Auditory attention detection (AAD) is promising for use in auditory-assistive devices to detect to which sound the user is attending. Being able to train subjects in achieving high AAD performance would greatly increase its application potential. In order to do so an acceptable temporal resolution and online implementation are essential prerequisites. Consequently, users of an online AAD can be presented with feedback about their performance. Here we describe two studies that investigate the effects of online AAD with feedback. In the first study, we implemented a fully automated closed-loop system that allows for user-friendly recording environments. Subjects were presented online with visual feedback on their ongoing AAD performance. Following these results we implemented a longitudinal case study in which two subjects were presented with AAD sessions during four weeks. The results prove the feasibility of a fully working online (neuro)feedback system for AAD decoding. The detected changes in AAD for the feedback subject during and after training suggest that changes in AAD may be achieved via training. This is early evidence of such training effects and needs to be confirmed in future studies to evaluate training of AAD in more detail. Finally, the large number of sessions allowed to examine the correlation between the stimuli (i.e. acoustic stories) and AAD performance which was found to be significant. Future studies are suggested to evaluate their acoustic stimuli with care to prevent spurious associations.

Background and purpose: In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. Methods: In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders. Results: Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). Conclusion: Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

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Selective neuromodulation using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) has become an increasingly important research tool, as well as an emerging therapeutic approach. However, the safety profile of DREADD expression is unknown. Here, different titers of adeno-associated viral (AAV) vector were administered in an attempt to vary total expression levels of the inhibitory DREADD hM4D(Gi) in excitatory hippocampal neurons. Male Sprague-Dawley rats were injected with AAV2/7 encoding DREADD-mCherry, DREADD or mCherry. Pronounced neuronal loss and neuroinflammatory reactions were observed after transduction with the high titer DREADD AAV, which also resulted in the highest DREADD expression levels. No such effects were observed in the mCherry control group, despite an equally high titer, nor in conditions where lower viral vector titers were injected. In the high titer DREADD conditions, dentate gyrus evoked potentials were inhibited upon clozapine-induced activation of hM4D(Gi), while in low titer conditions dentate gyrus evoked potentials were enhanced. Recordings of single neuronal activity nevertheless indicated a reduction in spontaneous firing of granule cell layer neurons. Our results indicate that prolonged, high levels of DREADD expression can have neurotoxic effects and that chemogenetic suppression of excitatory hippocampal neurons can paradoxically enhance dentate gyrus evoked potentials. Significance statementDesigner receptors exclusively activated by designer drugs (DREADDs) are engineered receptors that can be used to selectively modulate specific groups of cells. Especially in neuroscience, DREADDs are widely adopted. However, there is not much known on their safety profile. Here, we assess the effect of different expression levels of the DREADD hM4D(Gi) by varying the titer of the adeno-associated viral (AAV) vector used to transduce specific neurons in the rat's brain. We found that high expression levels result in strong neuromodulatory effects, but also induce neuronal loss and tissue damage. Less pronounced, non-toxic expression levels paradoxically seem to display opposite neuromodulatory effects at network level.

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