Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models.

Mutations in the TECPR2 gene are the cause of an ultra-rare neurological disorder characterized by intellectual disability, impaired speech, motor delay, and hypotonia evolving to spasticity, central sleep apnea, and premature death (SPG49 or HSAN9; OMIM: 615031). Little is known about the biological function of TECPR2, and there are currently no available disease-modifying therapies for this disease. Here we describe implementation of an antisense oligonucleotide (ASO) exon-skipping strategy targeting TECPR2 c.1319delT (p.Leu440Argfs∗19), a pathogenic variant that results in a premature stop codon within TECPR2 exon 8. We used patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons homozygous for the p.Leu440Argfs∗19 mutation to model the disease in vitro. Both patient-derived fibroblasts and neurons showed lack of TECPR2 protein expression. We designed and screened ASOs targeting sequences across the TECPR2 exon 8 region to identify molecules that induce exon 8 skipping and thereby remove the premature stop signal. TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids. Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts. To examine potential functional rescue induced by ASO-005-02, we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2. Finally, ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology. Broad distribution of ASO-005-02 and induction of TECPR2 exon 8 skipping was detected in multiple central nervous system (CNS) tissues, supporting the potential utility of this therapeutic strategy for a subset of patients suffering from this rare disease.

Functional MRI reveals evidence of a self-positivity bias in the medial prefrontal cortex during the comprehension of social vignettes.

A large literature in social neuroscience has associated the medial prefrontal cortex (mPFC) with the processing of self-related information. However, only recently have social neuroscience studies begun to consider the large behavioral literature showing a strong self-positivity bias, and these studies have mostly focused on its correlates during self-related judgments and decision-making. We carried out a functional MRI (fMRI) study to ask whether the mPFC would show effects of the self-positivity bias in a paradigm that probed participants' self-concept without any requirement of explicit self-judgment. We presented social vignettes that were either self-relevant or non-self-relevant with a neutral, positive or negative outcome described in the second sentence. In previous work using event-related potentials, this paradigm has shown evidence of a self-positivity bias that influences early stages of semantically processing incoming stimuli. In the present fMRI study, we found evidence for this bias within the mPFC: an interaction between self-relevance and valence, with only positive scenarios showing a self vs other effect within the mPFC. We suggest that the mPFC may play a role in maintaining a positively biased self-concept and discuss the implications of these findings for the social neuroscience of the self and the role of the mPFC.

Neural evidence for Bayesian trial-by-trial adaptation on the N400 during semantic priming.

When semantic information is activated by a context prior to new bottom-up input (i.e. when a word is predicted), semantic processing of that incoming word is typically facilitated, attenuating the amplitude of the N400 event related potential (ERP) - a direct neural measure of semantic processing. N400 modulation is observed even when the context is a single semantically related "prime" word. This so-called "N400 semantic priming effect" is sensitive to the probability of encountering a related prime-target pair within an experimental block, suggesting that participants may be adapting the strength of their predictions to the predictive validity of their broader experimental environment. We formalize this adaptation using a Bayesian learning model that estimates and updates the probability of encountering a related versus an unrelated prime-target pair on each successive trial. We found that our model's trial-by-trial estimates of target word probability accounted for significant variance in trial-by-trial N400 amplitude. These findings suggest that Bayesian principles contribute to how comprehenders adapt their semantic predictions to the statistical structure of their broader environment, with implications for the functional significance of the N400 component and the predictive nature of language processing.

Integrated assessment of visual perception abnormalities in psychotic disorders and relationship with clinical characteristics.

