Residual fMRI sensitivity for identity changes in acquired prosopagnosia.

While a network of cortical regions contribute to face processing, the lesions in acquired prosopagnosia are highly variable, and likely result in different combinations of spared and affected regions of this network. To assess the residual functional sensitivities of spared regions in prosopagnosia, we designed a rapid event-related functional magnetic resonance imaging (fMRI) experiment that included pairs of faces with same or different identities and same or different expressions. By measuring the release from adaptation to these facial changes we determined the residual sensitivity of face-selective regions-of-interest. We tested three patients with acquired prosopagnosia, and all three of these patients demonstrated residual sensitivity for facial identity changes in surviving fusiform and occipital face areas of either the right or left hemisphere, but not in the right posterior superior temporal sulcus. The patients also showed some residual capabilities for facial discrimination with normal performance on the Benton Facial Recognition Test, but impaired performance on more complex tasks of facial discrimination. We conclude that fMRI can demonstrate residual processing of facial identity in acquired prosopagnosia, that this adaptation can occur in the same structures that show similar processing in healthy subjects, and further, that this adaptation may be related to behavioral indices of face perception.

Evaluation of a short-form of the Berg Card Sorting Test.

The Psychology Experimental Building Language http://pebl.sourceforge.net/ Berg Card Sorting Test is an open-source neurobehavioral test. Participants (N = 207, ages 6 to 74) completed the Berg Card Sorting Test. Performance on the first 64 trials were isolated and compared to that on the full-length (128 trials) test. Strong correlations between the short and long forms (total errors: r = .87, perseverative response: r = .83, perseverative errors r = .77, categories completed r = .86) support the Berg Card Sorting Test-64 as an abbreviated alternative for the full-length executive function test.

Perceptual and anatomic patterns of selective deficits in facial identity and expression processing.

Whether a single perceptual process or separate and possibly independent processes support facial identity and expression recognition is unclear. We used a morphed-face discrimination test to examine sensitivity to facial expression and identity information in patients with occipital or temporal lobe damage, and structural and functional MRI to correlate behavioral deficits with damage to the core regions of the face-processing network. We found selective impairments of identity perception in two patients with right inferotemporal lesions and two prosopagnosic patients with damage limited to the anterior temporal lobes. Of these four patients one exhibited damage to the right fusiform and occipital face areas, while the remaining three showed sparing of these regions. Thus impaired identity perception can occur with damage not only to the fusiform and occipital face areas, but also to other medial occipitotemporal structures that likely form part of a face recognition network. Impaired expression perception was seen in the fifth patient with damage affecting the face-related portion of the posterior superior temporal sulcus. This subject also had difficulty in discriminating identity when irrelevant variations in expression needed to be discounted. These neuropsychological and neuroimaging data provide evidence to complement models which address the separation of expression and identity perception within the face-processing network.

The anatomic basis of the right face-selective N170 IN acquired prosopagnosia: a combined ERP/fMRI study.

The N170 waveform is larger over posterior temporal cortex when healthy subjects view faces than when they view other objects. Source analyses have produced mixed results regarding whether this effect originates in the fusiform face area (FFA), lateral occipital cortex, or superior temporal sulcus (STS), components of the core face network. In a complementary approach, we assessed the face-selectivity of the right N170 in five patients with acquired prosopagnosia, who also underwent structural and functional magnetic resonance imaging. We used a non-parametric bootstrap procedure to perform single-subject analyses, which reliably confirmed N170 face-selectivity in each of 10 control subjects. Anterior temporal lesions that spared the core face network did not affect the face-selectivity of the N170. A face-selective N170 was also present in another subject who had lost only the right FFA. However, face-selectivity was absent in two patients with lesions that eliminated the occipital face area (OFA) and FFA, sparing only the STS. Thus while the right FFA is not necessary for the face-selectivity of the N170, neither is the STS sufficient. We conclude that the face-selective N170 in prosopagnosia requires residual function of at least two components of the core face-processing network.

