Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.

OBJECTIVE: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. METHODS: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. RESULTS: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). CONCLUSIONS: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.

Auditory cortex activity related to perceptual awareness versus masking of tone sequences.

Sequences of repeating tones can be masked by other tones of different frequency. When these tone sequences are perceived, nevertheless, a prominent neural response in the auditory cortex is evoked by each tone of the sequence. When the targets are detected based on their isochrony, participants know that they are listening to the target once they detected it. To explore if the neural activity is more closely related to this detection task or to perceptual awareness, this magnetoencephalography (MEG) study used targets that could only be identified with cues provided after or before the masked target. In experiment 1, multiple mono-tone streams with jittered inter-stimulus interval were used, and the tone frequency of the target was indicated by a cue. Results showed no differential auditory cortex activity between hit and miss trials with post-stimulus cues. A late negative response for hit trials was only observed for pre-stimulus cues, suggesting a task-related component. Since experiment 1 provided no evidence for a link of a difference response with tone awareness, experiment 2 was planned to probe if detection of tone streams was linked to a difference response in auditory cortex. Random-tone sequences were presented in the presence of a multi-tone masker, and the sequence was repeated without masker thereafter. Results showed a prominent difference wave for hit compared to miss trials in experiment 2 evoked by targets in the presence of the masker. These results suggest that perceptual awareness of tone streams is linked to neural activity in auditory cortex.

Cortical networks for auditory detection with and without informational masking: Task effects and implications for conscious perception.

Ambiguous and masked stimuli have been used to study conscious perception by comparing neural activity during different percepts of identical physical stimuli. One limitation of this approach is that it typically requires a reporting task that may engage neural processes beyond those required for conscious perception. Here, we explored potential fMRI correlates of auditory conscious perception with and without overt report. In experiment 1, regular tone patterns were presented as targets under informational masking, and participants reported their percepts on each trial. In experiment 2, regular tone patterns were presented without masking, while the uninformed participants (i) passively fixated, (ii) performed an orthogonal visual task, and (iii) reported trial-wise the presence of the auditory pattern as in experiment 1 (in fixed order). Under informational masking, target-pattern detection was associated with activity in auditory cortex, superior temporal sulcus, and a distributed fronto-parieto-insular network. Unmasked and task-irrelevant tone patterns elicited activity that overlapped with the network observed under informational masking in auditory cortex, the right superior temporal sulcus, and the ventral precentral sulcus in an ROI analysis. We therefore consider these structures candidate regions for a neural substrate of auditory conscious perception. In contrast, activity in the intraparietal sulcus, insula, and dorsal precentral sulcus were only observed for unmasked tone patterns when they were task relevant. These areas therefore appear more closely related to task performance or top-down attention rather than auditory conscious perception, per se.

Context-dependent role of selective attention for change detection in multi-speaker scenes.

Disappearance of a voice or other sound source may often go unnoticed when the auditory scene is crowded. We explored the role of selective attention for this change deafness with magnetoencephalography in multi-speaker scenes. Each scene was presented two times in direct succession, and one target speaker was frequently omitted in Scene 2. When listeners were previously cued to the target speaker, activity in auditory cortex time locked to the target speaker's sound envelope was selectively enhanced in Scene 1, as was determined by a cross-correlation analysis. Moreover, the response was stronger for hit trials than for miss trials, confirming that selective attention played a role for subsequent change detection. If selective attention to the streams where the change occurred was generally required for successful change detection, neural enhancement of this stream would also be expected without cue in hit compared to miss trials. However, when listeners were not previously cued to the target, no enhanced activity for the target speaker was observed for hit trials, and there was no significant difference between hit and miss trials. These results, first, confirm a role for attention in change detection for situations where the target source is known. Second, they suggest that the omission of a speaker, or more generally an auditory stream, can alternatively be detected without selective attentional enhancement of the target stream. Several models and strategies could be envisaged for change detection in this case, including global comparison of the subsequent scenes.

Effects of Cross-modal Asynchrony on Informational Masking in Human Cortex.

In many everyday listening situations, an otherwise audible sound may go unnoticed amid multiple other sounds. This auditory phenomenon, called informational masking (IM), is sensitive to visual input and involves early (50-250 msec) activity in the auditory cortex (the so-called awareness-related negativity). It is still unclear whether and how the timing of visual input influences the neural correlates of IM in auditory cortex. To address this question, we obtained simultaneous behavioral and neural measures of IM from human listeners in the presence of a visual input stream and varied the asynchrony between the visual stream and the rhythmic auditory target stream (in-phase, antiphase, or random). Results show effects of cross-modal asynchrony on both target detectability (RT and sensitivity) and the awareness-related negativity measured with EEG, which were driven primarily by antiphasic audiovisual stimuli. The neural effect was limited to the interval shortly before listeners' behavioral report of the target. Our results indicate that the relative timing of visual input can influence the IM of a target sound in the human auditory cortex. They further show that this audiovisual influence occurs early during the perceptual buildup of the target sound. In summary, these findings provide novel insights into the interaction of IM and multisensory interaction in the human brain.

