Frequency-Dependent Reduction of Cybersickness in Virtual Reality by Transcranial Oscillatory Stimulation of the Vestibular Cortex.

Virtual reality (VR) applications are pervasive of everyday life, as in working, medical, and entertainment scenarios. There is yet no solution to cybersickness (CS), a disabling vestibular syndrome with nausea, dizziness, and general discomfort that most of VR users undergo, which results from an integration mismatch among visual, proprioceptive, and vestibular information. In a double-blind, controlled trial, we propose an innovative treatment for CS, consisting of online oscillatory imperceptible neuromodulation with transcranial alternating current stimulation (tACS) at 10 Hz, biophysically modelled to reach the vestibular cortex bilaterally. tACS significantly reduced CS nausea in 37 healthy subjects during a VR rollercoaster experience. The effect was frequency-dependent and placebo-insensitive. Subjective benefits were paralleled by galvanic skin response modulation in 25 subjects, addressing neurovegetative activity. Besides confirming the role of transcranially delivered oscillations in physiologically tuning the vestibular system function (and dysfunction), results open a new way to facilitate the use of VR in different scenarios and possibly to help treating also other vestibular dysfunctions.

The effect of HD-tDCS on brain oscillations and frontal synchronicity during resting-state EEG in violent offenders with a substance dependence

Violence is a major problem in our society and therefore research into the neural underpinnings of aggression has grown exponentially. Although in the past decade the biological underpinnings of aggressive behavior have been examined, research on neural oscillations in violent offenders during resting-state electroencephalography (rsEEG) remains scarce. In this study we aimed to investigate the effect of high-definition transcranial direct current stimulation (HD-tDCS) on frontal theta, alpha and beta frequency power, asymmetrical frontal activity, and frontal synchronicity in violent offenders.Fifty male violent forensic patients diagnosed with a substance dependence were included in a double-blind sham-controlled randomized study. The patients received 20 minutes of HD-tDCS two times a day on five consecutive days. Before and after the intervention, the patients underwent a rsEEG task.Results showed no effect of HD-tDCS on the power in the different frequency bands. Also, no increase in asymmetrical activity was found. However, we found increased synchronicity in frontal regions in the alpha and beta frequency bands indicating enhanced connectivity in frontal brain regions as a result of the HD-tDCS-intervention.This study has enhanced our understanding of the neural underpinnings of aggression and violence, pointing to the importance of alpha and beta frequency bands and their connectivity in frontal brain regions. Although future studies should further investigate the complex neural underpinnings of aggression in different populations and using whole-brain connectivity, it can be suggested with caution, that HD-tDCS could be an innovative method to regain frontal synchronicity in neurorehabilitation. (AU)

TMS-EEG perturbation biomarkers for Alzheimer's disease patients classification.

The combination of TMS and EEG has the potential to capture relevant features of Alzheimer's disease (AD) pathophysiology. We used a machine learning framework to explore time-domain features characterizing AD patients compared to age-matched healthy controls (HC). More than 150 time-domain features including some related to local and distributed evoked activity were extracted from TMS-EEG data and fed into a Random Forest (RF) classifier using a leave-one-subject out validation approach. The best classification accuracy, sensitivity, specificity and F1 score were of 92.95%, 96.15%, 87.94% and 92.03% respectively when using a balanced dataset of features computed globally across the brain. The feature importance and statistical analysis revealed that the maximum amplitude of the post-TMS signal, its Hjorth complexity and the amplitude of the TEP calculated in the window 45-80 ms after the TMS-pulse were the most relevant features differentiating AD patients from HC. TMS-EEG metrics can be used as a non-invasive tool to further understand the AD pathophysiology and possibly contribute to patients' classification as well as longitudinal disease tracking.

The effect of HD-tDCS on brain oscillations and frontal synchronicity during resting-state EEG in violent offenders with a substance dependence.

Violence is a major problem in our society and therefore research into the neural underpinnings of aggression has grown exponentially. Although in the past decade the biological underpinnings of aggressive behavior have been examined, research on neural oscillations in violent offenders during resting-state electroencephalography (rsEEG) remains scarce. In this study we aimed to investigate the effect of high-definition transcranial direct current stimulation (HD-tDCS) on frontal theta, alpha and beta frequency power, asymmetrical frontal activity, and frontal synchronicity in violent offenders. Fifty male violent forensic patients diagnosed with a substance dependence were included in a double-blind sham-controlled randomized study. The patients received 20 minutes of HD-tDCS two times a day on five consecutive days. Before and after the intervention, the patients underwent a rsEEG task. Results showed no effect of HD-tDCS on the power in the different frequency bands. Also, no increase in asymmetrical activity was found. However, we found increased synchronicity in frontal regions in the alpha and beta frequency bands indicating enhanced connectivity in frontal brain regions as a result of the HD-tDCS-intervention. This study has enhanced our understanding of the neural underpinnings of aggression and violence, pointing to the importance of alpha and beta frequency bands and their connectivity in frontal brain regions. Although future studies should further investigate the complex neural underpinnings of aggression in different populations and using whole-brain connectivity, it can be suggested with caution, that HD-tDCS could be an innovative method to regain frontal synchronicity in neurorehabilitation.