A case of persistent visual hallucinations of faces following LSD abuse: a functional Magnetic Resonance Imaging study.

In this study, we report the case of a patient experiencing hallucinations of faces that could be reliably precipitated by looking at trees. Using functional Magnetic Resonance Imaging (fMRI), we found that face hallucinations were associated with increased and decreased neural activity in a number of cortical regions. Within the same fusiform face area, however, we found significant decreased and increased neural activity according to whether the patient was experiencing hallucinations or veridical perception of faces, respectively. These findings may indicate key differences in how hallucinatory and veridical perceptions lead to the same phenomenological experience of seeing faces.

Encoding in the visual word form area: an fMRI adaptation study of words versus handwriting.

Written texts are not just words but complex multidimensional stimuli, including aspects such as case, font, and handwriting style, for example. Neuropsychological reports suggest that left fusiform lesions can impair the reading of text for word (lexical) content, being associated with alexia, whereas right-sided lesions may impair handwriting recognition. We used fMRI adaptation in 13 healthy participants to determine if repetition-suppression occurred for words but not handwriting in the left visual word form area (VWFA) and the reverse in the right fusiform gyrus. Contrary to these expectations, we found adaptation for handwriting but not for words in both the left VWFA and the right VWFA homologue. A trend to adaptation for words but not handwriting was seen only in the left middle temporal gyrus. An analysis of anterior and posterior subdivisions of the left VWFA also failed to show any adaptation for words. We conclude that the right and the left fusiform gyri show similar patterns of adaptation for handwriting, consistent with a predominantly perceptual contribution to text processing.

The correlates of subjective perception of identity and expression in the face network: an fMRI adaptation study.

The recognition of facial identity and expression are distinct tasks, with current models hypothesizing anatomic segregation of processing within a face-processing network. Using fMRI adaptation and a region-of-interest approach, we assessed how the perception of identity and expression changes in morphed stimuli affected the signal within this network, by contrasting (a) changes that crossed categorical boundaries of identity or expression with those that did not, and (b) changes that subjects perceived as causing identity or expression to change, versus changes that they perceived as not affecting the category of identity or expression. The occipital face area (OFA) was sensitive to any structural change in a face, whether it was identity or expression, but its signal did not correlate with whether subjects perceived a change or not. Both the fusiform face area (FFA) and the posterior superior temporal sulcus (pSTS) showed release from adaptation when subjects perceived a change in either identity or expression, although in the pSTS this effect only occurred when subjects were explicitly attending to expression. The middle superior temporal sulcus (mSTS) showed release from adaptation for expression only, and the precuneus for identity only. The data support models where the OFA is involved in the early perception of facial structure. However, evidence for a functional overlap in the FFA and pSTS, with both identity and expression signals in both areas, argues against a complete independence of identity and expression processing in these regions of the core face-processing network.

Developmental topographical disorientation: case one.

Topographical disorientation is the inability to orient within the environment, usually acquired from lesions to different cerebral regions participating in the attentional, perceptual or memory functions involved during navigation. We present the first case of a patient with topographical disorientation in the absence of any structural lesion and with intact sensory and intellectual function. Experimental tests in both real and virtual environments revealed a selective impairment in forming a mental representation of the environment, namely a cognitive map. Consistent with the patient's behavioural findings, a functional magnetic resonance imaging (fMRI) study showed lack of activation in the hippocampal complex and the retrosplenial cortex while forming a cognitive map of the environment. Although the lack of neural activity results in a negative finding that generally has low interpretative value, in this specific case our findings may provide useful information. First, in a group of healthy control subjects performing the same task, activity within the hippocampal complex and retrosplenial cortex were detected in each individual participant. Second, we found that within the same regions (showing lack of neural activity while forming a cognitive map of the environment) increased neural activity was detected while the patient was performing a different navigation task. This case is the first evidence reported in the literature showing that topographical disorientation may occur as a developmental defect causing a lifelong disorder affecting daily activities.

Defining the face processing network: optimization of the functional localizer in fMRI.

