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Background

Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology which has been described in children as well as in adults with and without chromosomal aberrations. LVHT has been reported in association with various cardiac and extracardiac abnormalities like epilepsy and facial dysmorphism.

Case presentation

A unique combination of LVHT, atrial septal defect, pulmonary valve stenosis, aortic stenosis, epilepsy and minor facial anomalies is presented in a 5.5 years old girl. Microarray-based genomic hybridization (array-CGH) detected six previously not described copy number variants (CNVs) inherited from a clinically unaffected father and minimally affected mother, thus, most likely, not clinically significant but rare benign variants.

Conclusions

Despite this complex phenotype de novo microdeletions or microduplications were not detected by array CGH. Further investigations, such as whole exome sequencing, could reveal point mutations and small indels as the possible cause.

Background

The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.

Aim

We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.

Results

We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10–5).

Conclusion

Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Why do some faces appear more similar than others? Beyond structural factors, we speculate that similarity is governed by the organization of faces located in a multi-dimensional face space. To test this hypothesis, we morphed a typical face with an atypical face. If similarity judgments are guided purely by their physical properties, the morph should be perceived to be equally similar to its typical parent as its atypical parent. However, contrary to the structural prediction, our results showed that the morph face was perceived to be more similar to the atypical face than the typical face. Our empirical studies show that the atypicality bias is not limited to faces, but extends to other object categories (birds) whose members share common shape properties. We also demonstrate atypicality bias is malleable and can change subject to category learning and experience. Collectively, the empirical evidence indicates that perceptions of face and object similarity are affected by the distribution of stimuli in a face or object space. In this framework, atypical stimuli are located in a sparser region of the space where there is less competition for recognition and therefore, these representations capture a broader range of inputs. In contrast, typical stimuli are located in a denser region of category space where there is increased competition for recognition and hence, these representation draw a more restricted range of face inputs. These results suggest that the perceived likeness of an object is influenced by the organization of surrounding exemplars in the category space.

Background

According to the traditional two-stage model of face processing, the face-specific N170 event-related potential (ERP) is linked to structural encoding of face stimuli, whereas later ERP components are thought to reflect processing of facial affect. This view has recently been challenged by reports of N170 modulations by emotional facial expression. This study examines the time-course and topography of the influence of emotional expression on the N170 response to faces.

Methods

Dense-array ERPs were recorded in response to a set (n = 16) of fear and neutral faces. Stimuli were normalized on dimensions of shape, size and luminance contrast distribution. To minimize task effects related to facial or emotional processing, facial stimuli were irrelevant to a primary task of learning associative pairings between a subsequently presented visual character and a spoken word.

Results

N170 to faces showed a strong modulation by emotional facial expression. A split half analysis demonstrates that this effect was significant both early and late in the experiment and was therefore not associated with only the initial exposures of these stimuli, demonstrating a form of robustness against habituation. The effect of emotional modulation of the N170 to faces did not show significant interaction with the gender of the face stimulus, or hemisphere of recording sites. Subtracting the fear versus neutral topography provided a topography that itself was highly similar to the face N170.

Conclusion

The face N170 response can be influenced by emotional expressions contained within facial stimuli. The topography of this effect is consistent with the notion that fear stimuli exaggerates the N170 response itself. This finding stands in contrast to previous models suggesting that N170 processes linked to structural analysis of faces precede analysis of emotional expression, and instead may reflect early top-down modulation from neural systems involved in rapid emotional processing.

SUMMARY

We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase-dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the past half a decade and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to non-allelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of around 1% at 15q13.3, 16p13.11 and 15q11.2, sites that also confer susceptibility for intellectual disability, autism and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counselling. CNVs play a significant role in the susceptibility profile for epilepsies with complex genetics and their comorbidities both from the “hotspots” defined by segmental duplication and elsewhere in the genome where their location and size are often novel.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Decades of research have documented the specialization of fusiform gyrus (FG) for facial information processes. Recent theories indicate that FG activity is shaped by input from amygdala, but effective connectivity from amygdala to FG remains undocumented. In this fMRI study, 39 participants completed a face recognition task. 11 participants underwent the same experiment approximately four months later. Robust face-selective activation of FG, amygdala, and lateral occipital cortex were observed. Dynamic causal modeling and Bayesian Model Selection (BMS) were used to test the intrinsic connections between these structures, and their modulation by face perception. BMS results strongly favored a dynamic causal model with bidirectional, face-modulated amygdala-FG connections. However, the right hemisphere connections diminished at time 2, with the face modulation parameter no longer surviving Bonferroni correction. These findings suggest that amygdala strongly influences FG function during face perception, and that this influence is shaped by experience and stimulus salience.

