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Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 May 2026) | Viewed by 13483

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Dr. Mattia Ferro

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Department of Psychology, Sigmund Freud University, 20143 Milan, Italy
Interests: molecular psychiatry; behavioral neuroscience; synaptic plasticity
Special Issues, Collections and Topics in MDPI journals

Dr. Jacopo Lamanna

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Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy
Interests: the role of neural plasticity in animal behavior and mental disorders; the neurophysiological bases of synaptic transmission and plasticity; the neural correlates of cognitive functioning in health and disease
Special Issues, Collections and Topics in MDPI journals

Dr. Andrea Stefano Moro

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Department of Psychology, Sigmund Freud University, 20143 Milan, Italy
Interests: decision-making; non-invasive brain stimulation

Special Issue Information

Dear Colleagues,

Non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have garnered significant attention in both basic and clinical neuroscience. These methods, which modulate brain activity without the need for surgical or pharmacological interventions, provide valuable insights into the neurophysiology of cognitive functions and hold substantial promise for neuropsychiatric rehabilitation. NIBS has been widely used to investigate the neural mechanisms underlying a variety of cognitive processes, including attention, memory, and executive function. Furthermore, these techniques have shown therapeutic potential for neuropsychiatric disorders, such as depression, schizophrenia, and post-stroke aphasia, by targeting specific brain regions implicated in these conditions. Recent advancements in NIBS have led to refined stimulation protocols and individualized treatment strategies, optimizing clinical outcomes. This Special Issue aims to highlight the latest developments in NIBS research, with a particular focus on its application in cognitive neuroscience and neurophysiology, as well as on its role in neuropsychiatric rehabilitation. By compiling cutting-edge studies, we seek to advance our understanding of brain plasticity and the potential of NIBS as a tool for both research and clinical intervention.

Dr. Mattia Ferro
Dr. Jacopo Lamanna
Dr. Andrea Stefano Moro
Guest Editors

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Keywords

non-invasive brain stimulation
neurophysiology
cognitive function
depression
schizophrenia

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Published Papers (9 papers)

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Research

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14 pages, 907 KB

Open AccessArticle

Non-Invasive Brain Stimulation in Older Inpatients with Depression: A Real-World Comparison of Repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation (tDCS) on Depressive Symptoms and Functional Recovery

by Michele Prato, Barbara Barbini, Filippo Frizzi, Matteo Carminati, Greta Verri, Sebastiano Busseni Cantoni, Thomas Kafka, Raffaella Zanardi and Cristina Colombo

Biomedicines 2026, 14(3), 650; https://doi.org/10.3390/biomedicines14030650 - 13 Mar 2026

Viewed by 805

Abstract

Background: Non-invasive brain stimulation (NIBS) is increasingly used as an adjunctive option in late-life depression (≥60 years), a condition frequently complicated by multimorbidity and incomplete response to standard treatments. Comparative real-world evidence between repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), particularly including functional outcomes, remains limited. Methods: We conducted a retrospective, naturalistic comparative study of 104 depressed inpatients (≥60 years), either unipolar or bipolar, treated with rTMS (n = 48) or tDCS (n = 56) as part of routine care. Depression severity was assessed with the 21-item Hamilton Depression Rating Scale (HDRS21) at baseline, 2 weeks, and 1 month; response was defined as ≥50% HDRS21 score reduction and remission as HDRS21 < 7 at 1 month. Global Assessment of Functioning (GAF) was assessed at admission and discharge (baseline and 1 month). Longitudinal changes were examined using covariate-adjusted mixed-effects models; categorical outcomes were compared using χ² tests. Propensity score matching was applied as an additional approach to reduce confounding due to the observational design. Results: At 1 month, response and remission rates were significantly higher in the rTMS group than in the tDCS group (87.5% vs. 55.4%, p < 0.001; 62.5% vs. 41.1%, p = 0.047, respectively). rTMS showed greater HDRS21 score reductions at 2 weeks and 1 month (Time × Treatment, p < 0.001). GAF scores significantly improved over time in both groups (Time effect, p < 0.001) without between-technique differences (Time × Treatment, p = 0.56), and GAF scores did not differ by response/remission status. Conclusions: In this cohort of inpatients aged ≥ 60 years with depressive episodes, rTMS was associated with greater short-term reductions in HDRS21 scores compared with tDCS, whereas both modalities showed comparable improvements in GAF from admission to discharge. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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20 pages, 6109 KB

Open AccessArticle

Binaural Beat Stimulation Enhances Cognitive Function in Alzheimer’s Disease via Temporal Lobe Activation: An sLORETA Study

by Muhammad Danish Mujib, Nayab Mubashir, Ahmad Zahid Rao, Nisha Nasir, Ayesha Ikhlaq, Syeda Sehar Hussain, Fizza Zia, Ghulam Mohiuddin Asim, Ahmad O. Alokaily, Mohamed A. Almadi, Saad Ahmed Qazi and Muhammad Abul Hasan