Boosting psychological change: Combining non-invasive brain stimulation with psychotherapy.

Mental health disorders and substance use disorders are a leading cause of morbidity and mortality worldwide, and one of the most important challenges for public health systems. While evidence-based psychotherapy is generally pursued to address mental health challenges, psychological change is often hampered by non-adherence to treatments, relapses, and practical barriers (e.g., time, cost). In recent decades, Non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to directly target dysfunctional neural circuitry and promote long-lasting plastic changes. While the therapeutic efficacy of NIBS protocols for mental illnesses has been established, neuromodulatory interventions might also be employed to support the processes activated by psychotherapy. Indeed, combining psychotherapy with NIBS might help tailor the treatment to the patient's unique characteristics and therapeutic goal, and would allow more direct control of the neuronal changes induced by therapy. Herein, we overview emerging evidence on the use of NIBS to enhance the psychotherapeutic effect, while highlighting the next steps in advancing clinical and research methods toward personalized intervention approaches.

Neural correlates of N-back task performance and proposal for corresponding neuromodulation targets in psychiatric and neurodevelopmental disorders.

AIM: Working memory (WM) deficit represents the most common cognitive impairment in psychiatric and neurodevelopmental disorders, making the identification of its neural substrates a crucial step towards the conceptualization of restorative interventions. We present a meta-analysis focusing on neural activations associated with the most commonly used task to measure WM, the N-back task, in patients with schizophrenia, depressive disorder, bipolar disorder, and attention-deficit/hyperactivity disorder. Showing qualitative similarities and differences in WM processing between patients and healthy controls, we propose possible targets for cognitive enhancement approaches. METHODS: Selected studies, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, were analyzed through the activation likelihood estimate statistical framework, with subsequent generation of disorder-specific N-back activation maps. RESULTS: Despite similar WM deficits shared across all disorders, results highlighted different brain activation patterns for each disorder compared with healthy controls. In general, results showed brain activity in frontal, parietal, subcortical, and cerebellar regions; however, reduced engagement of specific nodes of the fronto-parietal network emerged in patients compared with healthy controls. In particular, neither bipolar nor depressive disorders showed detectable activations in the dorsolateral prefrontal cortices, while their parietal activation patterns were lateralized to the left and right hemispheres, respectively. On the other hand, patients with attention-deficit/hyperactivity disorder showed a lack of activation in the left parietal lobe, whereas patients with schizophrenia showed lower activity over the left prefrontal cortex. CONCLUSION: These results, together with biophysical modeling, were then used to discuss the design of future disorder-specific cognitive enhancement interventions based on noninvasive brain stimulation.

Transcranial Direct Current Stimulation Targeting the Ventromedial Prefrontal Cortex Reduces Reactive Aggression and Modulates Electrophysiological Responses in a Forensic Population.

BACKGROUND: Studies have shown that impairments in the ventromedial prefrontal cortex play a crucial role in violent behavior in forensic patients who also abuse cocaine and alcohol. Moreover, interventions that aimed to reduce violence risk in those patients are found not to be optimal. A promising intervention might be to modulate the ventromedial prefrontal cortex by high-definition (HD) transcranial direct current stimulation (tDCS). The current study aimed to examine HD-tDCS as an intervention to increase empathic abilities and reduce violent behavior in forensic substance dependent offenders. In addition, using electroencephalography, we examined the effects on the P3 and the late positive potential of the event-related potentials in reaction to situations that depict victims of aggression. METHODS: Fifty male forensic patients with a substance dependence were tested in a double-blind, placebo-controlled randomized study. The patients received HD-tDCS 2 times a day for 20 minutes for 5 consecutive days. Before and after the intervention, the patients completed self-reports and performed the Point Subtraction Aggression Paradigm, and electroencephalography was recorded while patients performed an empathy task. RESULTS: Results showed a decrease in aggressive responses on the Point Subtraction Aggression Paradigm and in self-reported reactive aggression in the active tDCS group. Additionally, we found a general increase in late positive potential amplitude after active tDCS. No effects on trait empathy and the P3 were found. CONCLUSIONS: Current findings are the first to find positive effects of HD-tDCS in reducing aggression and modulating electrophysiological responses in forensic patients, showing the potential of using tDCS as an intervention to reduce aggression in forensic mental health care.

Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

Thalamic altered spontaneous activity and connectivity in obstructive sleep apnea syndrome.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) syndrome is a sleep disorder characterized by excessive snoring, repetitive apneas, and nocturnal arousals, that leads to fragmented sleep and intermittent nocturnal hypoxemia. Morphometric and functional brain alterations in cortical and subcortical structures have been documented in these patients via magnetic resonance imaging (MRI), even if correlational data between the alterations in the brain and cognitive and clinical indexes are still not reported. METHODS: We examined the impact of OSA on brain spontaneous activity by measuring the fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional MRI data of 20 drug-naïve patients with OSA syndrome and 20 healthy controls matched for age, gender, and body mass index. RESULTS: Patients showed a pattern of significantly abnormal subcortical functional activity as compared to controls, with increased activity selectively involving the thalami, specifically their intrinsic nuclei connected to somatosensory and motor-premotor cortical regions. Using these nuclei as seed regions, the subsequent functional connectivity analysis highlighted an increase in patients' thalamocortical connectivity at rest. Additionally, the correlation between fALFF and polysomnographic data revealed a possible link between OSA severity and fALFF of regions belonging to the central autonomic network. CONCLUSIONS: Our results suggest a hyperactivation in thalamic diurnal activity in patients with OSA syndrome, which we interpret as a possible consequence of increased thalamocortical circuitry activation during nighttime due to repeated arousals.

Emerging of new bioartificial corticospinal motor synergies using a robotic additional thumb.

It is likely that when using an artificially augmented hand with six fingers, the natural five plus a robotic one, corticospinal motor synergies controlling grasping actions might be different. However, no direct neurophysiological evidence for this reasonable assumption is available yet. We used transcranial magnetic stimulation of the primary motor cortex to directly address this issue during motor imagery of objects' grasping actions performed with or without the Soft Sixth Finger (SSF). The SSF is a wearable robotic additional thumb patented for helping patients with hand paresis and inherent loss of thumb opposition abilities. To this aim, we capitalized from the solid notion that neural circuits and mechanisms underlying motor imagery overlap those of physiological voluntary actions. After a few minutes of training, healthy humans wearing the SSF rapidly reshaped the pattern of corticospinal outputs towards forearm and hand muscles governing imagined grasping actions of different objects, suggesting the possibility that the extra finger might rapidly be encoded into the user's body schema, which is integral part of the frontal-parietal grasping network. Such neural signatures might explain how the motor system of human beings is open to very quickly welcoming emerging augmentative bioartificial corticospinal grasping strategies. Such an ability might represent the functional substrate of a final common pathway the brain might count on towards new interactions with the surrounding objects within the peripersonal space. Findings provide a neurophysiological framework for implementing augmentative robotic tools in humans and for the exploitation of the SSF in conceptually new rehabilitation settings.

Mindfulness-based stress reduction training modulates striatal and cerebellar connectivity.

Mindfulness is a meditation practice frequently associated with changes in subjective evaluation of cognitive and sensorial experience, as well as with modifications of brain activity and morphometry. Aside from the anatomical localization of functional changes induced by mindfulness practice, little is known about changes in functional and effective functional magnetic resonance imaging (fMRI) connectivity. Here we performed a connectivity fMRI analysis in a group of healthy individuals participating in an 8-week mindfulness-based stress reduction (MBSR) training program. Data from both a "mind-wandering" and a "meditation" state were acquired before and after the MBSR course. Results highlighted decreased local connectivity after training in the right anterior putamen and insula during spontaneous mind-wandering and the right cerebellum during the meditative state. A further effective connectivity analysis revealed (a) decreased modulation by the anterior cingulate cortex over the anterior portion of the putamen, and (b) a change in left and right posterior putamen excitatory input and inhibitory output with the cerebellum, respectively. Results suggest a rearrangement of dorsal striatum functional and effective connectivity in response to mindfulness practice, with changes in cortico-subcortical-cerebellar modulatory dynamics. Findings might be relevant for the understanding of widely documented mindfulness behavioral effects, especially those related to pain perception.

Sleep, Noninvasive Brain Stimulation, and the Aging Brain: Challenges and Opportunities.

As we age, sleep patterns undergo severe modifications of their micro and macrostructure, with an overall lighter and more fragmented sleep structure. In general, interventions targeting sleep represent an excellent opportunity not only to maintain life quality in the healthy aging population, but also to enhance cognitive performance and, when pathology arises, to potentially prevent/slow down conversion from e.g. Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Sleep abnormalities are, in fact, one of the earliest recognizable biomarkers of dementia, being also partially responsible for a cascade of cortical events that worsen dementia pathophysiology, including impaired clearance systems leading to build-up of extracellular amyloid-ß (Aß) peptide and intracellular hyperphosphorylated tau proteins. In this context, Noninvasive Brain Stimulation (NiBS) techniques, such as transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS), may help investigate the neural substrates of sleep, identify sleep-related pathology biomarkers, and ultimately help patients and healthy elderly individuals to restore sleep quality and cognitive performance. However, brain stimulation applications during sleep have so far not been fully investigated in healthy elderly cohorts, nor tested in AD patients or other related dementias. The manuscript discusses the role of sleep in normal and pathological aging, reviewing available evidence of NiBS applications during both wakefulness and sleep in healthy elderly individuals as well as in MCI/AD patients. Rationale and details for potential future brain stimulation studies targeting sleep alterations in the aging brain are discussed, including enhancement of cognitive performance, overall quality of life as well as protein clearance.