CASK pathogenic variant which expands the clinical spectrum for MICPCH syndrome in an adult patient.

The CASK gene and its product protein kinase have been associated with microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome and various other neurodevelopmental disorders. Clinical presentation is highly variable and generally includes intellectual disability, neurological disorders, and dysmorphic features, at a minimum. We present the case of one of the oldest known currently living patients with MICPCH syndrome with additional features not previously described in the literature (midface retrusion, macroglossia, dental crowding, adolescent-onset contractures at large joints, laxity at finger joints, and prominent wrist dystonia). Progressive hypertonicity throughout the patient's life has been managed with serial botulinum toxin injections. A comprehensive multimodal care team including physiatry, physical therapy, exercise therapy, and audiology has been assisting her with hearing deficits, communication skills, and mobility. This potentially expands the phenotype of MICPCH syndrome and provides information about the management of this condition into adulthood.

Movement trajectories as a window into the dynamics of emerging neural representations.

The rapid transformation of sensory inputs into meaningful neural representations is critical to adaptive human behaviour. While non-invasive neuroimaging methods are the de-facto method for investigating neural representations, they remain expensive, not widely available, time-consuming, and restrictive. Here we show that movement trajectories can be used to measure emerging neural representations with fine temporal resolution. By combining online computer mouse-tracking and publicly available neuroimaging data via representational similarity analysis (RSA), we show that movement trajectories track the unfolding of stimulus- and category-wise neural representations along key dimensions of the human visual system. We demonstrate that time-resolved representational structures derived from movement trajectories overlap with those derived from M/EEG (albeit delayed) and those derived from fMRI in functionally-relevant brain areas. Our findings highlight the richness of movement trajectories and the power of the RSA framework to reveal and compare their information content, opening new avenues to better understand human perception.

TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.

THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Different Mechanisms for Supporting Mental Imagery and Perceptual Representations: Modulation Versus Excitation.

Recent research suggests imagery is functionally equivalent to a weak form of visual perception. Here we report evidence across five independent experiments on adults that perception and imagery are supported by fundamentally different mechanisms: Whereas perceptual representations are largely formed via increases in excitatory activity, imagery representations are largely supported by modulating nonimagined content. We developed two behavioral techniques that allowed us to first put the visual system into a state of adaptation and then probe the additivity of perception and imagery. If imagery drives similar excitatory visual activity to perception, pairing imagery with perceptual adapters should increase the state of adaptation. Whereas pairing weak perception with adapters increased measures of adaptation, pairing imagery reversed their effects. Further experiments demonstrated that these nonadditive effects were due to imagery weakening representations of nonimagined content. Together these data provide empirical evidence that the brain uses categorically different mechanisms to represent imagery and perception.

Implicit bias training can remove bias from subliminal stimuli, restoring choice divergence: A proof-of-concept study.

Subliminal information can influence our conscious life. Subliminal stimuli can influence cognitive tasks, while endogenous subliminal neural information can sway decisions before volition. Are decisions inextricably biased towards subliminal information? Or can they diverge away from subliminal biases via training? We report that implicit bias training can remove biases from subliminal sensory primes. We first show that subliminal stimuli biased an imagery-content decision task. Participants (n = 17) had to choose one of two different patterns to subsequently imagine. Subliminal primes significantly biased decisions towards imagining the primed option. Then, we trained participants (n = 7) to choose the non-primed option, via post choice feedback. This training was successful despite participants being unaware of the purpose or structure of the reward schedule. This implicit bias training persisted up to one week later. Our proof-of-concept study indicates that decisions might not always have to be biased towards non-conscious information, but instead can diverge from subliminal primes through training.

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.

BACKGROUND: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. METHODS: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. RESULTS: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. CONCLUSIONS: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

Recommendations on the management of pudendal nerve entrapment syndrome: A formalised expert consensus.