Biomedicines 2026, 14(3), 540; https://doi.org/10.3390/biomedicines14030540 - 27 Feb 2026

Cited by 1 | Viewed by 2653

Abstract

Background: The global prevalence of Alzheimer’s disease (AD) has reached 55.2 million. AD is characterized by progressive deterioration in cognition and working memory (WM), which are essential for attention, reasoning, and learning. These impairments are associated with pathological changes in cortical and subcortical regions. Binaural beats (BBs), a non-invasive auditory neuromodulation technique, have demonstrated cognitive enhancement effects in healthy individuals; however, their impact on WM in patients with AD remains largely unexplored. Methods: This study investigated the effects of BB stimulation on WM and cognitive function in the temporal lobe of patients with AD using standardized Low-Resolution Electromagnetic Tomography (sLORETA). Twenty-five patients with AD were randomly assigned to either an experimental group (n = 15) that received BB stimulation or a control group (n = 10) that received standard auditory stimulation. EEG recordings were obtained before and after the intervention. Results: Paired t-tests conducted on timeframe and frequency-wise sLORETA images revealed significant increases (p < 0.05) in theta, alpha1, and alpha2 frequency bands in the experimental group. Activated regions included the inferior, middle, superior, and transverse temporal gyri; Brodmann areas (BA) 20, 21, 22, 40, and 42; as well as networks associated with working memory and cognition. Conclusions: These findings suggest that BB stimulation induces temporal lobe activation, thereby enhancing working memory and cognitive function in patients with AD. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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23 pages, 1753 KB

Open AccessArticle

Modulating the Interplay Between Impulsivity and Interoception Through HD-tDCS to the Right Insula and Anterior Cingulate Cortex

by Riccardo Pirone, Irene Gorrino, Anna Vedani, Carlotta Maiocchi and Giulia Mattavelli

Biomedicines 2026, 14(3), 519; https://doi.org/10.3390/biomedicines14030519 - 26 Feb 2026

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Abstract

Background: Interoception has been proposed as a key mechanism underlying impulsive behaviours, including maladaptive eating. However, the brain mechanisms supporting the interaction between interoception and impulsivity across different reward types remain unclear. This study investigated whether modulating the right insula and the dorsal anterior cingulate cortex (dACC) using high-definition transcranial direct current stimulation (HD-tDCS) could affect interoceptive accuracy and impulsive decision-making. Methods: Model-based HD-tDCS montages were defined to target the right insula and dACC. Two behavioural paradigms were administered: (i) the heartbeat detection task (HBD) to assess interoceptive accuracy and (ii) two versions of the delay discounting (DD) task with food and monetary rewards to measure impulsivity. Heart rate variability (HRV) was recorded as an index of autonomic activity. HD-tDCS was delivered online during the HBD, while DD tasks were completed offline. Twenty-four participants took part in four sessions in a within-subject design: baseline DD tasks, anodal HD-tDCS targeting the insula, dACC, or sham stimulation. Results: Stimulation of both the insula and dACC reduced participants’ ability to detect synchronous heartbeat while improving accuracy in exteroceptive trials. Discounting rates significantly increased following insula stimulation. Moreover, HD-tDCS effects on DD performance varied depending on reward type. Conclusions: These findings suggest differential contributions of the dACC and insula in interoceptive and exteroceptive processing and support the effect of HD-tDCS combined with interoceptive tasks to modulate impulsive decision-making. Reward-specific effects highlight the importance of stimulus type when designing interventions for impulsive eating behaviours. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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15 pages, 4524 KB

Open AccessArticle

Effects of Continuous Theta Burst Stimulation on Behavior and NMDA Receptor Subunits in the Trimethyltin-Induced Alzheimer’s-like Disease Model

by Marina Zaric Kontic, Milica Zeljkovic Jovanovic, Andjela Stekic, Jelena Stanojevic, Ivana Stevanovic, Dejan Stevic, Milica Ninkovic and Milorad Dragic

Biomedicines 2026, 14(2), 391; https://doi.org/10.3390/biomedicines14020391 - 8 Feb 2026

