Limited output transcranial electrical stimulation 2023 (LOTES-2023): Updates on engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.

The objective and scope of this Limited Output Transcranial Electrical Stimulation 2023 (LOTES-2023) guidance is to update the previous LOTES-2017 guidance. These documents should therefore be considered together. The LOTES provides a clearly articulated and transparent framework for the design of devices providing limited output (specified low-intensity range) transcranial electrical stimulation for a variety of intended uses. These guidelines can inform trial design and regulatory decisions, but most directly inform manufacturer activities - and hence were presented in LOTES-2017 as "Voluntary industry standard for compliance controlled limited output tES devices". In LOTES-2023 we emphasize that these standards are largely aligned across international standards and national regulations (including those in USA, EU, and South Korea), and so might be better understood as "Industry standards for compliance controlled limited output tES devices". LOTES-2023 is therefore updated to reflect a consensus among emerging international standards, as well as best available scientific evidence. "Warnings" and "Precautions" are updated to align with current biomedical evidence and applications. LOTES standards applied to a constrained device dose range, but within this dose range and for different use-cases, manufacturers are responsible to conduct device-specific risk management.

Making sense: Dopamine activates conscious self-monitoring through medial prefrontal cortex.

When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self-awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self-awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self-awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self-awareness. In a separate experiment with extended self-awareness dopamine improved the retrieval accuracy of memories of self-judgment (autonoetic, i.e., explicitly self-conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self-awareness, this explains the specific effect of dopamine on explicit self-awareness and autonoetic metacognition.

Ready for action: a role for the human midbrain in responding to infant vocalizations.

Infant vocalizations are among the most biologically salient sounds in the environment and can draw the listener to the infant rapidly in both times of distress and joy. A region of the midbrain, the periaqueductal gray (PAG), has long been implicated in the control of urgent, survival-related behaviours. To test for PAG involvement in the processing of infant vocalizations, we recorded local field potentials from macroelectrodes implanted in this region in four adults who had undergone deep brain stimulation. We found a significant difference occurring as early as 49 ms after hearing a sound in activity recorded from the PAG in response to infant vocalizations compared with constructed control sounds and adult and animal affective vocalizations. This difference was not present in recordings from thalamic electrodes implanted in three of the patients. Time frequency analyses revealed distinct patterns of activity in the PAG for infant vocalisations, constructed control sounds and adult and animal vocalisations. These results suggest that human infant vocalizations can be discriminated from other emotional or acoustically similar sounds early in the auditory pathway. We propose that this specific, rapid activity in response to infant vocalizations may reflect the initiation of a state of heightened alertness necessary to instigate protective caregiving.

How delays matter in an oscillatory whole-brain spiking-neuron network model for MEG alpha-rhythms at rest.

In recent years the study of the intrinsic brain dynamics in a relaxed awake state in the absence of any specific task has gained increasing attention, as spontaneous neural activity has been found to be highly structured at a large scale. This so called resting-state activity has been found to be comprised by nonrandom spatiotemporal patterns and fluctuations, and several Resting-State Networks (RSN) have been found in BOLD-fMRI as well as in MEG signal power envelope correlations. The underlying anatomical connectivity structure between areas of the brain has been identified as being a key to the observed functional network connectivity, but the mechanisms behind this are still underdetermined. Theoretical large-scale brain models for fMRI data have corroborated the importance of the connectome in shaping network dynamics, while the importance of delays and noise differ between studies and depend on the models' specific dynamics. In the current study, we present a spiking neuron network model that is able to produce noisy, distributed alpha-oscillations, matching the power peak in the spectrum of group resting-state MEG recordings. We studied how well the model captured the inter-node correlation structure of the alpha-band power envelopes for different delays between brain areas, and found that the model performs best for propagation delays inside the physiological range (5-10 m/s). Delays also shift the transition from noisy to bursting oscillations to higher global coupling values in the model. Thus, in contrast to the asynchronous fMRI state, delays are important to consider in the presence of oscillation.

Exploring mechanisms of spontaneous functional connectivity in MEG: how delayed network interactions lead to structured amplitude envelopes of band-pass filtered oscillations.

