Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Incidence and Risk Factors of Retro-Orbital Embolic Central Retinal Artery Occlusions

This retrospective study describes the incidence of retro-orbital emboli as a source of central retinal artery occlusion (CRAO) as detected by orbital color Doppler imaging (OCDI) in an eye emergency department. We additionally report association of retro-orbital embolic (ROE) events with vasculopathic risk factors and rates of co-incident cerebral vascular ischemia as assessed by MRI imaging

Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials.

Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity.We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma.These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2 receptors. Event-related gamma is strongly influenced by activation of α4β2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes

Sensorimotor Cortical Oscillations during Movement Preparation in 16p11.2 Deletion Carriers.

Sensorimotor deficits are prevalent in many neurodevelopmental disorders like autism, including one of its common genetic etiologies, a 600 kb reciprocal deletion/duplication at 16p11.2. We have previously shown that copy number variations of 16p11.2 impact regional brain volume, white matter integrity, and early sensory responses in auditory cortex. Here, we test the hypothesis that abnormal cortical neurophysiology is present when genes in the 16p11.2 region are haploinsufficient, and in humans that this in turn may account for behavioral deficits specific to deletion carriers. We examine sensorimotor cortical network activity in males and females with 16p11.2 deletions compared with both typically developing individuals, and those with duplications of 16p11.2, using magnetoencephalographic imaging during preparation of overt speech or hand movements in tasks designed to be easy for all participants. In deletion carriers, modulation of beta oscillations (12-30 Hz) were increased during both movement types over effector-specific regions of motor cortices compared with typically developing individuals or duplication carriers, with no task-related performance differences between cohorts, even when corrected for their own cognitive and sensorimotor deficits. Reduced left hemispheric language specialization was observed in deletion carriers but not in duplication carriers. Neural activity over sensorimotor cortices in deletion carriers was linearly related to clinical measures of speech and motor impairment. These findings link insufficient copy number repeats at 16p11.2 to excessive neural activity (e.g., increased beta oscillations) in motor cortical networks for speech and hand motor control. These results have significant implications for understanding the neural basis of autism and related neurodevelopmental disorders.SIGNIFICANCE STATEMENT The recurrent ∼600 kb deletion at 16p11.2 (BP4-BP5) is one of the most common genetic etiologies of ASD and, more generally, of neurodevelopmental disorders. Here, we use high-resolution magnetoencephalographic imaging (MEG-I) to define with millisecond precision the underlying neurophysiological signature of motor impairments for individuals with 16p11.2 deletions. We identify significant increases in beta (12-30 Hz) suppression in sensorimotor cortices related to performance during speech and hand movement tasks. These findings not only provide a neurophysiological phenotype for the clinical presentation of this genetic deletion, but also guide our understanding of how genetic variation encodes for neural oscillatory dynamics

Nicotine receptor subtype-specific effects on the P20 component of the ERP.

<p><b>A</b>) P20 amplitude following nicotine and nicotine receptor antagonists. Assessment of the effects of nicotine antagonists was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 24 hour washout period. N = 13 for each condition. Nicotine (1 mg/kg) produced a significant increase in P20 S1 (black) amplitude without concomitant changes in S2 (gray). The α4β4/α4β2 nicotinic receptor antagonist DHβE (2 mg/kg) blocked the effect of nicotine on P20 amplitude, while the α7 antagonist MLA (10 mg/kg) had no effect on P20. S1 was significantly higher than S2 in all conditions except nicotine plus DHβE. <b>B</b>) <b>P20 amplitude following the α4β2 specific agonist AZD3480.</b> Assessment of the effects of AZD3480 was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 72 hour washout period. The mice used to assess AZD3480 were a separate cohort from those shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039775#pone-0039775-g002" target="_blank">Figure 2A</a> used to assess nicotine antagonists. N = 9 for each condition. No significant changes were observed on P20 amplitude following either a low (1 mg/kg) or high (10 mg/kg) dose of the α4β2 AZD3480 antagonist. # indicates significant difference from saline vehicle (all p<0.05).</p

Nicotine receptor subtype-specific effects on auditory evoked gamma oscillations.

<p>(Top) Event-related Gamma (30 to 80 Hz) activity following nicotine and nicotine receptor antagonists. Assessment of the effects of nicotine antagonists was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 24 hour washout period. N = 13 for each condition. Depicted top left <b>A</b>) is the average event-related gamma power (in dB) for the period between 0 and 60 msec following stimulus onset, across all 50 stimulus presentations. This was done by calculating the time-frequency response for each wavelet cycle within the 0 to 60 msec period and averaging the resulting values to create a single number. All statistical analyses were conducted on these values. Nicotine (1 mg/kg) caused an increase in evoked gamma activity, which was blocked by DHβE (2 mg/kg) but not MLA (10 mg/kg), indicating that the positive effect of nicotine on gamma activity is mediated through the α4β2 receptor subtype. # indicates p<0.05. Top center <b>B</b>) depicts event-related gamma power across each individual wavelet cycle between 100 msec pre-stimulus and 200 msec post-stimulus across all 50 stimulus presentations. Depicted top left <b>C</b>) is a heat map showing event-related power in decibels (event-related spectral perturbation, i.e. the power following the stimulus expressed as a change from baseline) from 200 msec prior to stimulus onset to 200 msec post onset (0 = stimulus onset) across all 50 stimulus presentations following vehicle and nicotine treatment. (Bottom) Event-related Gamma activity following administration of the α4β2 specific agonist AZD3480. Assessment of the effects of AZD3480 was carried out using a within subjects design in which each mouse was assessed on each drug, with sessions being separated by a 72 hour washout period. The mice used to assess AZD3480 were a separate cohort from those shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039775#pone-0039775-g002" target="_blank">Figure 2A</a> used to assess nicotine antagonists. N = 9 for each condition. Bottom left D) shows a significant increase in event-related gamma following low (1 mg/kg), but not high (10 mg/kg) dose AZD3480. The methodology used to create bottom left <b>D</b>), center <b>E</b>) and right <b>F</b>) figures are the same used to create figures <b>A</b>, <b>B</b> and <b>C</b>, respectively. # - indicates significant differences from saline vehicle (all p<0.05).</p

Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications

Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833-2848, 2016. © 2016 Wiley Periodicals, Inc

Subject age distribution.

<p>Subject age distribution.</p

NDI logarithmic growth b2 map (eq. 2) plotted on a red-yellow color scale, where colored voxels are significantly fit by a logarithmic model (with TFCE-correction) and yellow represents higher b2.

<p>NDI logarithmic growth b2 map (eq. 2) plotted on a red-yellow color scale, where colored voxels are significantly fit by a logarithmic model (with TFCE-correction) and yellow represents higher b2.</p

Subject FA, ODI, and NDI age trajectories in each group of cortical RTZ tracts: prefrontal (blue), sensorimotor (magenta), parietal (cyan), temporal (red), occipital (green).

<p>Shaded regions represent 95% confidence intervals.</p