Optimizing transcranial magnetic stimulation for spaceflight applications.

As space agencies aim to reach and build installations on Mars, the crews will face longer exposure to extreme environments that may compromise their health and performance. Transcranial magnetic stimulation (TMS) is a painless non-invasive brain stimulation technique that could support space exploration in multiple ways. However, changes in brain morphology previously observed after long-term space missions may impact the efficacy of this intervention. We investigated how to optimize TMS for spaceflight-associated brain changes. Magnetic resonance imaging T1-weighted scans were collected from 15 Roscosmos cosmonauts and 14 non-flyer participants before, after 6 months on the International Space Station, and at a 7-month follow-up. Using biophysical modeling, we show that TMS generates different modeled responses in specific brain regions after spaceflight in cosmonauts compared to the control group. Differences are related to spaceflight-induced structural brain changes, such as those impacting cerebrospinal fluid volume and distribution. We suggest solutions to individualize TMS to enhance its efficacy and precision for potential applications in long-duration space missions.

Targeting neural correlates of placebo effects.

Harnessing the placebo effects would prompt critical ramifications for research and clinical practice. Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation and multifocal transcranial electric stimulation, could manipulate the placebo response by modulating the activity and excitability of its neural correlates. To identify potential stimulation targets, we conducted a meta-analysis to investigate placebo-associated regions in healthy volunteers, including studies with emotional components and painful stimuli. Using biophysical modeling, we identified NIBS solutions to manipulate placebo effects by targeting either a single key region or multiple connected areas. Moving to a network-oriented approach, we then ran a quantitative network mapping analysis on the functional connectivity profile of clusters emerging from the meta-analysis. As a result, we suggest a multielectrode optimized montage engaging the connectivity patterns of placebo-associated functional brain networks. These NIBS solutions hope to provide a starting point to actively control, modulate or enhance placebo effects in future clinical studies and cognitive enhancement studies.

Enhancement of semantic integration reasoning by tRNS.

The right hemisphere is involved with the integrative processes necessary to achieve global coherence during reasoning and discourse processing. Specifically, the right temporal lobe has been proven to facilitate the processing of distant associate relationships, such as generating novel ideas. Previous studies showed a specific swing of alpha and gamma oscillatory activity over the right parieto-occipital lobe and the right anterior temporal lobe respectively, when people solve semantic problems with a specific strategy, i.e., insight problem-solving. In this study, we investigated the specificity of the right parietal and temporal lobes for semantic integration using transcranial Random Noise Stimulation (tRNS). We administered a set of pure semantics (i.e., Compound Remote Associates [CRA]) and visuo-semantic problems (i.e., Rebus Puzzles) to a sample of 31 healthy volunteers. Behavioral results showed that tRNS stimulation over the right temporal lobe enhances CRA accuracy (+12%), while stimulation on the right parietal lobe causes a decrease of response time on the same task (-2,100 ms). No effects were detected for Rebus Puzzles. Our findings corroborate the involvement of the right temporal and parietal lobes when solving purely semantic problems but not when they involve visuo-semantic material, also providing causal evidence for their postulated different roles in the semantic integration process and promoting tRNS as a candidate tool to boost verbal reasoning in humans.

The Sleep Side of Aging and Alzheimer's Disease.

As we age, sleep patterns undergo significant modifications in micro and macrostructure, worsening cognition and quality of life. These are associated with remarkable brain changes, like deterioration in synaptic plasticity, gray and white matter, and significant modifications in hormone levels. Sleep alterations are also a core component of mild cognitive impairment (MCI) and Alzheimer's Disease (AD). AD night time is characterized by a gradual decrease in slow-wave activity and a substantial reduction of REM sleep. Sleep abnormalities can accelerate AD pathophysiology, promoting the accumulation of amyloid-ß (Aß) and phosphorylated tau. Thus, interventions that target sleep disturbances in elderly people and MCI patients have been suggested as a possible strategy to prevent or decelerate conversion to dementia. Although cognitive-behavioral therapy and pharmacological medications are still first-line treatments, despite being scarcely effective, new interventions have been proposed, such as sensory stimulation and Noninvasive Brain Stimulation (NiBS). The present review outlines the current state of the art of the relationship between sleep modifications in healthy aging and the neurobiological mechanisms underlying age-related changes. Furthermore, we provide a critical analysis showing how sleep abnormalities influence the prognosis of AD pathology by intensifying Aß and tau protein accumulation. We discuss potential therapeutic strategies to target sleep disruptions and conclude that there is an urgent need for testing new therapeutic sleep interventions.

Noninvasive Brain Stimulation & Space Exploration: Opportunities and Challenges.

As NASA prepares for longer space missions aiming for the Moon and Mars, astronauts' health and performance are becoming a central concern due to the threats associated with galactic cosmic radiation, unnatural gravity fields, and life in extreme environments. In space, the human brain undergoes functional and structural changes related to fluid shift and changes in intracranial pressure. Behavioral abnormalities, such as cognitive deficits, sleep disruption, and visuomotor difficulties, as well as psychological effects, are also an issue. We discuss opportunities and challenges of noninvasive brain stimulation (NiBS) methods - including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) - to support space exploration in several ways. NiBS includes safe and portable techniques already applied in a wide range of cognitive and motor domains, as well as therapeutically. NiBS could be used to enhance in-flight performance, supporting astronauts during pre-flight Earth-based training, as well as to identify biomarkers of post-flight brain changes for optimization of rehabilitation/compensatory strategies. We review these NiBS techniques and their effects on brain physiology, psychology, and cognition.