Stimulus dependence of contralateral dominance in human auditory cortex.

The auditory system is often considered to show little contralateral dominance but physiological reports on the contralateral dominance of activity evoked by monaural sound vary widely. Here, we show that part of this variation is stimulus-dependent: blood oxygen level dependent (BOLD) responses to 32 s of monaurally presented unmodulated noise (UN) showed activation in contralateral auditory cortex (AC) and deactivation in ipsilateral AC compared to nonstimulus baseline. Slow amplitude-modulated (AM) noise evoked strong contralateral activation and minimal ipsilateral activation. The contrast of AM-versus-UN was used to separate fMRI activity related to the slow amplitude modulation per se. This difference activation was bilateral although still stronger in contralateral AC. In magnetoencephalography (MEG), the response was dominated by the steady-state activity phase locked to the amplitude modulation. This MEG activity showed no consistent contralateral dominance across listeners. Subcortical BOLD activation was strongly contralateral subsequent to the superior olivary complex (SOC) and showed no significant difference between modulated and UN. An acallosal participant showed similar fMRI activation as the group, ruling transcallosal transmission an unlikely source of ipsilateral enhancement or ipsilateral deactivation. These results suggest that ascending activity subsequent to the SOC is strongly dominant contralateral to the stimulus ear. In contrast, the part of BOLD and MEG activity related to slow amplitude modulation is more bilateral and only observed in AC. Ipsilateral deactivation can potentially bias measures of contralateral BOLD dominance and should be considered in future studies.

Perceptual awareness of near-threshold tones scales gradually with auditory cortex activity and pupil dilation.

Negative-going responses in sensory cortex co-vary with perceptual awareness of sensory stimuli. Given that this awareness negativity has also been observed for undetected stimuli, some have challenged its role for perception. To address this question, we combined magnetoencephalography, electroencephalography, and pupillometry to study how sustained attention and response criterion affect the auditory awareness negativity. Participants first detected distractor sounds and denied hearing task-irrelevant near-threshold tones, which evoked neither awareness negativity nor pupil dilation. These same tones evoked both responses when task-relevant, stronger for hit but also present for miss trials. Participants then rated their perception on a six-point scale to test whether response criterion explains the presence of these responses for miss trials. Decreasing perception ratings were associated with gradually reduced evoked responses, consistent with signal detection theory. These results support the concept of an awareness negativity that is modulated by attention but does not require a non-linear threshold mechanism.

A role for retro-splenial cortex in the task-related P3 network.

OBJECTIVE: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. METHODS: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. RESULTS: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. CONCLUSIONS: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. SIGNIFICANCE: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

How anatomical asymmetry of human auditory cortex can lead to a rightward bias in auditory evoked fields.

Auditory evoked fields and potentials, such as the N1 or the 40-Hz steady state response, are often stronger in the right compared to the left auditory cortex. Here we investigated whether a greater degree of cortical folding in left auditory cortex could result in increased MEG signal cancelation and a subsequent bias in MEG auditory signals toward the right hemisphere. Signal cancelation, due to non-uniformity of the orientations of underlying neural currents, affects MEG and EEG signals generated by any neuronal activity of reasonable spatial extent. We simulated MEG signals in patches of auditory cortex in seventeen subjects, and measured the relationships between underlying activity distribution, cortical non-uniformity, signal cancelation and resulting (fitted) dipole strength and position. Our results suggest that the cancelation of MEG signals from auditory cortex is asymmetric, due to underlying anatomy, and this asymmetry may result in a rightward bias in measurable dipole amplitudes. The effect was significant across all auditory areas tested, with the exception of planum temporale. Importantly, we also show how the rightward bias could be partially or completely offset by increased cortical area, and therefore increased cortical activity, on the left side. We suggest that auditory researchers are aware of the impact of cancelation and its resulting rightward bias in signal strength from auditory cortex. These findings are important for studies seeking functional hemispheric specialization in the auditory cortex with MEG as well as for integration of MEG with other imaging modalities.

Role of pattern, regularity, and silent intervals in auditory stream segregation based on inter-aural time differences.

