Cognitive resilience/reserve: Myth or reality? A review of definitions and measurement methods.

INTRODUCTION: This review examines the concept of cognitive reserve (CR) in relation to brain aging, particularly in the context of dementia and its early stages. CR refers to an individual's ability to maintain or regain cognitive function despite brain aging, damage, or disease. Various factors, including education, occupation complexity, leisure activities, and genetics are believed to influence CR. METHODS: We revised the literature in the context of CR. A total of 842 articles were identified, then we rigorously assessed the relevance of articles based on titles and abstracts, employing a systematic approach to eliminate studies that did not align with our research objectives. RESULTS: We evaluate-also in a critical way-the methods commonly used to define and measure CR, including sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures. The challenges and limitations of these measures are discussed, emphasizing the need for more targeted research to improve the understanding, definition, and measurement of CR. CONCLUSIONS: The review underscores the significance of comprehending CR in the context of both normal and pathological brain aging and emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation in both healthy and neurologically impaired older individuals. HIGHLIGHTS: This review examines the concept of cognitive reserve in brain aging, in the context of dementia and its early stages. We have evaluated the methods commonly used to define and measure cognitive reserve. Sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures are discussed. The review emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation.

Global estimates on the number of persons across the Alzheimer's disease continuum.

INTRODUCTION: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology. METHODS: We synthesized the literature on prevalence across the AD continuum and derived a model estimating the number of persons, stratified by 5-year age groups, sex, and disease stage (AD dementia, prodromal AD, and preclinical AD). RESULTS: The global number of persons with AD dementia, prodromal AD, and preclinical AD were estimated at 32, 69, and 315 million, respectively. Together they constituted 416 million across the AD continuum, or 22% of all persons aged 50 and above. DISCUSSION: Considering predementia stages, the number of persons with AD is much larger than conveyed in available literature. Our estimates are uncertain, especially for predementia stages in low- and middle-income regions where biomarker studies are missing.

Direct and indirect neurological, cognitive, and behavioral effects of COVID-19 on the healthy elderly, mild-cognitive-impairment, and Alzheimer's disease populations.

INTRODUCTION: Healthy elderly, mild cognitive impairment and Alzheimer's disease populations have been among the most affected in the early stages of the COVID-19 pandemic due to the direct effects of the virus, and numerous indirect effects now emerge and will have to be carefully assessed over time. METHODS: This article reviews the main articles that have been published so far about the direct and indirect effects of the COVID-19 pandemic on these particularly fragile populations. RESULTS: The pandemic associated to COVID-19 has shifted most of the health resources to the emergency area and has consequently left the three main medical areas dealing with the elderly population (oncology, time-dependent diseases and degenerative disease) temporarily "uncovered". In the phase following the emergency, it will be crucial to guarantee to each area the economic and organizational resources to quickly return to the level of support of the prepandemic state. CONCLUSIONS: The emergency phase represented a significant occasion of discussion on the possibilities of telemedicine which will inevitably become increasingly important, but all the limits of its use in the elderly population have to be considered. In the post-lockdown recovery phase, alongside the classic medical evaluation, the psychological evaluation must become even more important for doctors caring about people with cognitive decline as well as with their caregivers.

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

BACKGROUND: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. METHODS: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. RESULTS: Significant MRI site and vendor effects (p â€‹< â€‹.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p â€‹< â€‹1.39E-36). In particular, volumes larger than 200 â€‹mm3 (for amygdalar nuclei) and 300 â€‹mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε â€‹< â€‹5% and DICE â€‹> â€‹0.80). CONCLUSION: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

Acute Phase Neuronal Activity for the Prognosis of Stroke Recovery.

