Selective 5HT3 antagonists and sensory processing: a systematic review

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson’s disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Auditory Sensory Gating in Children With Cochlear Implants: A P50-N100-P200 Study

Background: While a cochlear implant (CI) can restore access to audibility in deaf children, implanted children may still have difficulty in concentrating. Previous studies have revealed a close relationship between sensory gating and attention. However, whether CI children have deficient auditory sensory gating remains unclear.Methods: To address this issue, we measured the event-related potentials (ERPs), including P50, N100, and P200, evoked by paired tone bursts (S1 and S2) in CI children and normal-hearing (NH) controls. Suppressed amplitudes for S2 compared with S1 in these three ERPs reflected sensory gating during early and later phases, respectively. A Swanson, Nolan, and Pelham IV (SNAP-IV) scale was performed to assess the attentional performance.Results: Significant amplitude differences between S1 and S2 in N100 and P200 were observed in both NH and CI children, indicating the presence of sensory gating in the two groups. However, the P50 suppression was only found in NH children and not in CI children. Furthermore, the duration of deafness was significantly positively correlated with the score of inattention in CI children.Conclusion: Auditory sensory gating can develop but is deficient during the early phase in CI children. Long-term auditory deprivation has a negative effect on sensory gating and attentional performance.

Cross‐modal relationships of neural gating with the subjective perception of respiratory and somatosensory sensations

Neural gating is a phenomenon whereby the response to a stimulus recorded in the electroencephalogram (EEG) is attenuated when preceded by an identical stimulus. Such attenuation of paired auditory clicks (P50 suppression) has repeatedly been shown to be affected in multiple mental disorders, most notably schizophrenia. Neural gating has also been studied using respiratory and somatosensory sensations, however the attenuation of such bodily-relevant stimuli has not yet been systematically related to the subjective perception of bodily sensations. This research direction is potentially relevant to explaining disease trajectories in multiple psychosomatic conditions characterized by chronic breathlessness and/or pain. In the present study, we recorded high-density EEG from 85 healthy young adults while they experienced brief paired respiratory occlusions and brief paired electrocutaneous stimulation of the wrist. The event-related potential N1 at centro-lateral sites was measured in response to the second relative to the first stimulus to quantify neural gating in both sensory domains. Participants experienced resistive loaded breaths and electrocutaneous stimuli of various intensities, rated their perceived intensity and unpleasantness, and performed magnitude estimation. Both respiratory and somatosensory neural gating measures were related intra-modally and cross-modally to the subjective intensity and unpleasantness of sensations, as well as the ability to discriminate sensations of differing intensities. We report significant relationships of the somatosensory neural gating to the perceived intensity and unpleasantness of respiratory and somatosensory sensations, indicating that the stronger neural gating relates to a stronger subjective experience of intensity and unpleasantness. We discuss these unexpected findings through the lens of individual differences, as well as different theoretical accounts on the origins of cortical attenuation of repetitive stimuli.

Sensory Filtering and Sensory Memory in Breast Cancer Survivors

Survivors of breast and other cancers often report protracted difficulty in performing tasks involving concentration and memory, even years after the completion of treatment. The current study investigated whether cancer and treatment history is associated with deficits in sensory filtering (gating out) and sensory memory (gating in), early processes in stimulus processing that may contribute to difficulties in later remembering. A group of breast cancer survivors and age-matched healthy control participants (mean age 54 years) underwent testing with paired-click and oddball tasks while electroencephalographic (EEG) signals were recorded. The survivors showed relatively poor inhibition of redundant sensory stimulation (P50 suppression). Dipole source analysis localized the survivors’ impairment to the hippocampus, with preservation of function in gating mechanisms of the frontal lobe and auditory cortex. Survivors also showed disruption to sensory memory processes needed to register novel information in an otherwise uniform auditory environment (mismatch negativity). The findings suggest that survivors experience deficits in early, automatic mechanisms of sensory gating, which may trigger a cascade of later perceived attentional and memory deficits. If our account is accurate, ideal therapies might aim to restore early inhibitory processes, such as those gauged by P50 suppression.

The Influence of Background Auditory Noise on P50 and N100 Suppression Elicited by the Paired-Click Paradigm

Auditory sensory gating is commonly assessed using the Paired-Click Paradigm (PCP), an electroencephalography (EEG) task in which two identical sounds are presented sequentially and the brain’s inhibitory response to the second sound is measured. Many clinical populations demonstrate reduced P50 and/or N100 suppression. Testing sensory gating in children may help to identify individuals at risk for neurodevelopmental disorders earlier, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which could lead to more optimal outcomes. Minimal research has been done with children because of the difficulty of performing lengthy EEG experiments with young children, requiring them to sit still for long periods of time. We designed a modified, potentially child-friendly version of the PCP and evaluated it in typically developing adults. The PCP was administered twice, once in a traditional silent room (silent movie condition) and once with an audible movie playing (audible movie condition) to minimize boredom and enhance behavioral compliance. We tested whether P50 and N100 suppression were influenced by the presence of the auditory background noise from the movie. N100 suppression was observed in both hemispheres in the silent movie condition and in the left hemisphere only during the audible movie condition, though suppression was attenuated in the audible movie condition. P50 suppression was not observed in either condition. N100 sensory gating was successfully elicited with an audible movie playing during the PCP, supporting the use of the modified task for future research in both children and adults.