Tone triplets separated by a pause (ABA_) are a popular tone-repetition pattern to study auditory stream segregation. Such triplets produce a galloping rhythm when integrated, but isochronous rhythms when segregated. Other patterns lacking a pause may produce less-prominent rhythmic differences but stronger streaming. Here, we evaluated whether this difference is readily explained by the presence of the pause and potentially associated with the reduction of adaptation, or whether there is contribution of tone pattern per se. Sequences with repetitive ABA_ and ABAA patterns were presented in magnetoencephalography. A and B tones were separated by differences in inter-aural time differences (ΔITD). Results showed that the stronger streaming of ABAA was associated with a more prominent release from the adaptation of the P(1)m in auditory cortex. We further compared behavioral streaming responses for patterns with and without pauses, and varied the position of the pause and pattern regularity. Results showed a major effect of the pauses' presence, but no prominent effects of tone pattern or pattern regularity. These results make a case for the existence of an early, primitive streaming mechanism that does not require an analysis of the tone pattern at later stages suggested by predictive-coding models of auditory streaming. The results are better explained by the simpler population-separation model and stress the previously observed role of neural adaptation for streaming perception.

A role for retro-splenial cortex in the task-related P3 network.

Objective: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. Methods: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. Results: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. Conclusion: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. Significance: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

Correlates of perceptual awareness in human primary auditory cortex revealed by an informational masking experiment.

The presence of an auditory event may remain undetected in crowded environments, even when it is well above the sensory threshold. This effect, commonly known as informational masking, allows for isolating neural activity related to perceptual awareness, by comparing repetitions of the same physical stimulus where the target is either detected or not. Evidence from magnetoencephalography (MEG) suggests that auditory-cortex activity in the latency range 50-250 ms is closely coupled with perceptual awareness. Here, BOLD fMRI and MEG were combined to investigate at which stage in the auditory cortex neural correlates of conscious auditory perception can be observed. Participants were asked to indicate the perception of a regularly repeating target tone, embedded within a random multi-tone masking background. Results revealed widespread activation within the auditory cortex for detected target tones, which was delayed but otherwise similar to the activation of an unmasked control stimulus. The contrast of detected versus undetected targets revealed activity confined to medial Heschl's gyrus, where the primary auditory cortex is located. These results suggest that activity related to conscious perception involves the primary auditory cortex and is not restricted to activity in secondary areas.

Sustained BOLD and theta activity in auditory cortex are related to slow stimulus fluctuations rather than to pitch.

Human functional MRI (fMRI) and magnetoencephalography (MEG) studies indicate a pitch-specific area in lateral Heschl's gyrus. Single-cell recordings in monkey suggest that sustained-firing, pitch-specific neurons are located lateral to primary auditory cortex. We reevaluated whether pitch strength contrasts reveal sustained pitch-specific responses in human auditory cortex. Sustained BOLD activity in auditory cortex was found for iterated rippled noise (vs. noise or silence) but not for regular click trains (vs. jittered click trains or silence). In contrast, iterated rippled noise and click trains produced similar pitch responses in MEG. Subsequently performed time-frequency analysis of the MEG data suggested that the dissociation of cortical BOLD activity between iterated rippled noise and click trains is related to theta band activity. It appears that both sustained BOLD and theta activity are associated with slow non-pitch-specific stimulus fluctuations. BOLD activity in the inferior colliculus was sustained for both stimulus types and varied neither with pitch strength nor with the presence of slow stimulus fluctuations. These results suggest that BOLD activity in auditory cortex is much more sensitive to slow stimulus fluctuations than to constant pitch, compromising the accessibility of the latter. In contrast, pitch-related activity in MEG can easily be separated from theta band activity related to slow stimulus fluctuations.

Functional lateralization in auditory cortex under informational masking and in silence.

The N(1) m is an evoked magnetic field in auditory cortex that is automatically elicited by tones in silence but not in the context of multiple other tones: when listeners are unaware of a tone stream because of informational masking, no N(1) m-like activity is observed. In contrast, N(1) m-like activity is evoked when listeners are aware of the regular tone stream in the same context but in another trial. Here we compared this awareness-related negativity (ARN) with the automatic N(1) m. First, we evaluated whether stimulus lateralization by ear or interaural time differences modulates hemispheric lateralization of the response, as a putative marker of sensory processing. Second, we evaluated the stimulus-independent hemispheric balance thought to indicate higher level cortical processing. The results dissociate three, partly overlapping, time intervals: the P(1) m (45-85 ms) was evoked by missed and detected target tones alike. Subsequent negative activity was only observed when listeners indicated awareness of the target stream inside the multi-tone masker. In the N(1) m time interval (75-175 ms), hemispheric balance of the ARN and N(1) m was modulated by stimulus lateralization. In the subsequent time interval (175-275 ms), auditory-cortex activity was generally right-lateralized in silence and balanced under informational masking, but was not modulated by stimulus lateralization. These results suggest that the same auditory-cortex activity that varies with perceptual awareness also shows sensory response features. This is in accordance with models for visual perception, suggesting that sensory competition determines whether midlevel visual responses occur automatically or vary with perceptual state.