Objective

Rare copy number variants (CNVs) – deletions and duplications – have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure, group of epilepsies, has not been performed.

Methods

We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused whole-genome oligonucleotide array.

Results

We found that 25/315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least half being clearly or likely pathogenic. We identified two patients with overlapping deletions at 7q21 and two patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and four patients harbored two rare CNVs. We screened two novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.

Interpretation

Our data highlight the significance of rare copy number variants in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders.

We form first impressions from faces despite warnings not to do so. Moreover, there is considerable agreement in our impressions, which carry significant social outcomes. Appearance matters because some facial qualities are so useful in guiding adaptive behavior that even a trace of those qualities can create an impression. Specifically, the qualities revealed by facial cues that characterize low fitness, babies, emotion, and identity are overgeneralized to people whose facial appearance resembles the unfit (anomalous face overgeneralization), babies (babyface overgeneralization), a particular emotion (emotion face overgeneralization), or a particular identity (familiar face overgeneralization). We review studies that support the overgeneralization hypotheses and recommend research that incorporates additional tenets of the ecological theory from which these hypotheses are derived: the contribution of dynamic and multi-modal stimulus information to face perception; bidirectional relationships between behavior and face perception; perceptual learning mechanisms and social goals that sensitize perceivers to particular information in faces.

Early deprivation in audition can have striking effects on the development of visual processing. Here we investigated whether early deafness induces changes in holistic/configural face processing. To this end, we compared the results of a group of early deaf participants to those of a group of hearing participants in an inversion-matching task (Experiment 1) and a composite face task (Experiment 2). We hypothesized that deaf individuals would show an enhanced inversion effect and/or an increased composite face effect compared to hearing controls in case of enhanced holistic/configural face processing. Conversely, these effects would be reduced if they rely more on facial features than hearing controls. As a result, we found that deaf individuals showed an increased inversion effect for faces, but not for non-face objects. They were also significantly slower than hearing controls to match inverted faces. However, the two populations did not differ regarding the overall size of their composite face effect. Altogether these results suggest that early deafness does not enhance or reduce the amount of holistic/configural processing devoted to faces but may increase the dependency on this mode of processing.

The organization of the bony face is complex, its morphology being influenced in part by the rest of the cranium. Characterizing the facial morphological variation and craniofacial covariation patterns in extant hominids is fundamental to the understanding of their evolutionary history. Numerous studies on hominid facial shape have proposed hypotheses concerning the relationship between the anterior facial shape, facial block orientation and basicranial flexion. In this study we test these hypotheses in a sample of adult specimens belonging to three extant hominid genera (Homo, Pan and Gorilla). Intraspecific variation and covariation patterns are analyzed using geometric morphometric methods and multivariate statistics, such as partial least squared on three-dimensional landmarks coordinates. Our results indicate significant intraspecific covariation between facial shape, facial block orientation and basicranial flexion. Hominids share similar characteristics in the relationship between anterior facial shape and facial block orientation. Modern humans exhibit a specific pattern in the covariation between anterior facial shape and basicranial flexion. This peculiar feature underscores the role of modern humans' highly-flexed basicranium in the overall integration of the cranium. Furthermore, our results are consistent with the hypothesis of a relationship between the reduction of the value of the cranial base angle and a downward rotation of the facial block in modern humans, and to a lesser extent in chimpanzees.

Background

Most of our social interactions involve perception of emotional information from the faces of other people. Furthermore, such emotional processes are thought to be aberrant in a range of clinical disorders, including psychosis and depression. However, the exact neurofunctional maps underlying emotional facial processing are not well defined.

Methods

Two independent researchers conducted separate comprehensive PubMed (1990 to May 2008) searches to find all functional magnetic resonance imaging (fMRI) studies using a variant of the emotional faces paradigm in healthy participants. The search terms were: “fMRI AND happy faces,” “fMRI AND sad faces,” “fMRI AND fearful faces,” “fMRI AND angry faces,” “fMRI AND disgusted faces” and “fMRI AND neutral faces.” We extracted spatial coordinates and inserted them in an electronic database. We performed activation likelihood estimation analysis for voxel-based meta-analyses.