Transcranial Direct Current Stimulation over the Left Dorsolateral Prefrontal Cortex Improves Inhibitory Control and Endurance Performance in Healthy Individuals.

The dorsolateral prefrontal cortex (DLPFC) is a crucial brain region for inhibitory control, an executive function essential for behavioral self-regulation. Recently, inhibitory control has been shown to be important for endurance performance. Improvement in inhibitory control was found following transcranial direct current stimulation (tDCS) applied over the left DLPFC (L-DLPFC). This study examined the effect tDCS on both an inhibitory control and endurance performance in a group of healthy individuals. Twelve participants received either real tDCS (Real-tDCS) or placebo tDCS (Sham-tDCS) in randomized order. The anodal electrode was placed over the L-DLPFC while the cathodal electrode was placed above Fp2. Stimulation lasted 30min with current intensity set at 2mA. A Stroop test was administered to assess inhibitory control. Heart rate (HR), ratings of perceived exertion (RPE), and leg muscle pain (PAIN) were monitored during the cycling time to exhaustion (TTE) test, while blood lactate accumulation (∆B[La-]) was measured at exhaustion. Stroop task performance was improved after Real-tDCS as demonstrated by a lower number of errors for incongruent stimuli (p=0.012). TTE was significantly longer following Real-tDCS compared to Sham-tDCS (p=0.029, 17±8 vs 15±8min), with significantly lower HR (p=0.002) and RPE (p<0.001), while no significant difference was found for PAIN (p>0.224). ∆B[La-] was significantly higher at exhaustion in Real-tDCS (p=0.040). Our findings provide preliminary evidence that tDCS with the anodal electrode over the L-DLPFC can improve both inhibitory control and endurance cycling performance in healthy individuals.

Reduction of intratumoral brain perfusion by noninvasive transcranial electrical stimulation.

Malignant brain neoplasms have a poor prognosis despite aggressive treatments. Animal models and evidence from human bodily tumors reveal that sustained reduction in tumor perfusion via electrical stimulation promotes tumor necrosis, therefore possibly representing a therapeutic option for patients with brain tumors. Here, we demonstrate that transcranial electrical stimulation (tES) allows to safely and noninvasively reduce intratumoral perfusion in humans. Selected patients with glioblastoma or metastasis underwent tES, while perfusion was assessed using magnetic resonance imaging. Multichannel tES was applied according to personalized biophysical modeling, to maximize the induced electrical field over the solid tumor mass. All patients completed the study and tolerated the procedure without adverse effects, with tES selectively reducing the perfusion of the solid tumor. Results potentially open the door to noninvasive therapeutic interventions in brain tumors based on stand-alone tES or its combination with other available therapies.

Bilateral extracephalic transcranial direct current stimulation improves endurance performance in healthy individuals.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been used to enhance endurance performance but its precise mechanisms and effects remain unknown. OBJECTIVE: To investigate the effect of bilateral tDCS on neuromuscular function and performance during a cycling time to task failure (TTF) test. METHODS: Twelve participants in randomized order received a placebo tDCS (SHAM) or real tDCS with two cathodes (CATHODAL) or two anodes (ANODAL) over bilateral motor cortices and the opposite electrode pair over the ipsilateral shoulders. Each session lasted 10 min and current was set at 2 mA. Neuromuscular assessment was performed before and after tDCS and was followed by a cycling time to task failure (TTF) test. Heart rate (HR), ratings of perceived exertion (RPE), leg muscle pain (PAIN) and blood lactate accumulation (ΔB[La-]) in response to the cycling TTF test were measured. RESULTS: Corticospinal excitability increased in the ANODAL condition (P < 0.001) while none of the other neuromuscular parameters showed any change. Neuromuscular parameters did not change in the SHAM and CATHODAL conditions. TTF was significantly longer in the ANODAL (P = 0.003) compared to CATHODAL and SHAM conditions (12.61 ± 4.65 min; 10.61 ± 4.34 min; 10.21 ± 3.47 min respectively), with significantly lower RPE and higher ΔB[La-] (P < 0.001). No differences between conditions were found for HR (P = 0.803) and PAIN during the cycling TTF test (P = 0.305). CONCLUSION: Our findings demonstrate that tDCS with the anode over both motor cortices using a bilateral extracephalic reference improves endurance performance.

Multifocal tDCS targeting the resting state motor network increases cortical excitability beyond traditional tDCS targeting unilateral motor cortex.