Sustained responses for pitch and vowels map to similar sites in human auditory cortex.

Several studies have shown enhancement of auditory evoked sustained responses for periodic over non-periodic sounds and for vowels over non-vowels. Here, we directly compared pitch and vowels using synthesized speech with a "damped" amplitude modulation. These stimuli were parametrically varied to yield four classes of matched stimuli: (1) periodic vowels (2) non-periodic vowels, (3) periodic non-vowels, and (4) non-periodic non-vowels. 12 listeners were studied with combined MEG and EEG. Sustained responses were reliably enhanced for vowels and periodicity. Dipole source analysis revealed that a vowel contrast (vowel-non-vowel) and the periodicity-pitch contrast (periodic-non-periodic) mapped to the same site in antero-lateral Heschl's gyrus. In contrast, the non-periodic, non-vowel condition mapped to a more medial and posterior site. The sustained enhancement for vowels was significantly more prominent when the vowel identity was varied, compared to a condition where only one vowel was repeated, indicating selective adaptation of the response. These results render it unlikely that there are spatially distinct fields for vowel and pitch processing in the auditory cortex. However, the common processing of vowels and pitch raises the possibility that there is an early speech-specific field in Heschl's gyrus.

Potential fMRI correlates of 40-Hz phase locking in primary auditory cortex, thalamus and midbrain.

MEG and BOLD fMRI are both related to post-synaptic activity, but not all components of the MEG appear to be equally reflected by the BOLD response. To evaluate potential BOLD correlates of the auditory 40-Hz steady-state response (SSR), 40-Hz amplitude-modulated (AM) tones and pure-tones with 1000-Hz tone frequency and 32-s tone duration were presented to 12 listeners in fMRI and MEG. The SSR evoked by AM-tones is readily separated from the onset, offset and sustained fields in MEG by a high-pass filter. For fMRI, a contrast of AM- versus pure-tones was used to estimate activity related more specifically to the 40-Hz SSR, but excluding other activity that is evoked by AM and pure-tones alike. This contrast showed sustained BOLD activation confined to the medial part of Heschl's gyrus, the location of the primary auditory cortex, as well as activity in the medial geniculate body (MGB) and the inferior colliculus (IC). Transient BOLD onset and offset responses were prominent throughout the auditory cortex. In contrast, sustained BOLD activity for pure-tones was weak and did not match well with the time course of the sustained field, suggesting that there is no reliable BOLD correlate of the sustained field in MEG. The sustained BOLD activity in primary auditory cortex is therefore more likely linked to the phase-locked SSR. Enhanced BOLD for AM compared to pure-tones in the IC and MGB may similarly be related to phase locking.

Transient bold activity locked to perceptual reversals of auditory streaming in human auditory cortex and inferior colliculus.

Our auditory system separates and tracks temporally interleaved sound sources by organizing them into distinct auditory streams. This streaming phenomenon is partly determined by physical stimulus properties but additionally depends on the internal state of the listener. As a consequence, streaming perception is often bistable and reversals between one- and two-stream percepts may occur spontaneously or be induced by a change of the stimulus. Here, we used functional MRI to investigate perceptual reversals in streaming based on interaural time differences (ITD) that produce a lateralized stimulus perception. Listeners were continuously presented with two interleaved streams, which slowly moved apart and together again. This paradigm produced longer intervals between reversals than stationary bistable stimuli but preserved temporal independence between perceptual reversals and physical stimulus transitions. Results showed prominent transient activity synchronized with the perceptual reversals in and around the auditory cortex. Sustained activity in the auditory cortex was observed during intervals where the ΔITD could potentially produce streaming, similar to previous studies. A localizer-based analysis additionally revealed transient activity time locked to perceptual reversals in the inferior colliculus. These data suggest that neural activity associated with streaming reversals is not limited to the thalamo-cortical system but involves early binaural processing in the auditory midbrain, already.

Neural correlates of auditory perceptual awareness under informational masking.

Our ability to detect target sounds in complex acoustic backgrounds is often limited not by the ear's resolution, but by the brain's information-processing capacity. The neural mechanisms and loci of this "informational masking" are unknown. We combined magnetoencephalography with simultaneous behavioral measures in humans to investigate neural correlates of informational masking and auditory perceptual awareness in the auditory cortex. Cortical responses were sorted according to whether or not target sounds were detected by the listener in a complex, randomly varying multi-tone background known to produce informational masking. Detected target sounds elicited a prominent, long-latency response (50-250 ms), whereas undetected targets did not. In contrast, both detected and undetected targets produced equally robust auditory middle-latency, steady-state responses, presumably from the primary auditory cortex. These findings indicate that neural correlates of auditory awareness in informational masking emerge between early and late stages of processing within the auditory cortex.