Results

Of the originally identified studies, 105 met our inclusion criteria. The overall database consisted of 1785 brain coordinates that yielded an overall sample of 1600 healthy participants. Quantitative voxel-based meta-analysis of brain activation provided neurofunctional maps for 1) main effect of human faces; 2) main effect of emotional valence; and 3) modulatory effect of age, sex, explicit versus implicit processing and magnetic field strength. Processing of emotional faces was associated with increased activation in a number of visual, limbic, temporoparietal and prefrontal areas; the putamen; and the cerebellum. Happy, fearful and sad faces specifically activated the amygdala, whereas angry or disgusted faces had no effect on this brain region. Furthermore, amygdala sensitivity was greater for fearful than for happy or sad faces. Insular activation was selectively reported during processing of disgusted and angry faces. However, insular sensitivity was greater for disgusted than for angry faces. Conversely, neural response in the visual cortex and cerebellum was observable across all emotional conditions.

Limitations

Although the activation likelihood estimation approach is currently one of the most powerful and reliable meta-analytical methods in neuroimaging research, it is insensitive to effect sizes.

Conclusion

Our study has detailed neurofunctional maps to use as normative references in future fMRI studies of emotional facial processing in psychiatric populations. We found selective differences between neural networks underlying the basic emotions in limbic and insular brain regions.

Objective

Comparison of reporting of recent epileptic seizures by patients to a doctor and anonymously.

Design

Cross sectional study of patients with epilepsy by comparison of paired questionnaires.

Setting

Rural and urban general practices in Norfolk.

Participants

122 patients aged over 16 years and able to self complete a questionnaire who were recruited by 31 general practitioners when attending for review of their epilepsy.

Main outcome measure

The difference in reported occurrence of seizure to general practitioners and in a linked anonymous questionnaire.

Results

18 patients failed to report a seizure in the past year to their general practitioner (uncontrolled epilepsy). 40% (24/60) of people with epilepsy who anonymously reported a seizure in the past year held a driving licence, but only six revealed this to their general practitioner. The unemployment rate was 34%, substantially higher than the 9% in the general population. Measures of anxiety, depression, and stigmatisation were higher in patients with uncontrolled epilepsy.

Conclusions

A significant proportion of patients with epilepsy underreport their seizures. Recognition of underreporting is important if patients are to benefit from adequate and appropriate treatment. General practitioners' ability to treat epilepsy is hampered by their role in regulating the rights of epileptic patients to hold a driving licence or access certain occupations.

Key messagesPeople with epilepsy may be reluctant to report seizures to their general practitioners as epilepsy affects their eligibility for a driving licence and access to various employment and leisure activities In this study about a sixth of patients anonymously reported seizures in the past year which they had not revealed to their general practitioner40% of patients who anonymously reported a seizure in the past year held a driving licence, but only a quarter of these admitted this to their general practitionerPeople who had had seizures in the past year were significantly more depressed and felt more stigmatised than those who had not had a seizureUnderreporting of seizures has important consequences for treatment, and doctors need to put more effort into explaining this to patients

Objective

Various lines of evidence suggest that face shape may be a predisposing factor for nonsyndromic cleft lip with or without cleft palate (CL/P). In the present study, 3D surface imaging and statistical shape analysis were used to evaluate face shape differences between the unaffected (non-cleft) parents of individuals with CL/P and unrelated controls.

Methods

Sixteen facial landmarks were collected from 3D captures of 80 unaffected parents and 80 matched controls. Prior to analysis, each unaffected parent was assigned to a subgroup on the basis of prior family history (positive or negative). A geometric morphometric approach was utilized to scale and superimpose the landmark coordinate data (Procrustes analysis), test for omnibus group differences in face shape, and uncover specific modes of shape variation capable of discriminating unaffected parents from controls.

Results

Significant disparity in face shape was observed between unaffected parents and controls (p < 0.01). Notably, these changes were specific to parents with a positive family history of CL/P. Shape changes associated with CL/P predisposition included marked flattening of the facial profile (midface retrusion), reduced upper facial height, increased lower facial height and excess interorbital width. Additionally, a sex-specific pattern of parent-control difference was evident in the transverse dimensions of the nasolabial complex.

Conclusions

The faces of unaffected parents from multiplex cleft families display meaningful shape differences compared with the general population. Quantitative assessment of the facial phenotype in cleft families may enhance efforts to discover the root causes of CL/P.

Background: The human amygdala is implicated in the formation of emotional memories and the perception of emotional stimuli—particularly fear—across various modalities.

Objectives: To discern the extent to which these functions are related.