Strokes causing similar lesions and clinical states can be followed by diverse regains of neurological functions, indicating that the clinical recovery can depend on individual modulating factors. A promising line to disclose these factors, to finally open new therapeutic strategies, is to search for individual indices of recovery prognosis. Here, we pursued on strengthening the value of acute phase electrophysiological biomarkers for poststroke functional recovery in a wide group of patients. We enrolled 120 patients affected by a monohemispheric stroke within the middle cerebral artery territory (70 left and 50 right damages) and collected the NIH stroke scale (NIHSS) score in the acute phase (T0, median 4 days) and chronic follow-up (T1, median 6 months). At T0, we executed electrophysiological noninvasive assessment (19-channel electroencephalography (EEG) or 28 channels per side magnetoencephalography (MEG)) of brain activity at rest by means of band powers in the contra- and ipsilesional hemispheres (CLH, ILH) or the homologous area symmetry (HArS). Low-band (2-6 Hz) HArS entered the regression model for predicting the stabilized clinical state (p < 0.001), with bilateral impairment correlated with a poor outcome. Present data strengthen the fact that low-band impairment of homologous ipsi- and contralesional hemispheric regions in the acute stroke indicate a negative prognosis of clinical recovery.

Prognostic Value of EEG Microstates in Acute Stroke.

Given the importance of neuronal plasticity in recovery from a stroke and the huge variability of recovery abilities in patients, we investigated neuronal activity in the acute phase to enhance information about the prognosis of recovery in the stabilized phase. We investigated the microstates in 47 patients who suffered a first-ever mono-lesional ischemic stroke in the middle cerebral artery territory and in 20 healthy control volunteers. Electroencephalographic (EEG) activity at rest with eyes closed was acquired between 2 and 10 days (T0) after ischemic attack. Objective criteria allowed for the selection of an optimal number of microstates. Clinical condition was quantified by the National Institute of Health Stroke Scale (NIHSS) both in acute (T0) and stabilized (T1, 5.4 ± 1.7 months) phases and Effective Recovery (ER) was calculated as (NIHSS(T1)-NIHSS(T0))/NIHSS(T0). The microstates A, B, C and D emerged as the most stable. In patients with a left lesion inducing a language impairment, microstate C topography differed from controls. Microstate D topography was different in patients with a right lesion inducing neglect symptoms. In patients, the C vs D microstate duration differed after both a left and a right lesion with respect to controls (C lower than D in left and D lower than C in right lesion). A preserved microstate B in acute phase correlated with a better effective recovery. A regression model indicated that the microstate B duration explained the 11% of ER variance. This first ever study of EEG microstates in acute stroke opens an interesting path to identify neuronal impairments with prognostic relevance, to develop enriched compensatory treatments to drive a better individual recovery.

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis.

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1ß. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains.

Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.

OBJECTIVE: Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. METHODS: The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis-with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates-was applied to predict the conversion from MCI to AD. RESULTS: Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03-1.47, p = 0.022); for each additional micromole per liter unit (µmol/l) of non-Cp copper, the hazard increased by ~20%. Subjects with non-Cp copper levels >1.6 µmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ~3× higher than those with values ≤1.6 µmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4. INTERPRETATION: Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk.

Idiopathic inflammatory myopathies evaluated by near-infrared spectroscopy.

INTRODUCTION: In this study we evaluated whether near-infrared spectroscopy (NIRS) can determine the metabolic patterns of dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). METHODS: We enrolled 10 consecutive patients affected by DM, 11 by PM, and 9 by IBM, and 3 groups of healthy controls. We measured changes in oxygenated and deoxygenated hemoglobin/myoglobin in the extensor digitorum communis during venous and arterial occlusion testing (VOT) and post-occlusion hyperemia. RESULTS: DM showed lower oxygen consumption (P=0.04) during VOT and reduced oxygen supply after VOT (P=0.04) compared with controls. IBM patients showed higher oxygen consumption (P=0.04) during VOT and higher oxygen supply after VOT (P=0.03) than controls. DM patients showed reduced oxidative metabolism compared with IBM (P=0.001), and an impaired ability to supply oxygen compared with PM (P=0.03) and IBM (P=0.001) patients. CONCLUSIONS: NIRS differentiated samples of DM and IBM patients from controls, but it could not distinguish PM patients from a sample of healthy subjects.