Spontaneous (or resting-state) brain activity has attracted a growing body of neuroimaging research over the last decades. Whole-brain network models have proved helpful to investigate the source of slow (<0.1 Hz) correlated hemodynamic fluctuations revealed in fMRI during rest. However, the mechanisms mediating resting-state long-distance correlations and the relationship with the faster neural activity remain unclear. Novel insights coming from MEG studies have shown that the amplitude envelopes of alpha- and beta-frequency oscillations (~8-30 Hz) display similar correlation patterns as the fMRI signals. In this work, we combine experimental and theoretical work to investigate the mechanisms of spontaneous MEG functional connectivity. Using a simple model of coupled oscillators adapted to incorporate realistic whole-brain connectivity and conduction delays, we explore how slow and structured amplitude envelopes of band-pass filtered signals - fairly reproducing MEG data collected from 10 healthy subjects at rest - are generated spontaneously in the space-time structure of the brain network. Our simulation results show that the large-scale neuroanatomical connectivity provides an optimal network structure to support a regime with metastable synchronization. In this regime, different subsystems may temporarily synchronize at reduced collective frequencies (falling in the 8-30 Hz range due to the delays) while the global system never fully synchronizes. This mechanism modulates the frequency of the oscillators on a slow time-scale (<0.1 Hz) leading to structured amplitude fluctuations of band-pass filtered signals. Taken overall, our results reveal that the structured amplitude envelope fluctuations observed in resting-state MEG data may originate from spontaneous synchronization mechanisms naturally occurring in the space-time structure of the brain.

Minor structural abnormalities in the infant face disrupt neural processing: a unique window into early caregiving responses.

Infant faces elicit early, specific activity in the orbitofrontal cortex (OFC), a key cortical region for reward and affective processing. A test of the causal relationship between infant facial configuration and OFC activity is provided by naturally occurring disruptions to the face structure. One such disruption is cleft lip, a small change to one facial feature, shown to disrupt parenting. Using magnetoencephalography, we investigated neural responses to infant faces with cleft lip compared with typical infant and adult faces. We found activity in the right OFC at 140 ms in response to typical infant faces but diminished activity to infant faces with cleft lip or adult faces. Activity in the right fusiform face area was of similar magnitude for typical adult and infant faces but was significantly lower for infant faces with cleft lip. This is the first evidence that a minor change to the infant face can disrupt neural activity potentially implicated in caregiving.

Altered paralimbic interaction in behavioral addiction.

The introduction of magnetoencephalography has made it possible to study electromagnetic signaling in deeper, paralimbic cortical structures such as the medial prefrontal/anterior cingulate (ACC) and medial parietal/posterior cingulate (PCC) cortices. Self-awareness and self-control have been attributed to these regions. To test the hypothesis that they are dysfunctional in pathological gambling with poor self-control, we studied gamblers with and without previous stimulant abuse and age- and sex-matched controls. We found that pathological gamblers were more impulsive than controls in a stop-signal task and attributed this to changes in the activity of the paralimbic network: Pathological gamblers had reduced synchronization at rest in the high gamma range (55-100 Hz) compared with controls and failed to show an increase in gamma synchronization during rest compared with the task, as observed in controls. Subgroup analysis revealed that pathological gamblers without a history of stimulant abuse had lower PCC power during the stop-signal task compared with controls and gamblers with previous stimulant abuse. Furthermore, gamblers with a history of stimulant abuse had up to four times higher power at the ACC site during rest and the task compared with controls. In conclusion, pathological gamblers had higher impulsivity and functional paralimbic abnormalities, which could not be explained by a history of stimulant abuse. In addition, previous stimulant abuse had a marked effect on the amplitude of oscillatory brain activity in the ACC and PCC, suggesting long-term deleterious effects of repeated dopaminergic drug exposure. These consequences should be investigated in more detail in longitudinal studies.

Yoga lessons for consciousness research: a paralimbic network balancing brain resource allocation.