Methods: 28 patients who had anterior temporal lobectomy (13 left and 15 right) for intractable epilepsy were recruited. Structural magnetic resonance imaging showed that three of them had atrophy of their remaining amygdala. All participants were given tests of affect perception from facial and vocal expressions and of emotional memory, using a standard narrative test and a novel test of word recognition. The results were standardised against matched healthy controls.

Results: Performance on all emotion tasks in patients with unilateral lobectomy ranged from unimpaired to moderately impaired. Perception of emotions in faces and voices was (with exceptions) significantly positively correlated, indicating multimodal emotional processing. However, there was no correlation between the subjects' performance on tests of emotional memory and perception. Several subjects showed strong emotional memory enhancement but poor fear perception. Patients with bilateral amygdala damage had greater impairment, particularly on the narrative test of emotional memory, one showing superior fear recognition but absent memory enhancement.

Conclusions: Bilateral amygdala damage is particularly disruptive of emotional memory processes in comparison with unilateral temporal lobectomy. On a cognitive level, the pattern of results implies that perception of emotional expressions and emotional memory are supported by separate processing systems or streams.

The use of 3D surface imaging technology is becoming increasingly common in craniofacial clinics and research centers. Due to fast capture speeds and ease of use, 3D digital stereophotogrammetry is quickly becoming the preferred facial surface imaging modality. These systems can serve as an unparalleled tool for craniofacial surgeons, proving an objective digital archive of the patient's face without exposure to radiation. Acquiring consistent high-quality 3D facial captures requires planning and knowledge of the limitations of these devices. Currently, there are few resources available to help new users of this technology with the challenges they will inevitably confront. To address this deficit, this report will highlight a number of common issues that can interfere with the 3D capture process and offer practical solutions to optimize image quality.

Face perception remains one of the most intensively researched areas in psychology and allied disciplines, and there has been much debate regarding the early origins and experiential determinants of face processing. This article reviews studies, the majority of which have appeared in the past decade, that discuss possible mechanisms underlying face perception at birth and document the prominent role of experience in shaping infants’ face-processing abilities. In the first months of life, infants develop a preference for female and own-race faces and become better able to recognize and categorize own-race and own-species faces. This perceptual narrowing and shaping of the “face space” forms a foundation for later face expertise in childhood and adulthood and testifies to the remarkable plasticity of the developing visual system.

Background

Metamorphopsia includes a broad spectrum of visual perceptual distortions, such as alteration of perceived object size or, rarely, altered perception of faces, termed prosopometamorphopsia.

Case Report

This report describes a patient who complained of metamorphopsia restricted to the center of the face, particularly the lower part of the face (nose and mouth), following infarction of the right medial temporooccipital lobe that included the fusiform face area.

Conclusions

The fusiform face area is commonly believed to be a face-selective cortical region dedicated to the visual analysis of face stimuli. We speculate that any injury to this brain area could bring about prosopometamorphopsia involving whole or unilateral face perception, or very rarely, as in our case, distortion restricted to the central area of the face. Furthermore, there could be topographical correspondences between facial structures and the fusiform face area.

Research suggests that configural cues (second-order relations) play a major role in the representation and classification of face images; making faces a “special” class of objects, since object recognition seems to use different encoding mechanisms. It is less clear, however, how this representation emerges and whether this representation is also used in the recognition of facial expressions of emotion. In this paper, we show how configural cues emerge naturally from a classical analysis of shape in the recognition of anger and sadness. In particular our results suggest that at least two of the dimensions of the computational (cognitive) space of facial expressions of emotion correspond to pure configural changes. The first of these dimensions measures the distance between the eyebrows and the mouth, while the second is concerned with the height-width ratio of the face. Under this proposed model, becoming a face “expert” would mean to move from the generic shape representation to that based on configural cues. These results suggest that the recognition of facial expressions of emotion shares this expertise property with the other processes of face processing.

Objective

To report a case of temporal lobe epilepsy with clinical presentation of paroxysmal episodes of “tightness” over the right hemiface, and ictal crying, and review electroclinical localisation of this phenomenon.

Methods

Clinical semiology, neurophysiological localising tests, and epilepsy surgery outcome are reported in a subject presenting with paroxysmal right hemifacial movements and ictal crying. Pertinent past reports of somato‐motor signs and ictal crying in temporal lobe epilepsy are reviewed and the findings correlated with proposed human facial cortical representation.

Results

Simple partial seizures caused by temporal lobe epilepsy presented with right sided tonic facial movements and ictal crying. Intracranial EEG monitoring documented a left medial temporal onset of seizures that remained asymptomatic until they propagated to the left cingulate region. Anterior temporal lobectomy with resection of the amygdala and anterior hippocampus resulted in cessation of seizures.