Functional localizers that contrast brain signal when viewing faces versus objects are commonly used in functional magnetic resonance imaging studies of face processing. However, current protocols do not reliably show all regions of the core system for face processing in all subjects when conservative statistical thresholds are used, which is problematic in the study of single subjects. Furthermore, arbitrary variations in the applied thresholds are associated with inconsistent estimates of the size of face-selective regions-of-interest (ROIs). We hypothesized that the use of more natural dynamic facial images in localizers might increase the likelihood of identifying face-selective ROIs in individual subjects, and we also investigated the use of a method to derive the statistically optimal ROI cluster size independent of thresholds. We found that dynamic facial stimuli were more effective than static stimuli, identifying 98% (versus 72% for static) of ROIs in the core face processing system and 69% (versus 39% for static) of ROIs in the extended face processing system. We then determined for each core face processing ROI, the cluster size associated with maximum statistical face-selectivity, which on average was approximately 50 mm(3) for the fusiform face area, the occipital face area, and the posterior superior temporal sulcus. We suggest that the combination of (a) more robust face-related activity induced by a dynamic face localizer and (b) a cluster-size determination based on maximum face-selectivity increases both the sensitivity and the specificity of the characterization of face-related ROIs in individual subjects.

Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

Disconnection in prosopagnosia and face processing.

Face perception is a function with significant complexity, reflected in cognitive models that propose a hierarchy of parallel and serial processing stages. Current neuroimaging data also show that face perception involves a core processing network of cortical modules, which are likely specialized for different functions involved in face processing. The core face processing network is further linked to an extended face processing network which is not solely involved in the perception of faces, but rather contains modules mediating the processing of semantic, biographic and emotional information about people. The segregation of these processes within discrete anatomic regions creates the potential for disconnection between regions to generate neuropsychological deficits involving faces. In this review we consider the types of disconnection possible both within the core face processing system and between the core and extended systems, the pattern of deficits that would be considered as evidence of such disconnections, the potential anatomy of lesions that would create them, and whether any cases exist that meet these criteria.

It doesn't matter how you feel. The facial identity aftereffect is invariant to changes in facial expression.

Previous studies have shown that facial expression aftereffects are modulated by the identity of the adapting face, suggesting both identity-dependent and identity-independent representations of facial expression. In this study, we asked whether facial identity aftereffects were similarly modulated by expression. In Experiment 1, the congruency of expression between adapting and test faces did not affect the identity aftereffect for novel faces, suggesting that the neural representations activated by novel identities are independent of expression. In Experiment 2, we examined whether expression dependency might be found with more familiar faces but still did not find any modulation of identity aftereffects by the congruency of expression. In Experiment 3, we measured the similarity between faces used to probe expression and identity adaptation, using both an ideal observer and human subjects, to determine if the discrepancy between the results of these two studies is related to greater similarity between faces from the same person with different expressions than between faces of different people with the same expression. However, the contrast thresholds required to discriminate between faces of differing expression were similar to those for faces with differing identity. We conclude that, in contrast to the significant identity-dependent component seen in representations of expression, representations of facial identity are independent of variations in expression.

Detection of unexpected events during spatial navigation in humans: bottom-up attentional system and neural mechanisms.

Navigation is a complex cognitive ability requiring the processing and integration of several different types of information extracted from the environment. While navigating, however, an unexpected event may suddenly occur, which individuals are required to detect promptly in order to apply an appropriate behavioural response. The alerting mechanism that is integral to the detection of unexpected events is referred to as the bottom-up attentional system. Using event-related functional magnetic resonance imaging, we investigated the neural basis of bottom-up detection of unexpected events while individuals moved within a virtual environment. We identified activation within a right fronto-temporo-parietal network in response to unexpected events while navigating in this virtual environment. Furthermore, when an unexpected event requires an adjusted behavioural response, a region of the right ventrolateral pre-frontal cortex (areas 45 and 47/12) is selectively activated. Our data replicate earlier findings on the neural mechanisms underlying visual attention and extend these findings to the more complex real-life ability of spatial navigation, thereby suggesting that these neural mechanisms subserve the bottom-up attentional systems that are crucial for effective locomotion in real surroundings.