Resting state cortical electroencephalographic rhythms are related to gray matter volume in subjects with mild cognitive impairment and Alzheimer's disease.

Cortical gray matter volume and resting state cortical electroencephalographic rhythms are typically abnormal in subjects with amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here we tested the hypothesis that in amnesic MCI and AD subjects, abnormalities of EEG rhythms are a functional reflection of cortical atrophy across the disease. Eyes-closed resting state EEG data were recorded in 57 healthy elderly (Nold), 102 amnesic MCI, and 108 AD patients. Cortical gray matter volume was indexed by magnetic resonance imaging recorded in the MCI and AD subjects according to Alzheimer's disease neuroimaging initiative project (http://www.adni-info.org/). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). These rhythms were indexed by LORETA. Compared with the Nold, the MCI showed a decrease in amplitude of alpha 1 sources. With respect to the Nold and MCI, the AD showed an amplitude increase of delta sources, along with a strong amplitude reduction of alpha 1 sources. In the MCI and AD subjects as a whole group, the lower the cortical gray matter volume, the higher the delta sources, the lower the alpha 1 sources. The better the score to cognitive tests the higher the gray matter volume, the lower the pathological delta sources, and the higher the alpha sources. These results suggest that in amnesic MCI and AD subjects, abnormalities of resting state cortical EEG rhythms are not epiphenomena but are strictly related to neurodegeneration (atrophy of cortical gray matter) and cognition.

Resting state cortical EEG rhythms in Alzheimer's disease: toward EEG markers for clinical applications: a review.

The human brain contains an intricate network of about 100 billion neurons. Aging of the brain is characterized by a combination of synaptic pruning, loss of cortico-cortical connections, and neuronal apoptosis that provoke an age-dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promote maintenance of brain activity and cognitive status in healthy elderly subjects for everyday life. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Growing evidence supports the idea that AD targets specific and functionally connected neuronal networks and that oscillatory electromagnetic brain activity might be a hallmark of the disease. In this line, digital electroencephalography (EEG) allows noninvasive analysis of cortical neuronal synchronization, as revealed by resting state brain rhythms. This review provides an overview of the studies on resting state eyes-closed EEG rhythms recorded in amnesic mild cognitive impairment (MCI) and AD subjects. Several studies support the idea that spectral markers of these EEG rhythms, such as power density, spectral coherence, and other quantitative features, differ among normal elderly, MCI, and AD subjects, at least at group level. Regarding the classification of these subjects at individual level, the most previous studies showed a moderate accuracy (70-80%) in the classification of EEG markers relative to normal and AD subjects. In conclusion, resting state EEG makers are promising for large-scale, low-cost, fully noninvasive screening of elderly subjects at risk of AD.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

Brains "in concert": frontal oscillatory alpha rhythms and empathy in professional musicians.

Playing music in ensemble represents a unique human condition/performance where musicians should rely on empathic relationships. Recent theories attribute to frontal Brodmann areas (BAs) 44/45 and 10/11 a neural basis for "emotional" and "cognitive" empathy. We hypothesized that activity of these structures reflects empathy trait in professional musicians playing in ensemble. Simultaneous electroencephalographic (EEG) alpha rhythms (8-12 Hz) were recorded in three saxophone quartets during music performance in ensemble (EXECUTION), video observation of their own performance (OBSERVATION), a control task (CONTROL), and resting state (RESTING). EEG source estimation was performed. Results showed that the higher the empathy quotient test score, the higher the alpha desynchronization in right BA 44/45 during the OBSERVATION referenced to RESTING condition. Empathy trait score and alpha desynchronization were not correlated in other control areas or in EXECUTION/CONTROL conditions. These results suggest that alpha rhythms in BA 44/45 reflect "emotional" empathy in musicians observing own performance.

One century of healing currents into the brain from the scalp: From electroconvulsive therapy to repetitive transcranial magnetic stimulation for neuropsychiatric disorders.