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Background: Trimethyltin (TMT)-induced neurodegeneration leads to molecular and behavioral changes resembling those of Alzheimer’s disease (AD), making it a relevant model for investigating potential therapeutic interventions. Continuous theta burst stimulation (cTBS) has shown promise in psychiatric and neurological disorders but remains largely unexplored in AD models. Methods: Adult male Wistar rats were divided into four experimental groups: intact, TMT (8 mg/kg, ip) and TMT treated with cTBS or a sham protocol for three weeks. The open field test and novel object recognition test were used to assess anxiety-like behavior, memory, and learning, respectively. The extent of microgliosis in the hippocampus was assessed by immunohistochemistry, while protein expression was estimated by Western blot. Results: cTBS improved TMT-mediated changes in anxiety-like behavior, learning, and memory and reduced microgliosis in the CA1 hippocampal region. Both TMT and cTBS affected NMDAR subunits, with the most significant finding being a cTBS-mediated decrease in NR2B, which was previously increased by TMT. Conclusions: These are the first data on the beneficial effects of cTBS on behavioral and molecular changes in a model of neurodegeneration that mimics some of the key aspects of AD pathology. Further research is needed to clarify the therapeutic potential of cTBS in AD treatment. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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15 pages, 2879 KB

Open AccessArticle

The Right PPC Plays an Important Role in the Interaction of Temporal Attention and Expectation: Evidence from a tACS-EEG Study

by Bingbing Fu, Kaishi Lin, Ying Chen, Junjun Zhang, Zhenlan Jin and Ling Li

Biomedicines 2026, 14(2), 336; https://doi.org/10.3390/biomedicines14020336 - 31 Jan 2026

Cited by 1 | Viewed by 635

Abstract

Background/Objectives: Temporal attention and temporal expectation are two key mechanisms that facilitate perception by prioritizing information at specific moments and by leveraging temporal predictability, respectively. While their behavioral interaction is established, the underlying neural mechanisms remain poorly understood. Building on functional magnetic resonance imaging (fMRI) evidence linking temporal attention to parietal cortex activity and the role of alpha oscillations in temporal prediction, we investigated whether the right posterior parietal cortex (rPPC) may be involved in integrating these two processes. Methods: Experiment 1 used a behavioral paradigm to dissociate temporal expectation from attention across 600 ms and 1400 ms intervals. Experiment 2 retained only the 600 ms interval, combining behavioral assessments with electroencephalography (EEG), recording following transcranial alternating current stimulation (tACS) applied to the rPPC to probe neural mechanisms. Results: Experiment 1 showed an attention/expectation interaction exclusively at 600 ms: enhanced expectation improved response times under attended, not unattended, conditions. Experiment 2 replicated these behavioral and event-related potential (ERP) findings. Temporal attention modulated N1 amplitude: in attended conditions, the N1 was significantly more negative under high versus low expectation, while no difference was observed in unattended contexts. Anodal tACS over the rPPC reduced this N1 amplitude difference between high and low attentional expectation conditions to non-significance. Restricting analyses to attended conditions, paired-samples t-tests revealed that alpha-band power differed between high and low expectation under sham tACS, but this difference was absent under anodal tACS, which also attenuated the corresponding behavioral attention/expectation interaction effects. Conclusions: These findings provide suggestive evidence that the rPPC may be key to integrating temporal attention and expectation, occurring in early processing stages and specific to brief intervals. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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15 pages, 3617 KB

Open AccessArticle

Neuroprotective Effects of Anodal tDCS on Oxidative Stress and Neuroinflammation in Temporal Lobe Epilepsy

by Ali Osman Arslan, Sevdenur Akcay, Guven Akcay, Dana Zaqzouq and Aydın Him

Biomedicines 2026, 14(1), 23; https://doi.org/10.3390/biomedicines14010023 - 22 Dec 2025

Viewed by 848

Abstract

Background: Epilepsy affects over 50 million people worldwide, and about 30% remain drug-resistant—underscoring the urgent need for new therapies. This study evaluated the neuroprotective effects of anodal transcranial direct current stimulation (tDCS) in PTZ-induced epilepsy at acute and chronic stages in rats. Methods: Sixty male Wistar Albino rats (12 per group) were randomly assigned to five groups: control, acute epilepsy, acute epilepsy+ tDCS, chronic epilepsy, and chronic epilepsy+ tDCS. Behavioral tests—including the open-field, novel-object recognition, and Y-maze—assessed locomotion, recognition, and spatial memory. Hippocampal tissues were analyzed for oxidative stress markers (SOD, MDA), inflammatory cytokines (IL-1β, TNF-α), histopathology, and mechanistic markers of astrocytic and nitric oxide-mediated neuronal damage (GFAP and nNOS immunohistochemistry). Results: PTZ-induced epilepsy resulted in cognitive deficits, increased oxidative stress, neuroinflammation, neuronal degeneration, and astrocytic activation. Specifically, SOD decreased, while MDA, IL-1β, and TNF-α increased; GFAP and nNOS upregulation indicated activation of astrocytes and nitric oxide-mediated neuronal damage. tDCS mitigated these effects by enhancing SOD, reducing MDA, IL-1β, and TNF-α, and modulating the NO/GFAP axis, which corresponded to decreased neuronal degeneration and vascular hyperemia. Behaviorally, tDCS improved recognition memory and partially rescued spatial memory deficits. Conclusions: Anodal tDCS exerts neuroprotective effects in acute and chronic epilepsy by modulating oxidative stress, neuroinflammation, and the astrocytic/nitric oxide pathways, supporting its potential as a non-invasive adjunct therapy for cognitive and cellular protection. Future studies should investigate its effects on hippocampal glutamatergic and GABAergic pathways, as well as calcium homeostasis. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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20 pages, 4405 KB

