Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review.

Despite the numerous pharmacological interventions targeting dementia, no disease-modifying therapy is available, and the prognosis remains unfavorable. A promising perspective involves tackling high-frequency gamma-band (> 30 Hz) oscillations involved in hippocampal-mediated memory processes, which are impaired from the early stages of typical Alzheimer's Disease (AD). Particularly, the positive effects of gamma-band entrainment on mouse models of AD have prompted researchers to translate such findings into humans using transcranial alternating current stimulation (tACS), a methodology that allows the entrainment of endogenous cortical oscillations in a frequency-specific manner. This systematic review examines the state-of-the-art on the use of gamma-tACS in Mild Cognitive Impairment (MCI) and dementia patients to shed light on its feasibility, therapeutic impact, and clinical effectiveness. A systematic search from two databases yielded 499 records resulting in 10 included studies and a total of 273 patients. The results were arranged in single-session and multi-session protocols. Most of the studies demonstrated cognitive improvement following gamma-tACS, and some studies showed promising effects of gamma-tACS on neuropathological markers, suggesting the feasibility of gamma-tACS in these patients anyhow far from the strong evidence available for mouse models. Nonetheless, the small number of studies and their wide variability in terms of aims, parameters, and measures, make it difficult to draw firm conclusions. We discuss results and methodological limitations of the studies, proposing possible solutions and future avenues to improve research on the effects of gamma-tACS on dementia.

The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders.

Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.

Transcranial alternating current stimulation for neuropsychiatric disorders: a systematic review of treatment parameters and outcomes.

Background: Transcranial alternating current stimulation (tACS) alters cortical excitability with low-intensity alternating current and thereby modulates aberrant brain oscillations. Despite the recent increase in studies investigating the feasibility and efficacy of tACS in treating neuropsychiatric disorders, its mechanisms, as well as optimal stimulation parameters, are not fully understood. Objectives: This systematic review aimed to compile human research on tACS for neuropsychiatric disorders to delineate typical treatment parameters for these conditions and evaluate its outcomes. Methods: A search for published studies and unpublished registered clinical trials was conducted through OVID (MEDLINE, PsycINFO, and Embase), ClinicalTrials.gov, and the International Clinical Trials Registry Platform. Studies utilizing tACS to treat neuropsychiatric disorders in a clinical trial setting were included. Results: In total, 783 published studies and 373 clinical trials were screened; 53 published studies and 70 clinical trials were included. Published studies demonstrated a low risk of bias, as assessed by the Joanna Briggs Institute Critical Appraisal Tools. Neurocognitive, psychotic, and depressive disorders were the most common disorders treated with tACS. Both published studies (58.5%) and registered clinical trials (52%) most commonly utilized gamma frequency bands and tACS was typically administered at an intensity of 2 mA peak-to-peak, once daily for 20 or fewer sessions. Although the targeted brain locations and tACS montages varied across studies based on the outcome measures and specific pathophysiology of the disorders, the dorsolateral prefrontal cortex (DLPFC) was the most common target in both published studies (30.2%) and registered clinical trials (25.6%). Across studies that published results on tACS outcome measures, tACS resulted in enhanced symptoms and/or improvements in overall psychopathology for neurocognitive (all 11 studies), psychotic (11 out of 14 studies), and depressive (7 out of 8 studies) disorders. Additionally, 17 studies reported alterations in the power spectrum of the electroencephalogram around the entrained frequency band at the targeted locations following tACS. Conclusion: Behavioral and cognitive symptoms have been positively impacted by tACS. The most consistent changes were reported in cognitive symptoms following gamma-tACS over the DLPFC. However, the paucity of neuroimaging studies for each neuropsychiatric condition highlights the necessity for replication studies employing biomarker- and mechanism-centric approaches.

The Neural Correlates of Developmental Prosopagnosia: Twenty-Five Years on.