Electroconvulsive therapy (ECT) was applied for the first time in humans in 1938: after 80 years, it remains conceptually similar today except for modifications of the original protocol aimed to reduce adverse effects (as persistent memory deficits) without losing clinical efficacy. We illustrate the stages of development as well as ups and downs of ECT use in the last eighty years, and the impact that it still maintains for treatment of certain psychiatric conditions. Targeted, individualized and safe noninvasive neuromodulatory interventions are now possible for many neuropsychiatric disorders thanks to repetitive transcranial magnetic stimulation (rTMS) that injects currents in the brain through electromagnetic induction, powerful enough to depolarize cortical neurons and related networks. Although ECT and rTMS differ in basic concepts, mechanisms, tolerability, side effects and acceptability, and beyond their conceptual remoteness (ECT) or proximity (rTMS) to "precision medicine" approaches, the two brain stimulation techniques may be considered as complementary rather than competing in the current treatment of certain neuropsychiatric disorders.

Adaptive and Maladaptive Brain Functional Network Reorganization After Stroke in Hemianopia Patients: An Electroencephalogram-Tracking Study.

Objective: Hemianopia after occipital stroke is believed to be mainly due to local damage at or near the lesion site. However, magnetic resonance imaging studies suggest functional connectivity network (FCN) reorganization also in distant brain regions. Because it is unclear whether reorganization is adaptive or maladaptive, compensating for, or aggravating vision loss, we characterized FCNs electrophysiologically to explore local and global brain plasticity and correlated FCN reorganization with visual performance. Methods: Resting-state electroencephalography (EEG) was recorded in chronic, unilateral stroke patients and healthy age-matched controls (n = 24 each). This study was approved by the local ethics committee. The correlation of oscillating EEG activity was calculated with the imaginary part of coherence between pairs of regions of interest, and FCN graph theory metrics (degree, strength, clustering coefficient) were correlated with stimulus detection and reaction time. Results: Stroke brains showed altered FCNs in the alpha- and low beta-band in numerous occipital, temporal brain structures. On a global level, FCN had a less efficient network organization whereas on the local level node networks were reorganized especially in the intact hemisphere. Here, the occipital network was 58% more rigid (with a more "regular" network structure) whereas the temporal network was 32% more efficient (showing greater "small-worldness"), both of which correlated with worse or better visual processing, respectively. Conclusions: Occipital stroke is associated with both local and global FCN reorganization, but this can be both adaptive and maladaptive. We propose that the more "regular" FCN structure in the intact visual cortex indicates maladaptive plasticity, where less processing efficacy with reduced signal/noise ratio may cause the perceptual deficits in the intact visual field (VF). In contrast, reorganization in intact temporal brain regions is presumably adaptive, possibly supporting enhanced peripheral movement perception.

Corrigendum: A Psychometric Platform to Collect Somatosensory Sensations for Neuroprosthetic Use.

[This corrects the article DOI: 10.3389/fmedt.2021.619280.].

Toward noninvasive brain stimulation 2.0 in Alzheimer's disease.

Noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia, considered their possible role in help defining diagnostic biomarkers of altered neural activity for early disease detection and monitoring of its pathophysiological course, as well as for their therapeutic potential of boosting residual cognitive functions. Nevertheless, current approaches suffer from some limitations. In this study, we review and discuss experimental NiBS applications that might help improve the efficacy of future NiBS uses in Alzheimer's Disease (AD), including perturbation-based biomarkers for early diagnosis and disease tracking, solutions to enhance synchronization of oscillatory electroencephalographic activity across brain networks, enhancement of sleep-related memory consolidation, image-guided stimulation for connectome control, protocols targeting interneuron pathology and protein clearance, and finally hybrid-brain models for in-silico modeling of AD pathology and personalized target selection. The present work aims to stress the importance of multidisciplinary, translational, model-driven interventions for precision medicine approaches in AD.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.