Scientists and clinicians have traditionally targeted single brain regions with stimulation to modulate brain function and disease. However, brain regions do not operate in isolation, but interact with other regions through networks. As such, stimulation of one region may impact and be impacted by other regions in its network. Here we test whether the effects of brain stimulation can be enhanced by simultaneously targeting a region and its network, identified with resting state functional connectivity MRI. Fifteen healthy participants received two types of transcranial direct current stimulation (tDCS): a traditional two-electrode montage targeting a single brain region (left primary motor cortex [M1]) and a novel eight-electrode montage targeting this region and its associated resting state network. As a control, 8 participants also received multifocal tDCS mismatched to this network. Network-targeted tDCS more than doubled the increase in left M1 excitability over time compared to traditional tDCS and the multifocal control. Modeling studies suggest these results are unlikely to be due to tDCS effects on left M1 itself, however it is impossible to completely exclude this possibility. It also remains unclear whether multifocal tDCS targeting a network selectively modulates this network and which regions within the network are most responsible for observed effects. Despite these limitations, network-targeted tDCS appears to be a promising approach for enhancing tDCS effects beyond traditional stimulation targeting a single brain region. Future work is needed to test whether these results extend to other resting state networks and enhance behavioral or therapeutic effects.

High-gamma oscillations in the motor cortex during visuo-motor coordination: A tACS interferential study.

BACKGROUND: While the role of beta (∼20Hz), theta (∼5Hz) and alpha (∼10Hz) oscillations in the motor areas have been repeatedly associated with defined properties of motor performance, the investigation of gamma (∼40-90Hz) oscillatory activity is a more recent and still not fully understood component of motor control physiology, despite its potential clinical relevance for motor disorders. OBJECTIVE/HYPOTHESIS: We have implemented an online neuromodulation paradigm based on transcranial alternating current stimulation (tACS) of the dominant motor cortex during a visuo-motor coordination task. This approach would allow a better understanding of the role of gamma activity, as well as that of other oscillatory bands, and their chronometry throughout the task. METHODS: We tested the effects of 5Hz, 20Hz, 60Hz (mid-gamma) 80Hz (high-gamma) and sham tACS on the performance of a sample of right-handed healthy volunteers, during a custom-made unimanual tracking task addressing several randomly occurring components of visuo-motor coordination (i.e., constant velocity or acceleration pursuits, turns, loops). RESULTS: Data showed a significant enhancement of motor performance during high-gamma stimulation - as well as a trending effect for mid-gamma - with the effect being prominent between 200 and 500ms after rapid changes in tracking trajectory. No other effects during acceleration or steady pursuit were found. CONCLUSIONS: Our findings posit a role for high-frequency motor cortex gamma oscillations during complex visuo-motor tasks involving the sudden rearrangement of motor plan/execution. Such a "prokinetic" effect of high-gamma stimulation might be worth to be tested in motor disorders, like Parkinson's disease, where the switching between different motor programs is impaired.

Individual differences and specificity of prefrontal gamma frequency-tACS on fluid intelligence capabilities.

Emerging evidence suggests that transcranial alternating current stimulation (tACS) is an effective, frequency-specific modulator of endogenous brain oscillations, with the potential to alter cognitive performance. Here, we show that reduction in response latencies to solve complex logic problem indexing fluid intelligence is obtained through 40 Hz-tACS (gamma band) applied to the prefrontal cortex. This improvement in human performance depends on individual ability, with slower performers at baseline receiving greater benefits. The effect could have not being explained by regression to the mean, and showed task and frequency specificity: it was not observed for trials not involving logical reasoning, as well as with the application of low frequency 5 Hz-tACS (theta band) or non-periodic high frequency random noise stimulation (101-640 Hz). Moreover, performance in a spatial working memory task was not affected by brain stimulation, excluding possible effects on fluid intelligence enhancement through an increase in memory performance. We suggest that such high-level cognitive functions are dissociable by frequency-specific neuromodulatory effects, possibly related to entrainment of specific brain rhythms. We conclude that individual differences in cognitive abilities, due to acquired or developmental origins, could be reduced during frequency-specific tACS, a finding that should be taken into account for future individual cognitive rehabilitation studies.

Intrinsic cerebral connectivity analysis in an untreated female-to-male transsexual subject: a first attempt using resting-state fMRI.

BACKGROUND/AIMS: Transsexualism is a gender identity disorder whose symptomatology could involve cognitive, neurobiological and psychological variance from biological sex standard. Several evidences support the hypothesis of a structural and functional brain reorganization in transgender subjects, with a different impact for male-to-female and female-to-male (FtM) subjects. Here we used resting-state fMRI to understand the similarities between the spontaneous brain connectivity of an untreated FtM subject and two male and female control groups. METHODS: Both seed-voxel and atlas-based region-of-interest (ROI) approaches were used. RESULTS: Brain areas sensitive to gender dimorphism like left lingual gyrus and precuneus showed strong similarities between the FtM subject and female control group with respect to control males, with comparable extension and location of functional connectivity maps. ROI analysis confirmed this evidence, highlighting a greater pattern of differences between the FtM subject and males and the FtM subject and females. No difference between seed-voxel results in the FtM subject and females was found. CONCLUSION: These data partially support the idea that untreated FtM transgender shows a functional connectivity profile comparable to female control subjects.