Chemogenetic Attenuation of Acute Nociceptive Signaling Enhances Functional Outcomes Following Spinal Cord Injury.

Identifying novel therapeutic approaches to promote recovery of neurological functions following spinal cord injury (SCI) remains a great unmet need. Nociceptive signaling in the acute phase of SCI has been shown to inhibit recovery of locomotor function and promote the development of chronic neuropathic pain. We therefore hypothesized that inhibition of nociceptive signaling in the acute phase of SCI might improve long-term functional outcomes in the chronic phase of injury. To test this hypothesis, we took advantage of a selective strategy utilizing AAV6 to deliver inhibitory (hM4Di) Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to nociceptors of the L4-L6 dorsal root ganglia to evaluate the effects of transient nociceptor silencing on long-term sensory and motor functional outcomes in a rat thoracic contusion SCI model. Following hM4Di-mediated nociceptor inhibition from 0-14 days post-SCI, we conducted behavioral assessments until 70 days post-SCI, then performed histological assessments of lesion severity and axon plasticity. Our results show highly selective expression of hM4Di within small diameter nociceptors including calcitonin gene-related peptide (CGRP)+ and IB4-binding neurons. Expression of hM4Di in less than 25% of nociceptors was sufficient to increase hindlimb thermal withdrawal latency in naïve rats. Compared with subjects who received AAV-yellow fluorescent protein (YFP; control), subjects who received AAV-hM4Di exhibited attenuated thermal hyperalgesia, greater coordination, and improved hindlimb locomotor function. However, treatment did not impact the development of cold allodynia or mechanical hyperalgesia. Histological assessments of spinal cord tissue suggested trends toward reduced lesion volume, increased neuronal sparing and increased CGRP+ axon sprouting in hM4Di-treated animals. Together, these findings suggest that nociceptor silencing early after SCI may promote beneficial plasticity in the acute phase of injury that can impact long-term functional outcomes, and support previous work highlighting primary nociceptors as possible therapeutic targets for pain management after SCI.

Out of sight, out of mind: Foveal processing is necessary for semantic integration of words into sentence context.

Word recognition begins before a reader looks directly at a word, as demonstrated by the parafoveal preview benefit and word skipping. Both low-level form and high-level semantic features can be accessed in parafoveal vision and used to promote reading efficiency. However, words are not recognized in isolation during reading; once a semantic representation is retrieved, it must be integrated with the broader sentence context. One open question about parafoveal processing is whether it is limited to shallow stages of lexico-semantic activation or extends to semantic integration. In the present two-experiment study, we recorded event-related brain potentials in response to a sentence-final word that was presented in foveal or parafoveal vision and was either expected, unexpected, or anomalous in the sentence context. We found that word recognition, indexed by the N400, ensued regardless of perception location whereas identification of the semantic fit of a word in its sentence context, indexed by the late positive component, was only observed for foveally perceived but not parafoveally perceived words. This pattern was not sensitive to task differences that promote different levels of orthographic scrutiny, as manipulated between the two experiments. These findings demonstrate separate roles for parafoveal and foveal processing in reading. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Event-related potentials show that parafoveal vision is insufficient for semantic integration.

Readers extract information from a word from parafoveal vision prior to looking at it. It has been argued that parafoveal perception allows readers to initiate linguistic processes, but it is unclear which stages of word processing are engaged: the process of extracting letter information to recognize words, or the process of extracting meaning to comprehend them. This study used the event-related brain potential (ERP) technique to investigate how word recognition (indexed by the N400 effect for unexpected or anomalous compared to expected words) and semantic integration (indexed by the Late-positive component; LPC effect for anomalous compared to expected words) are or are not elicited when the word is perceived only in parafoveal vision. Participants read a target word following a sentence that made it expected, unexpected, or anomalous, and read the sentences presented three words at a time in the Rapid Serial Visual Presentation (RSVP) with flankers paradigm so that words were perceived in parafoveal and foveal vision. We orthogonally manipulated whether the target word was masked in parafoveal and/or foveal vision to dissociate the processing associated with perception of the target word from either location. We found that the N400 effect was generated from parafoveally perceived words, and was reduced for foveally perceived words if they were previously perceived parafoveally. In contrast, the LPC effect was only elicited if the word was perceived foveally, suggesting that readers must attend to a word directly in foveal vision in order to attempt to integrate its meaning into the sentence context.

Readers scrutinize lexical familiarity only in the absence of expectations: Evidence from lexicality effects on event-related potentials.

Readers generate predictions about the meaning of upcoming words while reading constraining sentences. These predictions feed down to predictions about orthographic form. For example, orthographic neighbors of predicted words yield reduced N400 amplitudes compared to non-neighbors regardless of lexical status (Laszlo & Federmeier, 2009). We investigated whether readers are sensitive to lexicality in low constraint sentences when they must scrutinize the perceptual input more closely for word recognition. In a replication and extension of Laszlo and Federmeier (2009), we observed similar patterns as the original study in high constraint sentences, but found a lexicality effect in low constraint sentences that was not present when the sentence was highly constraining. This suggests that, in the absence of strong expectations, readers adopt a different reading strategy to scrutinize the structure of words more in depth to make sense of what they have read compared to when they encounter a supportive sentence context.

Are eye movements and EEG on the same page?: A coregistration study on parafoveal preview and lexical frequency.

Readers extract visual and linguistic information not only from fixated words but also upcoming parafoveal words to introduce new input efficiently into the language processing pipeline. The lexical frequency of upcoming words and similarity with subsequent foveal information both influence the amount of time people spend once they fixate the word foveally. However, it is unclear from eye movements alone the extent to which parafoveal word processing, and the integration of that word with foveally obtained information, continues after saccade plans have been initiated. To investigate the underlying neural processes involved in word recognition after saccade planning, we coregistered electroencephalogram (EEG) and eye movements during a gaze-contingent display change paradigm. We orthogonally manipulated the frequency of the parafoveal and foveal words and measured fixation related potentials (FRPs) upon foveal fixation. Eye movements showed primarily an effect of preview frequency, suggesting that saccade planning is based on the familiarity of the parafoveal input. FRPs, on the other hand, demonstrated a disruption in downstream processing when parafoveal and foveal input differed, but only when the parafoveal word was high frequency. These findings demonstrate that lexical processing continues after the eyes have moved away from a word and that eye movements and FRPs provide distinct but complementary accounts about oculomotor behavior and neural processing that cannot be obtained from either method in isolation. Furthermore, these findings put constraints on models of reading by suggesting that lexical processes that occur before an eye movement program is initiated are qualitatively different from those that occur afterward. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Semantic parafoveal processing in natural reading: Insight from fixation-related potentials & eye movements.

Prior research suggests that we may access the meaning of parafoveal words during reading. We explored how semantic-plausibility parafoveal processing takes place in natural reading through the co-registration of eye movements (EM) and fixation-related potentials (FRPs), using the boundary paradigm. We replicated previous evidence of semantic parafoveal processing from highly controlled reading situations, extending their findings to more ecologically valid reading scenarios. Additionally, and exploring the time-course of plausibility preview effects, we found distinct but complementary evidence from EM and FRPs measures. FRPs measures, showing a different trend than EM evidence, revealed that plausibility preview effects may be long-lasting. We highlight the importance of a co-registration set-up in ecologically valid scenarios to disentangle the mechanisms related to semantic-plausibility parafoveal processing.