Consciousness has been proposed to play a key role in shaping flexible learning and as such is thought to confer an evolutionary advantage. Attention and awareness are the perhaps most important underlying processes, yet their precise relationship is presently unclear. Both of these processes must, however, serve the evolutionary imperatives of survival and procreation. They are thus intimately bound by reward and emotion to help to prioritize efficient brain resource allocation in order to predict and optimize behavior. Here we show how this process is served by a paralimbic network consisting primarily of regions located on the midline of the human brain. Using many different techniques, experiments have demonstrated that this network is effective and specific for self-awareness and contributes to the sense of unity of consciousness by acting as a common neural path for a wide variety of conscious experiences. Interestingly, hemodynamic activity in the network decreases with focusing on external stimuli, which has led to the idea of a default mode network. This network is one of many networks that wax and vane as resources are allocated to accommodate the different cyclical needs of the organism primarily related to the fundamental pleasures afforded by evolution: food, sex, and conspecifics. Here we hypothesize, however, that the paralimbic network serves a crucial role in balancing and regulating brain resource allocation, and discuss how it can be thought of as a link between current theories of so-called "default mode," "resting state networks," and "global workspace." We show how major developmental disorders of self-awareness and self-control can arise from problems in the paralimbic network as demonstrated here by the example of Asperger syndrome. We conclude that attention, awareness, and emotion are integrated by a paralimbic network that helps to efficiently allocate brain resources to optimize behavior and help survival.

Recurrent activity in higher order, modality non-specific brain regions: a Granger causality analysis of autobiographic memory retrieval.

It has been proposed that the workings of the brain are mainly intrinsically generated recurrent neuronal activity, with sensory inputs as modifiers of such activity in both sensory and higher order modality non-specific regions. This is supported by the demonstration of recurrent neuronal activity in the visual system as a response to visual stimulation. In contrast recurrent activity has never been demonstrated before in higher order modality non-specific regions. Using magneto-encephalography and Granger causality analysis, we tested in a paralimbic network the hypothesis that stimulation may enhance causal recurrent interaction between higher-order, modality non-specific regions. The network includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices together with pulvinar thalami, a network known to be effective in autobiographic memory retrieval and self-awareness. Autobiographic memory retrieval of previous personal judgments of visually presented words was used as stimuli. It is demonstrated that the prestimulus condition is characterized by causal, recurrent oscillations which are maximal in the lower gamma range. When retrieving previous judgments of visually presented adjectives, this activity is dramatically increased during the stimulus task as ascertained by Granger causality analysis. Our results confirm the hypothesis that stimulation may enhance causal interaction between higher order, modality non-specific brain regions, exemplified in a network of autobiographical memory retrieval.

Impact of emotion on consciousness: positive stimuli enhance conscious reportability.

Emotion and reward have been proposed to be closely linked to conscious experience, but empirical data are lacking. The anterior cingulate cortex (ACC) plays a central role in the hedonic dimension of conscious experience; thus potentially a key region in interactions between emotion and consciousness. Here we tested the impact of emotion on conscious experience, and directly investigated the role of the ACC. We used a masked paradigm that measures conscious reportability in terms of subjective confidence and objective accuracy in identifying the briefly presented stimulus in a forced-choice test. By manipulating the emotional valence (positive, neutral, negative) and the presentation time (16 ms, 32 ms, 80 ms) we measured the impact of these variables on conscious and subliminal (i.e. below threshold) processing. First, we tested normal participants using face and word stimuli. Results showed that participants were more confident and accurate when consciously seeing happy versus sad/neutral faces and words. When stimuli were presented subliminally, we found no effect of emotion. To investigate the neural basis of this impact of emotion, we recorded local field potentials (LFPs) directly in the ACC in a chronic pain patient. Behavioural findings were replicated: the patient was more confident and accurate when (consciously) seeing happy versus sad faces, while no effect was seen in subliminal trials. Mirroring behavioural findings, we found significant differences in the LFPs after around 500 ms (lasting 30 ms) in conscious trials between happy and sad faces, while no effect was found in subliminal trials. We thus demonstrate a striking impact of emotion on conscious experience, with positive emotional stimuli enhancing conscious reportability. In line with previous studies, the data indicate a key role of the ACC, but goes beyond earlier work by providing the first direct evidence of interaction between emotion and conscious experience in the human ACC.