Navigational skills correlate with hippocampal fractional anisotropy in humans.

Individuals vary widely in their ability to orient within the environment. We used diffusion tensor imaging to investigate whether this ability, as measured by navigational performance in a virtual environment, correlates with the anatomic structural properties of the hippocampus, i.e., fractional anisotropy. We found that individuals with high fractional anisotropy in the right hippocampus are (a) faster in forming a cognitive map of the environment, and (b) more efficient in using this map for the purpose of orientation, than individuals with low fractional anisotropy. These results are consistent with the role of the hippocampus in navigation, and suggest that its microstructural properties may contribute to the intersubject variability observed in spatial orientation.

Factors contributing to the adaptation aftereffects of facial expression.

Previous studies have demonstrated the existence of adaptation aftereffects for facial expressions. Here we investigated which aspects of facial stimuli contribute to these aftereffects. In Experiment 1, we examined the role of local adaptation to image elements such as curvature, shape and orientation, independent of expression, by using hybrid faces constructed from either the same or opposing expressions. While hybrid faces made with consistent expressions generated aftereffects as large as those with normal faces, there were no aftereffects from hybrid faces made from different expressions, despite the fact that these contained the same local image elements. In Experiment 2, we examined the role of facial features independent of the normal face configuration by contrasting adaptation with whole faces to adaptation with scrambled faces. We found that scrambled faces also generated significant aftereffects, indicating that expressive features without a normal facial configuration could generate expression aftereffects. In Experiment 3, we examined the role of facial configuration by using schematic faces made from line elements that in isolation do not carry expression-related information (e.g. curved segments and straight lines) but that convey an expression when arranged in a normal facial configuration. We obtained a significant aftereffect for facial configurations but not scrambled configurations of these line elements. We conclude that facial expression aftereffects are not due to local adaptation to image elements but due to high-level adaptation of neural representations that involve both facial features and facial configuration.

Tyrosine phosphorylation of the GluR2 subunit is required for long-term depression of synaptic efficacy in young animals in vivo.

The study of the intracellular mechanics that underlay changes in synaptic efficacy is a rapidly evolving field of research. It is currently believed that NMDA receptors play a significant role in the induction of synaptic plasticity, whereas AMPA receptors play a significant role in its expression. For AMPA receptors, it has been shown that tyrosine phosphorylation of the GluR2 carboxyl termini is required for the expression of long-term depression of synaptic efficacy (LTD) in vitro (Ahmadian et al. (2004) EMBO J 23:1040-1050). In the present study, we sought to determine whether similar mechanisms are involved in vivo, where different stimulation parameters are required for the induction of LTD. We initially used a paired-burst (PB) paradigm that reliably induces LTD in vivo. In these animals we were able to prevent the induction and expression of PB-LTD by administering a peptide (GluR-3Y) that acted as a competitive inhibitor of tyrosine phosphorylation. In a separate set of animals, we exposed animals to brief periods of stress (S) before using low-frequency stimuli to induce LTD (S-LTD). Again, GluR2-3Y blocked both the induction and expression of S-LTD. In contrast, an inert version of the peptide, with alanine replacing the three tyrosine residues, did not inhibit LTD induction. In addition, we demonstrated that GluR2-3Y did not affect the induction of long-term potentiation in vivo. These findings support the hypothesis that tyrosine phosphorylation and AMPA receptor endocytosis are necessary steps for the induction and maintenance of two forms of LTD in the CA1 region.

What is adapted in face adaptation? The neural representations of expression in the human visual system.