Using high density EEG to assess TMS treatment in patients with schizophrenia

We present preliminary results from the ongoing study entitled “Icelandic AVH-TMS” which aim is to study the effectiveness of repetitive transcranial magnetic stimulation (rTMS) treatment for patients with schizophrenia and with persistent auditory verbal hallucinations (AVH) using symptoms and psychometric scales and high-density EEG system (256 channels). The aim of the present work was to describe cortical topography of the auditory evoked responses like P50 and N100-P300 complex in healthy participants and patients with schizophrenia and to define a robust methodology of signal quantification using dense-array EEG. Preliminary data is shown for three healthy participants and three patients in baseline conditions and for two patients we show the results recorded before and after 10 days rTMS treatment. Our results show differences in sensory gating (P50 suppresion) and a stronger N100-P300 response to rare audio stimulus after the treatment. Moreover we show the value of assessing brain electrical activity from high-density EEG (256 channels) analyzing the results in different regions of interest. However, it is premature and hazardous to assume that rTMS treatment effectiveness in patients with AVH can be assessed using P50 suppression ratio.

Simultaneous assessment of P50, MMN, ERN and P300 event-related potentials among patients with Schizophrenia – an exploratory study

PurposeP50 suppression (sensory gating or inhibition), MMN (mismatch negativity; bottom-up detection of change), ERN (error related negativity; conflict monitoring) and P300 (attention allocation and memory updating for salient events) are event related potentials (ERPs) widely reported to show abnormal cognitive functioning among patients with schizophrenia. In real-life scenarios the brain processing underlying these ERPs occur simultaneously, and yet prior ERP studies have evaluated them in isolation. The current study uses a novel paradigm that can examine these multiple ERPs simultaneously, and explore if the reported ERP deficits would hold true during a more realistic setting.MethodData from 21 patients with schizophrenia and 25 age- and gender-matched healthy controls were used, who underwent ERP recordings during the Assessing Neurocognition via Gamified Experimental Logic (ANGEL) paradigm. This is a gamified visual odd-ball paradigm that generates P300, the error responses generate ERN, and paired-tone audio distractors generate P50 and MMN. Peak-peak amplitude, mean amplitude and area-under-curve measures of ERP were measured at electrodes reflecting best morphology.ResultsThough patients showed apparent ERP morphology differences relative to the controls, the standard ERP measures were comparable between groups, except for reduced ERN among patients. Interestingly, significant group differences were seen in N1-P2 complex suppression, despite comparable P50 suppression.Contribution of the researchThe current study is the first to report multiple ERP component measures simultaneously evoked among patients with schizophrenia, and shows greater signs for impaired prediction mechanism. The findings of the study would provide a more ecologically valid evaluation of ERP-based cognitive functioning, and need to be replicated in a larger sample as well as other mental disorders.

Startle habituation, sensory, and sensorimotor gating in trauma-affected refugees with posttraumatic stress disorder

BackgroundImpairments in mechanisms underlying early information processing have been reported in posttraumatic stress disorder (PTSD); however, findings in the existing literature are inconsistent. This current study capitalizes on technological advancements of research on electroencephalographic event-related potential and applies it to a novel PTSD population consisting of trauma-affected refugees.MethodsA total of 25 trauma-affected refugees with PTSD and 20 healthy refugee controls matched on age, gender, and country of origin completed the study. In two distinct auditory paradigms sensory gating, indexed as P50 suppression, and sensorimotor gating, indexed as prepulse inhibition (PPI), startle reactivity, and habituation of the eye-blink startle response were examined. Within the P50 paradigm, N100 and P200 amplitudes were also assessed. In addition, correlations between psychophysiological and clinical measures were investigated.ResultsPTSD patients demonstrated significantly elevated stimuli responses across the two paradigms, reflected in both increased amplitude of the eye-blink startle response, and increased N100 and P200 amplitudes relative to healthy refugee controls. We found a trend toward reduced habituation in the patients, while the groups did not differ in PPI and P50 suppression. Among correlations, we found that eye-blink startle responses were associated with higher overall illness severity and lower levels of functioning.ConclusionsFundamental gating mechanisms appeared intact, while the pattern of deficits in trauma-affected refugees with PTSD point toward a different form of sensory overload, an overall neural hypersensitivity and disrupted the ability to down-regulate stimuli responses. This study represents an initial step toward elucidating sensory processing deficits in a PTSD subgroup.