Conclusions

This is a rare example of epileptic seizures of medial temporal onset presenting with isolated somato‐motor manifestations and ictal crying. Anatomical‐electrical‐clinical correlations with cortical regions controlling facial movements were highly suggestive that this case represents secondary activation of “emotional” motor cortex M3 and M4 (rostral and caudal cingulate motor cortex), giving rise to focal hemifacial movements and ictal crying.

Epilepsy is one of the most common neurological disorders, with a prevalence of 1% and lifetime incidence of 3%. There are numerous epilepsy syndromes, most of which are considered to be genetic epilepsies. Despite the discovery of more than 20 genes for epilepsy to date, much of the genetic contribution to epilepsy is not yet known. Copy number variants have been established as an important source of mutation in other complex brain disorders, including intellectual disability, autism and schizophrenia. Recent advances in technology now facilitate genome-wide searches for copy number variants and are beginning to be applied to epilepsy. Here, we discuss what is currently known about the contribution of copy number variants to epilepsy, and how that knowledge is redefining classification of clinical and genetic syndromes.

Epilepsy is a neurological disorder characterized by recurrent seizures which affects about 1% people worldwide. During the past decades, some mechanisms involved in ictogenesis (generation of seizures) have been identified and, to some extent, partially understood. However, regarding epileptogenesis (process by which a neuronal system becomes epileptic), underlying mechanisms remain elusive. This difficulty is mostly related to the fact that epileptogenesis can only be addressed using experimental models. In this study, we have analyzed the shape of a specific electrophysiological pattern, referred to as “epileptic spike”, encountered during the epileptogenesis process in an in vivo model of temporal lobe epilepsy (mouse, kainate). Results show that the features of these transient events (duration and amplitude) change as a function of time as the brain evolves towards the chronic epileptic state characterized by the appearance of spontaneous seizures. Using a detailed computational model of the hippocampus (CA1 sub-field), an interpretation of observed modifications is provided, in relationship with possible alterations that take place in underlying neuronal circuits.

Background

Many copy number variants (CNVs) are documented to be associated with neuropsychiatric disorders, including intellectual disability, autism, epilepsy, schizophrenia, and bipolar disorder. Chromosomal deletions of 1q21.1, 3q29, 15q13.3, 22q11.2, and NRXN1 and duplications of 15q11-q13 (maternal), 16p11, and 16p13.3 have the strongest association with schizophrenia. We hypothesized that cases with both schizophrenia and epilepsy would have a higher frequency of disease-associated CNVs and would represent an enriched sample for detection of other mutations associated with schizophrenia.

Methods

We used array comparative genomic hybridization (CGH) to analyze 235 individuals with both schizophrenia and epilepsy, 80 with bipolar disorder and epilepsy, and 191 controls.

Results

We detected 10 schizophrenia plus epilepsy cases in 235 (4.3%) with the above mentioned CNVs compared to 0 in 191 controls (p = 0.003). Other likely pathological findings in schizophrenia plus epilepsy cases included 1 deletion 16p13 and 1 duplication 7q11.23 for a total of 12/235 (5.1%) while a possibly pathogenic duplication of 22q11.2 was found in one control for a total of 1 in 191 (0.5%) controls (p = 0.008). The rate of abnormality in the schizophrenia plus epilepsy of 10/235 for the more definite CNVs compares to a rate of 75/7336 for these same CNVs in a series of unselected schizophrenia cases (p = 0.0004).

Conclusion

We found a statistically significant increase in the frequency of CNVs known or likely to be associated with schizophrenia in individuals with both schizophrenia and epilepsy compared to controls. We found an overall 5.1% detection rate of likely pathological findings which is the highest frequency of such findings in a series of schizophrenia patients to date. This evidence suggests that the frequency of disease-associated CNVs in patients with both schizophrenia and epilepsy is significantly higher than for unselected schizophrenia.

In a prospective survey of patients attending a general medical outpatient clinic roughly half the current cigarette smokers who had smoked for 10 years or more were identified, using defined criteria, by their facial features alone. These facial features, designated "smoker's face," were present in three (8%) of those who had smoked cigarettes for 10 years or more in the past and in none of the non-smokers. The association of smoker's face with current smoking that had continued for 10 years or more was significant (p less than 0.001) and remained after the patient's age, social class, exposure to sunlight, recent change of weight, and estimated lifetime consumption of cigarettes were controlled for. Smoker's face may be a helpful indicator in antismoking campaigns.

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