BACKGROUND: Since the development and publication of diagnostic criteria for pudendal nerve entrapment (PNE) syndrome in 2008, no comprehensive work has been published on the clinical knowledge in the management of this condition. The aim of this work was to develop recommendations on the diagnosis and the management of PNE. METHODS: The methodology of this study was based on French High Authority for Health Method for the development of good practice and the literature review was based on the PRISMA method. The selected articles have all been evaluated according to the American Society of Interventional Pain Physicians assessment grid. RESULTS: The results of the literature review and expert consensus are incorporated into 10 sections to describe diagnosis and management of PNE: (1) diagnosis of PNE, (2) patients advice and precautions, (3) drugs treatments, (4) physiotherapy, (5) transcutaneous electrostimulations (TENS), (6) psychotherapy, (7) injections, (8) surgery, (9) pulsed radiofrequency, and (10) Neuromodulation. The following major points should be noted: (i) the relevance of 4+1 Nantes criteria for diagnosis; (ii) the preference for initial monotherapy with tri-tetracyclics or gabapentinoids; (iii) the lack of effect of opiates, (iv) the likely relevance (pending more controlled studies) of physiotherapy, TENS and cognitive behavioural therapy; (v) the incertitudes (lack of data) regarding corticoid injections, (vi) surgery is a long term effective treatment and (vii) radiofrequency needs a longer follow-up to be currently proposed in this indication. CONCLUSION: These recommendations should allow rational and homogeneous management of patients suffering from PNE. They should also allow to shorten the delays of management by directing the primary care. SIGNIFICANCE: Pudendal nerve entrapment (PNE) has only been known for about 20 years and its management is heterogeneous from one practitioner to another. This work offers a synthesis of the literature and international experts' opinions on the diagnosis and management of PNE.

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.

Why do imagery and perception look and feel so different?

Despite the past few decades of research providing convincing evidence of the similarities in function and neural mechanisms between imagery and perception, for most of us, the experience of the two are undeniably different, why? Here, we review and discuss the differences between imagery and perception and the possible underlying causes of these differences, from function to neural mechanisms. Specifically, we discuss the directional flow of information (top-down versus bottom-up), the differences in targeted cortical layers in primary visual cortex and possible different neural mechanisms of modulation versus excitation. For the first time in history, neuroscience is beginning to shed light on this long-held mystery of why imagery and perception look and feel so different. This article is part of the theme issue 'Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation'.

Decoding Nonconscious Thought Representations during Successful Thought Suppression.

Controlling our thoughts is central to mental well-being, and its failure is at the crux of a number of mental disorders. Paradoxically, behavioral evidence shows that thought suppression often fails. Despite the broad importance of understanding the mechanisms of thought control, little is known about the fate of neural representations of suppressed thoughts. Using fMRI, we investigated the brain areas involved in controlling visual thoughts and tracked suppressed thought representations using multivoxel pattern analysis. Participants were asked to either visualize a vegetable/fruit or suppress any visual thoughts about those objects. Surprisingly, the content (object identity) of successfully suppressed thoughts was still decodable in visual areas with algorithms trained on imagery. This suggests that visual representations of suppressed thoughts are still present despite reports that they are not. Thought generation was associated with the left hemisphere, and thought suppression was associated with right hemisphere engagement. Furthermore, general linear model analyses showed that subjective success in thought suppression was correlated with engagement of executive areas, whereas thought-suppression failure was associated with engagement of visual and memory-related areas. These results suggest that the content of suppressed thoughts exists hidden from awareness, seemingly without an individual's knowledge, providing a compelling reason why thought suppression is so ineffective. These data inform models of unconscious thought production and could be used to develop new treatment approaches to disorders involving maladaptive thoughts.

Expectation and attention increase the integration of top-down and bottom-up signals in perception through different pathways.