BACKGROUND: The visual system is recognized as an important site of pathology and dysfunction in schizophrenia. In this study, we evaluated different visual perceptual functions in patients with psychotic disorders using a potentially clinically applicable task battery and assessed their relationship with symptom severity in patients, and with schizotypal features in healthy participants. METHODS: Five different areas of visual functioning were evaluated in patients with schizophrenia and schizoaffective disorder (n = 28) and healthy control subjects (n = 31) using a battery that included visuospatial working memory (VSWM), velocity discrimination (VD), contour integration, visual context processing, and backward masking tasks. RESULTS: The patient group demonstrated significantly lower performance in VD, contour integration, and VSWM tasks. Performance did not differ between the two groups on the visual context processing task and did not differ across levels of interstimulus intervals in the backward masking task. Performances on VSWM, VD, and contour integration tasks were correlated with negative symptom severity but not with other symptom dimensions in the patient group. VSWM and VD performances were also correlated with negative sychizotypal features in healthy controls. CONCLUSION: Taken together, these results demonstrate significant abnormalities in multiple visual processing tasks in patients with psychotic disorders, adding to the literature implicating visual abnormalities in these conditions. Furthermore, our results show that visual processing impairments are associated with the negative symptom dimension in patients as well as healthy individuals.

Multimodal neuroimaging evidence for looser lexico-semantic networks in schizophrenia:Evidence from masked indirect semantic priming.

It has been hypothesized that schizophrenia is characterized by overly broad automatic activity within lexico-semantic networks. We used two complementary neuroimaging techniques, Magnetoencephalography (MEG) and functional Magnetic Resonance Imaging (fMRI), in combination with a highly automatic indirect semantic priming paradigm, to spatiotemporally localize this abnormality in the brain. Eighteen people with schizophrenia and 20 demographically-matched control participants viewed target words ("bell") preceded by directly related ("church"), indirectly related ("priest"), or unrelated ("hammer") prime words in MEG and fMRI sessions. To minimize top-down processing, the prime was masked, the target appeared only 140 ms after prime onset, and participants simply monitored for words within a particular semantic category that appeared in filler trials. Both techniques revealed a significantly larger automatic indirect priming effect in people with schizophrenia than in control participants. MEG temporally localized this enhanced effect to the N400 time window (300-500 ms) - the critical stage of accessing meaning from words. fMRI spatially localized the effect to the left temporal fusiform cortex, which plays a role in mapping of orthographic word-form on to meaning. There was no evidence of an enhanced automatic direct semantic priming effect in the schizophrenia group. These findings provide converging neural evidence for abnormally broad highly automatic lexico-semantic activity in schizophrenia. We argue that, rather than arising from an unconstrained spread of automatic activation across semantic memory, this broader automatic lexico-semantic activity stems from looser mappings between the form and meaning of words.

Spared bottom-up but impaired top-down interactive effects during naturalistic language processing in schizophrenia: evidence from the visual-world paradigm.

BACKGROUND: People with schizophrenia process language in unusual ways, but the causes of these abnormalities are unclear. In particular, it has proven difficult to empirically disentangle explanations based on impairments in the top-down processing of higher level information from those based on the bottom-up processing of lower level information. METHODS: To distinguish these accounts, we used visual-world eye tracking, a paradigm that measures spoken language processing during real-world interactions. Participants listened to and then acted out syntactically ambiguous spoken instructions (e.g. 'tickle the frog with the feather', which could either specify how to tickle a frog, or which frog to tickle). We contrasted how 24 people with schizophrenia and 24 demographically matched controls used two types of lower level information (prosody and lexical representations) and two types of higher level information (pragmatic and discourse-level representations) to resolve the ambiguous meanings of these instructions. Eye tracking allowed us to assess how participants arrived at their interpretation in real time, while recordings of participants' actions measured how they ultimately interpreted the instructions. RESULTS: We found a striking dissociation in participants' eye movements: the two groups were similarly adept at using lower level information to immediately constrain their interpretations of the instructions, but only controls showed evidence of fast top-down use of higher level information. People with schizophrenia, nonetheless, did eventually reach the same interpretations as controls. CONCLUSIONS: These data suggest that language abnormalities in schizophrenia partially result from a failure to use higher level information in a top-down fashion, to constrain the interpretation of language as it unfolds in real time.

Priming production: Neural evidence for enhanced automatic semantic activity preceding language production in schizophrenia.

