showed that when attention was engaged in a previous stimulus (at the shortest lag times), both upright and inverted faces showed a decreased amplitude in the 150-260 ms time period, in addition to a lower P3. At longer lags, when the AB was no longer observed, no ERP differences were found. Our data demonstrate that, although faces escape the attentional blink, previous attentional involvement occurs much earlier than described for other categories of stimuli. This suggests that faces are subjected to an early selection which might allow rapid re-allocation of attention to the stimulus if it is deemed meaningful.

Does mental rotation emulate motor processes? An electrophysiological study of objects and body parts.

Several arguments suggest that motor planning may share embodied neural mechanisms with mental rotation (MR). However, it is not well established whether this overlap occurs regardless of the type of stimulus that is manipulated, in particular manipulable or non-manipulable objects and body parts. We here used high-density electroencephalography (EEG) to examine the cognitive similarity between MR of objects that do not afford specific hand actions (chairs) and bodily stimuli (hands). Participants had identical response options for both types of stimuli, and they gave responses orally in order to prevent possible interference with motor imagery. MR of hands and chairs generated very similar behavioral responses, time-courses and neural sources of evoked-response potentials (ERPs). ERP segmentation analysis revealed distinct time windows during which differential effects of stimulus type and angular disparity were observed. An early period (90-160 ms) differentiated only between stimulus types, and was associated with occipito-temporal activity. A later period (290-330 ms) revealed strong effects of angular disparity, associated with electrical sources in the right angular gyrus and primary motor/somatosensory cortex. These data suggest that spatial transformation processes and motor planning are recruited simultaneously, supporting the involvement of motor emulation processes in MR.

Flexible adjustment of anticipations in human outcome processing.

To sense whether thoughts refer to current reality or not, a capacity called orbitofrontal reality filtering, depends on an orbitofrontal signal when anticipated outcomes fail to occur. Here, we explored the flexibility and precision of outcome processing in a deterministic reversal learning task. Healthy subjects decided which one of two colored squares hid a target stimulus. Brain activity was measured with high-density electroencephalography. Stimuli resembling, but not identical with, the target stimuli were initially processed like different stimuli from 210 to 250 ms, irrespective of behavioral relevance. From 250 ms on, they were processed according to behavioral relevance: If they required a subsequent switch, they were processed like different stimuli; if they had been declared potential targets, they were treated like true targets. Stimuli requiring a behavioral switch induced strong theta activity in orbitofrontal, ventromedial, and medial temporal regions. The study indicates flexible adaptation of anticipations but precise processing of outcomes, mainly determined by behavioral relevance.

Distinct outcome processing in deterministic and probabilistic reversal learning.

Anticipations that fail to happen are important drivers of behavioral adaptation. Their processing appears to depend on the context. In a deterministic environment, where a stimulus unequivocally predicts the outcome, processing of absent outcomes involves the posterior orbitofrontal cortex (OFC). Failure has been linked to reality confusion with confabulations and disorientation. In a probabilistic environment, absent outcomes appear to be processed by the anterior cingulate cortex (ACC) rather than the OFC. Failure has been associated with poor decision making and schizophrenia. These data suggest different mechanisms depending on the context. Here, healthy human subjects made two formally similar reversal learning tasks, but one with deterministic, the other with probabilistic instructions. Brain activity was monitored using high-density electroencephalography. We found that in the deterministic task, negative outcomes, which unequivocally call for a behavioral switch, induced a distinct frontal potential at 200-300 msec. Computational modeling indicated a strong association of evoked potentials with prediction error, surprise, and behavioral adaptation. In the probabilistic task, where behavioral adaptation follows the cumulated processing of outcomes, negative outcomes evoked potentials that were associated with prediction error and surprise, but had a weak link with subsequent behavior. Outcome processing in the probabilistic task induced stronger activation than the deterministic task of an extended network including the ACC, OFC and striatum at 300-400 msec. In both tasks, negative outcomes were processed differently from positive outcomes at 400-600 msec, possibly reflecting updating of the outcome record. We conclude that the brain disposes of at least two distinct systems processing outcomes with unequivocal or ambiguous behavioral significance. These systems differ along behavioral, clinical, electrophysiological and anatomical dimensions.

Rapid Sequential Implication of the Human Medial Temporal Lobe in Memory Encoding and Recognition.

The medial temporal lobe (MTL) is crucial for memory encoding and recognition. The time course of these processes is unknown. The present study juxtaposed encoding and recognition in a single paradigm. Twenty healthy subjects performed a continuous recognition task as brain activity was monitored with a high-density electroencephalography. The task presented New pictures thought to evoke encoding. The stimuli were then repeated up to 4 consecutive times to produce over-familiarity. These repeated stimuli served as "baseline" for comparison with the other stimuli. Stimuli later reappeared after 9-15 intervening items, presumably associated with new encoding and recognition. Encoding-related differences in evoked response potential amplitudes and in spatiotemporal analysis were observed at 145-300 ms, whereby source estimation indicated MTL and orbitofrontal activity from 145 to 205 ms. Recognition-related activity evoked by late repetitions occurred at 405-470 ms, implicating the MTL and neocortical structures. These findings indicate that encoding of information is initiated before it is recognized. The result helps to explain modifications of memories over time, including false memories, confabulation, and consolidation.

Effects of stereoscopic disparity on early ERP components during classification of three-dimensional objects.