Perception likely results from the interplay between sensory information and top-down signals. In this electroencephalography (EEG) study, we utilised the hierarchical frequency tagging (HFT) method to examine how such integration is modulated by expectation and attention. Using intermodulation (IM) components as a measure of nonlinear signal integration, we show in three different experiments that both expectation and attention enhance integration between top-down and bottom-up signals. Based on a multispectral phase coherence (MSPC) measure, we present two direct physiological measures to demonstrate the distinct yet related mechanisms of expectation and attention, which would not have been possible using other amplitude-based measures. Our results link expectation to the modulation of descending signals and to the integration of top-down and bottom-up information at lower levels of the visual hierarchy. Meanwhile, the results link attention to the modulation of ascending signals and to the integration of information at higher levels of the visual hierarchy. These results are consistent with the predictive coding account of perception.

Measuring Thought-Control Failure: Sensory Mechanisms and Individual Differences.

The ability to control one's thoughts is crucial for attention, focus, ideation, and mental well-being. Although there is a long history of research into thought control, the inherent subjectivity of thoughts has made objective examination, and thus mechanistic understanding, difficult. Here, we report a novel method to objectively investigate thought-control success and failure by measuring the sensory strength of visual thoughts using binocular rivalry, a perceptual illusion. Across five experiments (N = 67), we found that thought-control failure may occur because of the involuntary and antithetical formation of nonreportable sensory representations during attempts at thought suppression but not during thought substitution. Notably, thought control was worse in individuals with high levels of anxiety and schizotypy but more successful in mindful individuals. Overall, our study offers insight into the underlying mechanisms of thought control and suggests that individual differences play an important role in the ability to control thoughts.

Decoding the contents and strength of imagery before volitional engagement.

Is it possible to predict the freely chosen content of voluntary imagery from prior neural signals? Here we show that the content and strength of future voluntary imagery can be decoded from activity patterns in visual and frontal areas well before participants engage in voluntary imagery. Participants freely chose which of two images to imagine. Using functional magnetic resonance (fMRI) and multi-voxel pattern analysis, we decoded imagery content as far as 11 seconds before the voluntary decision, in visual, frontal and subcortical areas. Decoding in visual areas in addition to perception-imagery generalization suggested that predictive patterns correspond to visual representations. Importantly, activity patterns in the primary visual cortex (V1) from before the decision, predicted future imagery vividness. Our results suggest that the contents and strength of mental imagery are influenced by sensory-like neural representations that emerge spontaneously before volition.

A new endoscopic minimal invasive approach for pudendal nerve and inferior cluneal nerve neurolysis: An anatomical study.

AIM: To describe a new minimal invasive approach of the gluteal region which will permit to perform neurolysis of the pudendal and cluneal nerves in case of perineal neuralgia due to an entrapment of these nerve trunks. METHOD: Ten transgluteal approaches were performed on five cadavers. Relevant anatomic structures were dissected and further described. Neurolysis of the pudendal nerve or cluneal nerves were performed. Landmarks for secure intraoperative navigation were indicated. RESULTS: The first operative trocar for the camera was inserted with regards to the iliac crest in the deep gluteal space. With the aid of pneumodissection, the infragluteal plane was dissected. The piriformis muscle was identified as well as the sciatic and the posterior femoral cutaneous nerve. Consequently, the sciatic tuberosity was visualized together with the cluneal nerves. Hereafter, the second trocar was introduced caudal to the first one and placed on an horizontal line passing at the level of the coccyx, allowing access to the ischial spine and the visualization of the pudendal nerve and vessels. A third 5 mm trocar was then inserted medial from the first one, permitting to dissect and transsect the sacrospinous ligament. The pudendal nerve was subsequently transposed and followed on its course in the pudendal channel. CONCLUSIONS: A reliable exploration of the gluteal region including identification of the sciatic, pudendal, and posterior femoral cutaneous nerves is feasible using a minimal invasive transgluteal procedure. Consequently, the transposition of the pudendal nerve and the liberation of the cluneal nerves can be performed.