Introduction: Lexico-semantic disturbances are considered central to schizophrenia. Clinically, their clearest manifestation is in language production. However, most studies probing their underlying mechanisms have used comprehension or categorization tasks. Here, we probed automatic semantic activity prior to language production in schizophrenia using event-related potentials (ERPs). Methods: 19 people with schizophrenia and 16 demographically-matched healthy controls named target pictures that were very quickly preceded by masked prime words. To probe automatic semantic activity prior to production, we measured the N400 ERP component evoked by these targets. To determine the origin of any automatic semantic abnormalities, we manipulated the type of relationship between prime and target such that they overlapped in (a) their semantic features (semantically related, e.g. "cake" preceding a < picture of a pie >, (b) their initial phonemes (phonemically related, e.g. "stomach" preceding a < picture of a starfish >), or (c) both their semantic features and their orthographic/phonological word form (identity related, e.g. "socks" preceding a < picture of socks >). For each of these three types of relationship, the same targets were paired with unrelated prime words (counterbalanced across lists). We contrasted ERPs and naming times to each type of related target with its corresponding unrelated target. Results: People with schizophrenia showed abnormal N400 modulation prior to naming identity related (versus unrelated) targets: whereas healthy control participants produced a smaller amplitude N400 to identity related than unrelated targets, patients showed the opposite pattern, producing a larger N400 to identity related than unrelated targets. This abnormality was specific to the identity related targets. Just like healthy control participants, people with schizophrenia produced a smaller N400 to semantically related than to unrelated targets, and showed no difference in the N400 evoked by phonemically related and unrelated targets. There were no differences between the two groups in the pattern of naming times across conditions. Conclusion: People with schizophrenia can show abnormal neural activity associated with automatic semantic processing prior to language production. The specificity of this abnormality to the identity related targets suggests that that, rather than arising from abnormalities of either semantic features or lexical form alone, it may stem from disruptions of mappings (connections) between the meaning of words and their form.

Vivid: How valence and arousal influence word processing under different task demands.

In this study, we used event-related potentials to examine how different dimensions of emotion-valence and arousal-influence different stages of word processing under different task demands. In two experiments, two groups of participants viewed the same single emotional and neutral words while carrying out different tasks. In both experiments, valence (pleasant, unpleasant, and neutral) was fully crossed with arousal (high and low). We found that the task made a substantial contribution to how valence and arousal modulated the late positive complex (LPC), which is thought to reflect sustained evaluative processing (particularly of emotional stimuli). When participants performed a semantic categorization task in which emotion was not directly relevant to task performance, the LPC showed a larger amplitude for high-arousal than for low-arousal words, but no effect of valence. In contrast, when participants performed an overt valence categorization task, the LPC showed a large effect of valence (with unpleasant words eliciting the largest positivity), but no effect of arousal. These data show not only that valence and arousal act independently to influence word processing, but that their relative contributions to prolonged evaluative neural processes are strongly influenced by the situational demands (and by individual differences, as revealed in a subsequent analysis of subjective judgments).

Friendly drug-dealers and terrifying puppies: affective primacy can attenuate the N400 effect in emotional discourse contexts.

Words that are semantically congruous with their preceding discourse context are easier to process than words that are semantically incongruous with their context. This facilitation of semantic processing is reflected by an attenuation of the N400 event-related potential (ERP). We asked whether this was true of emotional words in emotional contexts where discourse congruity was conferred through emotional valence. ERPs were measured as 24 participants read two-sentence scenarios with critical words that varied by emotion (pleasant, unpleasant, or neutral) and congruity (congruous or incongruous). Semantic predictability, constraint, and plausibility were comparable across the neutral and emotional scenarios. As expected, the N400 was smaller to neutral words that were semantically congruous (vs. incongruous) with their neutral discourse context. No such N400 congruity effect was observed on emotional words following emotional discourse contexts. Rather, the amplitude of the N400 was small to all emotional words (pleasant and unpleasant), regardless of whether their emotional valence was congruous with the valence of their emotional discourse context. However, consistent with previous studies, the emotional words produced a larger late positivity than did the neutral words. These data suggest that comprehenders bypassed deep semantic processing of valence-incongruous emotional words within the N400 time window, moving rapidly on to evaluate the words' motivational significance.