The neural representation of facial expression within the human visual system is not well defined. Using an adaptation paradigm, we examined aftereffects on expression perception produced by various stimuli. Adapting to a face, which was used to create morphs between two expressions, substantially biased expression perception within the morphed faces away from the adapting expression. This adaptation was not based on low-level image properties, as a different image of the same person displaying that expression produced equally robust aftereffects. Smaller but significant aftereffects were generated by images of different individuals, irrespective of gender. Non-face visual, auditory, or verbal representations of emotion did not generate significant aftereffects. These results suggest that adaptation affects at least two neural representations of expression: one specific to the individual (not the image), and one that represents expression across different facial identities. The identity-independent aftereffect suggests the existence of a 'visual semantic' for facial expression in the human visual system.

Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo.

It has recently been proposed that activation of the NR2A subunit results in Long-term potentiation (LTP) induction, whereas activation of the NR2B subunit results in long-term depression (LTD) induction. The present study undertakes to replicate these findings in vivo to determine if a role for specific subunits in synaptic plasticity can be shown in the intact brain. Field recordings were made from the CA1 subfield of the hippocampus using Schaffer collateral stimulation in anesthetized male Sprague-Dawley rats. Antagonists of the N-methyl-D-aspartate receptors NR2A and NR2B subunits were administered by either intraperitoneal (i.p.) or intrahippocampal (i.h.) injections to assess their involvement in LTP (100 Hz stimuli) and LTD (200 Paired-burst stimuli). i.h. injection of Ro25-6981 (100 microM) significantly attenuated hippocampal LTP expression and completely blocked LTD expression. When administered i.p., Ro25-6981 (6 mg/kg) again blocked LTD, but did not significantly diminish the expression of LTP. When NVP-AAM077 was administered i.h. (80 microM) both LTP and LTD were completely abolished. The administration of this compound i.p. (1.2 mg/kg) also significantly attenuated LTP, but did not affect LTD. These data suggest that both NR2A and NR2B subunits can play roles in LTP and LTD in the hippocampus in vivo.

Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male rats.

Prenatal ethanol exposure can lead to long-lasting impairments in the ability to process spatial information in rats, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation, a biological model of learning and memory processing. Conversely, we have recently shown that both spatial memory and long-term potentiation can be enhanced in animals that are given access to a running wheel in their home cage. In the present study, Sprague-Dawley rat dams were given one of three diets throughout gestation: (i) a liquid diet containing ethanol (35.5% ethanol-derived calories); (ii) a liquid diet, isocaloric to the ethanol diet, but with maltose-dextrin substituting for the ethanol derived calories and (iii) an ad libitum diet of standard rat chow. At weaning (28 days) animals were housed individually in either a standard rat cage, or a cage that contained a running wheel. Adult offspring were tested on a two trial version of the Morris water maze beginning at postnatal day 60, for five consecutive days. Following this, the capacity of the perforant path to dentate gyrus pathway to sustain long-term potentiation was examined in these animals using theta-patterned conditioning stimuli. Our results demonstrate that prenatal ethanol exposure can produce pronounced deficits in both spatial memory and long-term potentiation, but that allowing animal's access to voluntary exercise can attenuate these deficits to the point that those exposed to ethanol prenatally can no longer be differentiated from control animals. These findings indicate that voluntary exercise may have therapeutic benefits for individuals that have undergone prenatal ethanol exposure.

Prolonged cannabinoid treatment results in spatial working memory deficits and impaired long-term potentiation in the CA1 region of the hippocampus in vivo.

Adult male Long-Evans rats were administered the potent cannabinoid 1 receptor agonist HU-210 (100 microg/kg, i.p.) for 15 days continuously and their performance on a matching-to-place version of the Morris water maze was subsequently evaluated. Overall, experimental animals performed significantly worse initially on the reference memory component of this task, but their performance improved over 5 days until it was indistinguishable from that of control animals. Animals given HU-210 did not exhibit working memory impairments at short intertrial delays (30 s); however, significant impairments were observed in learning performance with longer intertrial delays (300 s). In vivo electrophysiological analyses revealed that long-term potentiation in the CA1 region of the hippocampus was significantly impaired following the administration of HU-210 for 15 days. These results indicate that long-term cannabinoid exposure can produce marked deficits in reference and working memory performance, and also impair hippocampal synaptic plasticity in vivo.