Faces play a crucial role in social interactions. Developmental prosopagnosia (DP) refers to the lifelong difficulty in recognizing faces despite the absence of obvious signs of brain lesions. In recent decades, the neural substrate of this condition has been extensively investigated. While early neuroimaging studies did not reveal significant functional and structural abnormalities in the brains of individuals with developmental prosopagnosia (DPs), recent evidence identifies abnormalities at multiple levels within DPs' face-processing networks. The current work aims to provide an overview of the convergent and contrasting findings by examining twenty-five years of neuroimaging literature on the anatomo-functional correlates of DP. We included 55 original papers, including 63 studies that compared the brain structure (MRI) and activity (fMRI, EEG, MEG) of healthy control participants and DPs. Despite variations in methods, procedures, outcomes, sample selection, and study design, this scoping review suggests that morphological, functional, and electrophysiological features characterize DPs' brains, primarily within the ventral visual stream. Particularly, the functional and anatomical connectivity between the Fusiform Face Area and the other face-sensitive regions seems strongly impaired. The cognitive and clinical implications as well as the limitations of these findings are discussed in light of the available knowledge and challenges in the context of DP.

Investigating the impact of disposable surgical face-masks on face identity and emotion recognition in adults with autism spectrum disorder.

With the outburst of the COVID-19 pandemic, disposable surgical face-masks (DSFMs) have been widely adopted as a preventive measure. DSFMs hide the bottom half of the face, thus making identity and emotion recognition very challenging, both in typical and atypical populations. Individuals with autism spectrum disorder (ASD) are often characterized by face processing deficits; thus, DSFMs could pose even a greater challenge for this population compared to typically development (TD) individuals. In this study, 48 ASDs of level 1 and 110 TDs underwent two tasks: (i) the Old-new face memory task, which assesses whether DSFMs affect face learning and recognition, and (ii) the Facial affect task, which explores DSFMs' effect on emotion recognition. Results from the former show that, when faces were learned without DSFMs, identity recognition of masked faces decreased for both ASDs and TDs. In contrast, when faces were first learned with DSFMs, TDs but not ASDs benefited from a "context congruence" effect, that is, faces wearing DSFMs were better recognized if learned wearing DSFMs. In addition, results from the Facial affect task show that DSFMs negatively impacted specific emotion recognition in both TDs and ASDs, although differentially between the two groups. DSFMs negatively affected disgust, happiness and sadness recognition in TDs; in contrast, ASDs performance decreased for every emotion except anger. Overall, our study demonstrates a general, although different, disruptive effect on identity and emotion recognition both in ASD and TD population.

Face pareidolia is enhanced by 40 Hz transcranial alternating current stimulation (tACS) of the face perception network.

Pareidolia refers to the perception of ambiguous sensory patterns as carrying a specific meaning. In its most common form, pareidolia involves human-like facial features, where random objects or patterns are illusionary recognized as faces. The current study investigated the neurophysiological correlates of face pareidolia via transcranial alternating current stimulation (tACS). tACS was delivered at gamma (40 Hz) frequency over critical nodes of the "face perception" network (i.e., right lateral occipito-temporal and left prefrontal cortex) of 75 healthy participants while completing four face perception tasks ('Mooney test' for faces, 'Toast test', 'Noise pareidolia test', 'Pareidolia task') and an object perception task ('Mooney test' for objects). In this single-blind, sham-controlled between-subjects study, participants received 35 min of either Sham, Online, (40Hz-tACS_ON), or Offline (40Hz-tACS_PRE) stimulation. Results showed that face pareidolia was causally enhanced by 40Hz-tACS_PRE in the Mooney test for faces in which, as compared to sham, participants more often misperceived scrambled stimuli as faces. In addition, as compared to sham, participants receiving 40Hz-tACS_PRE showed similar reaction times (RTs) when perceiving illusory faces and correctly recognizing noise stimuli in the Toast test, thus not exhibiting hesitancy in identifying faces where there were none. Also, 40Hz-tACS_ON induced slower rejections of face pareidolia responses in the Noise pareidolia test. The current study indicates that 40 Hz tACS can enhance pareidolic illusions in healthy individuals and, thus, that high frequency (i.e., gamma band) oscillations are critical in forming coherent and meaningful visual perception.

Corrigendum to "Self-reported face recognition abilities moderately predict face-learning skills: Evidence from Italian samples" [Heliyon 9 (3) (March 2023) Article e14125].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e14125.].

Self-reported face recognition abilities moderately predict face-learning skills: Evidence from Italian samples.