This study investigates the effects of stereo disparity on the perception of three-dimensional (3D) object shape. We tested the hypothesis that stereo input modulates the brain activity related to perceptual analyses of 3D shape configuration during image classification. High-density (256-channel) electroencephalogram (EEG) was used to record the temporal dynamics of visual shape processing under conditions of two-dimensional (2D) and 3D visual presentation. On each trial, observers made image classification judgements ('Same'/'Different') to two briefly presented, multi-part, novel objects. On different-object trials, stimuli could either share volumetric parts but not the global 3D shape configuration and have different parts but the same global 3D shape configuration or differ on both aspects. Analyses using mass univariate contrasts showed that the earliest sensitivity to 2D versus 3D viewing appeared as a negative deflection over posterior locations on the N1 component between 160 and 220 ms post-stimulus onset. Subsequently, event-related potential (ERP) modulations during the N2 time window between 240 and 370 ms were linked to image classification. N2 activity reflected two distinct components - an early N2 (240-290 ms) and a late N2 (290-370 ms) - that showed different patterns of responses to 2D and 3D input and differential sensitivity to 3D object structure. The results revealed that stereo input modulates the neural correlates of 3D object shape. We suggest that this reflects differential perceptual processing of object shape under conditions of stereo or mono input. These findings challenge current theories that attribute no functional role for stereo input during 3D shape perception.

An electrophysiological investigation of attentional blink in schizophrenia: separating perceptual and attentional processes.

When two visual targets are presented in a rapid serial visual presentation (RSVP) paradigm, the ability to identify the second target is reduced when it is presented 200-500ms after the initial target. This phenomenon is referred to as the "attentional blink (AB)." Previous behavioral studies have reported aberrant AB in schizophrenia. The underlying cause, however, of the AB deficit in schizophrenia remains ambiguous. Individuals with schizophrenia consistently demonstrate impairments in early visual processing stages and later attentionally-mediated stages, yet the stage of processing that is contributing to patient-control differences on AB is unknown. The current study attempted to resolve this ambiguity by applying electrophysiological methodology to an RSVP paradigm with 70 clinically stable outpatients with schizophrenia and 63 healthy controls. The task was simplified to reduce task demands, and a suppression ratio was employed to control for possible differences between groups in the ability to identify a single stimulus within a visual stream. Early perceptual processing was assessed using the steady-state visual evoked potential (ssVEP), and attentional processing was assessed using the P300 event-related potential. Relative to the healthy controls, patients showed the expected behavioral AB deficits. These deficits coincided with reduced P300 amplitude: both performance and P300 reductions extended beyond the traditional AB window. Mean ssVEP amplitude did not differ between the groups, and the differences in P300 remained after controlling for ssVEP. These results suggest that the observed AB deficits were due to attentional, not perceptual, processing deficits.

Early ERP Modulation for Task-Irrelevant Subliminal Faces.

A number of investigations have reported that emotional faces can be processed subliminally, and that they give rise to specific patterns of brain activation in the absence of awareness. Recent event-related potential (ERP) studies have suggested that electrophysiological differences occur early in time (<200 ms) in response to backward-masked emotional faces. These findings have been taken as evidence of a rapid non-conscious pathway, which would allow threatening stimuli to be processed rapidly and subsequently allow appropriate avoidance action to be taken. However, for this to be the case, subliminal processing should arise even if the threatening stimulus is not attended. This point has in fact not yet been clearly established. In this ERP study, we investigated whether subliminal processing of fearful faces occurs outside the focus of attention. Fourteen healthy participants performed a line judgment task while fearful and non-fearful (happy or neutral) faces were presented both subliminally and supraliminally. ERPs were compared across the four experimental conditions (i.e., subliminal and supraliminal; fearful and non-fearful). The earliest differences between fearful and non-fearful faces appeared as an enhanced posterior negativity for the former at 170 ms (the N170 component) over right temporo-occipital electrodes. This difference was observed for both subliminal (p < 0.05) and supraliminal presentations (p < 0.01). Our results confirm that subliminal processing of fearful faces occurs early in the course of visual processing, and more importantly, that this arises even when the subject's attention is engaged in an incidental task.

When the brain remembers, but the patient doesn't: converging fMRI and EEG evidence for covert recognition in a case of prosopagnosia.

The role of the occipito-temporal cortex in visual awareness remains an open question and with respect to faces in particular, it is unclear to what extent the fusiform face area (FFA) may be involved in conscious identification. An answer may be gleaned from prosopagnosia, a disorder in which familiar faces are no longer recognized. This impairment has sometimes been reported to be associated with implicit processing of facial identity, although the neural substrates responsible for unconscious processing remain unknown. In this study, we addressed these issues by investigating the functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) responses to familiar and unfamiliar faces in a well-known prosopagnosic patient (P.S.). Our fMRI results show that faces known prior to the onset of prosopagnosia produce an increase in activation in the lateral fusiform gyrus encompassing the FFA, as well as the right middle frontal gyrus, when compared to unknown faces. This effect is not observed with photographs of celebrities dating after the onset of prosopagnosia. Furthermore, electrophysiological responses show that previously familiar faces differ from unfamiliar ones at around 550 msec. Since covert processing of familiarity is associated with activation in FFA, this structure does not appear to be sufficient to produce awareness of identity. Furthermore, the results support the view that FFA participates in face individuation.