Face Recognition Ability (FRA) varies widely throughout the population. Previous research highlights a positive relationship between self-perceived and objectively measured FRA in the healthy population, suggesting that people do have insight into their FRA. Given that this relationship has not been investigated in Italian samples yet, the main aim of the present work was to develop an Italian translation of the Prosopagnosia Index-20 (PI-20), a self-report measure of FRA, to investigate the relationship between PI-20 performances and an objective assessment given by the Cambridge Face Memory Test Long Form (CFMT+) in the Italian population. A sample of 553 participants filled in the PI-20 Italian version 1 or 2 (PI-20_GE or PI-20_BA) and completed the CFMT+. Results showed a negative correlation between both versions of the Italian PI-20 and CFMT+ scores, meaning that the more self-evaluations were negative, the worse they objectively performed. The same results applied to the extreme limits of the distribution (i.e., 10% of the highest and lowest PI-20 scores). Furthermore, both age and administration order of the tests were predictor variables of CFMT+ scores. Overall, our results suggest that people possess insight, although relatively limited, into their FRA.

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.

Non-invasive neuromodulation can reduce aggressive behaviors in humans: A critical perspective.

Containing aggressive behavior is an ongoing challenge in modern society. Aggressiveness is a multi-level construct that can be driven by emotions (reactive aggression) or can be "cold-blooded" and goal-directed (proactive). Aggressive behavior could arise because of a misjudgment of others' intentions or can follow frontal brain lesions leading to a reduction of impulse control and emotion regulation. In the last few years, interventional and basic research studies adopting Non-Invasive Brain Stimulation (NIBS) have significantly risen. Those techniques have been used both in healthy people, to better understand the role of certain brain regions in psychological processes, and in aggressive subjects to improve their symptoms. From an overview of the literature, focusing on the paper that uses transcranial direct current stimulation (tDCS) to reduce aggressiveness, it emerges that tDCS can (i) enhance facial emotion expression recognition, (ii) improve impulses control, and (iii) affect approach/withdrawal motivation. The current work shows the strengths and weaknesses of tDCS intervention on aggressive individuals, suggesting that this instrument could be adopted on violent people, and paves the way for intervention in some applied settings such as prison.

An update on the use of gamma (multi)sensory stimulation for Alzheimer's disease treatment.

Alzheimer's disease (AD) is characterized by reduced fast brain oscillations in the gamma band (γ, > 30 Hz). Several animal studies show that inducing gamma oscillations through (multi)sensory stimulation at 40 Hz has the potential to impact AD-related cognitive decline and neuropathological processes, including amyloid plaques deposition, neurofibrillary tangles formation, and neuronal and synaptic loss. Therefore Gamma Entrainment Using Sensory stimulation (GENUS) is among the most promising approaches for AD patients' treatment. This review summarizes the evidence on GENUS effectiveness, from animal models to AD patients. Despite the application on human is in its infancy, the available findings suggest its feasibility for the treatment of AD. We discuss such results in light of parameter improvement and possible underlying mechanisms. We finally emphasize the need for further research for its development as a disease-modifying non-pharmacological intervention.

Anodal tDCS effects over the left dorsolateral prefrontal cortex (L-DLPFC) on the rating of facial expression: evidence for a gender-specific effect.

The accurate recognition of others' facial expressions is a core skill for social interactions. The left Dorsolateral Prefrontal Cortex (L-DLPFC) represents a key node in the network for facial emotion recognition. However, its specific role is still under debate. As such, the aim of the current neuromodulation study was to assess the causal role of the L-DLPFC in humans' rating of facial expressions of emotions and implicit attitudes toward other races. In this sham-controlled single-blind between-subject experiment, we offline administered L-DLPFC transcranial direct current stimulation (tDCS) to 69 healthy participants who were divided into three groups of 23 (each receiving anodal 1 mA tDCS, anodal 2 mA tDCS, or Sham), before completing an "Emotion Rating task and two Implicit Association Tests (IATs). The former required the intensity rating of 192 faces (half black and half white) displaying happiness, sadness, anger, or fear. The IATs were designed to assess participants' automatic associations of positive or negative attributes with racial contents. Results on the Emotion Rating task showed participants' gender-specific effect of tDCS. Specifically, a gender bias, with only males showing a tendency to underestimate negative emotions was found in Sham, and absent in the tDCS groups. When considering the race of the stimuli, females but not males in Sham exhibited a racial bias, that is, the tendency to overestimate negative emotions of other-race faces. Again, the bias disappeared in the tDCS groups. Concerning the IATs, no significant effects emerged. We conclude that the L-DLPFC plays a critical role in humans' rating of facial expressions, and for variability in other-race emotional judgements. These results shed light on the neural bases of the human emotional system and its gender-related differences, and have potential implications for interventional settings.