Open AccessArticle

Transcranial Direct Current Stimulation over the Orbitofrontal Cortex Enhances Self-Reported Confidence but Reduces Metacognitive Sensitivity in a Perceptual Decision-Making Task

by Daniele Saccenti, Andrea Stefano Moro, Gianmarco Salvetti, Sandra Sassaroli, Antonio Malgaroli, Jacopo Lamanna and Mattia Ferro

Biomedicines 2025, 13(7), 1522; https://doi.org/10.3390/biomedicines13071522 - 21 Jun 2025

Cited by 3 | Viewed by 2377

Abstract

Background: Metacognition refers to the ability to reflect on and regulate cognitive processes. Despite advances in neuroimaging and lesion studies, its neural correlates, as well as their interplay with other cognitive domains, remain poorly understood. The orbitofrontal cortex (OFC) is proposed as a potential substrate for metacognitive processing due to its contribution to evaluating and integrating reward-related information, decision-making, and self-monitoring. Methods: This study examined OFC involvement in metacognition using transcranial direct current stimulation (tDCS) while participants performed a two-alternative forced choice task with confidence ratings to assess their metacognitive sensitivity. Before stimulation, the subjects completed the Metacognitions Questionnaire-30 and a monetary intertemporal choice task for the quantification of delay discounting. Results: Linear mixed-effects models showed that anodal tDCS over the left OFC reduced participants’ metacognitive sensitivity compared to sham stimulation, leaving perceptual decision-making accuracy unaffected. Moreover, real stimulation increased self-reported confidence ratings compared to the sham. Significant correlations were found between metacognitive sensitivity and negative beliefs about thinking. Conclusions: These results highlight the potential involvement of the OFC in the processing of retrospective second-order judgments about decision-making performance. Additionally, they support the notion that OFC overstimulation contributes to metacognitive dysfunctions detected in clinical conditions, such as difficulties in assessing the reliability of one’s thoughts and decision outcomes. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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Review

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15 pages, 449 KB

Open AccessReview

Unveiling Major Depressive Disorder Through TMS-EEG: From Traditional to Emerging Approaches

by Antonietta Stango, Claudia Fracassi, Andrea Cesareni, Barbara Borroni and Agnese Zazio

Biomedicines 2025, 13(10), 2474; https://doi.org/10.3390/biomedicines13102474 - 11 Oct 2025

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Abstract

Major depressive disorder (MDD) is one of the most prevalent psychiatric conditions and is characterized by alterations in cortical excitability, network connectivity, and neuroplasticity. Despite significant progress in neuroimaging and neurophysiology, the identification of objective and reliable biomarkers remains a major challenge, limiting diagnostic accuracy and treatment optimization. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) has emerged as a powerful methodology to probe causal brain dynamics with high temporal resolution. This review aims to summarize recent advances in the application of TMS-EEG to MDD, highlighting the transition from traditional TMS-evoked potential (TEP) analyses to more advanced, multidimensional approaches. We reviewed original research articles published between 2020 and 2025 that investigated neurophysiological markers and approaches to MDD using TMS-EEG. Traditional TEP measures provide markers of local cortical responses but are limited in capturing distributed network dysfunction. Emerging approaches expand the scope of TMS-EEG, allowing for the characterization of oscillatory activity, connectivity patterns, and large-scale network dynamics. Recent contributions also demonstrate the potential of computational and multivariate techniques to enhance biomarker sensitivity and predictive value. Taken together, recent evidence highlights TMS-EEG as a uniquely positioned methodology to investigate the neurophysiological substrates of MDD. By linking conventional TEP-based indices with innovative analytic strategies, TMS-EEG enables a multidimensional assessment of cortical function and dysfunction that transcends traditional descriptive markers. This integrative perspective not only refines mechanistic models of MDD but also opens new avenues for biomarker discovery, patient stratification, and treatment monitoring. Ultimately, the convergence of advanced TMS-EEG approaches with clinical applications holds promise for translating neurophysiological insights into precision psychiatry interventions aimed at improving outcomes in MDD. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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Other

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15 pages, 10544 KB

Open AccessBrief Report

Effects of Transcutaneous Spinal Direct Current Stimulation on Cognitive and Psychological Outcomes in Multiple Sclerosis: A Preliminary Case Series

by Carmelo Campo, Daniele Saccenti, Angelica De Sandi, Denise Mellace, Simona Mrakic-Sposta, Sara Marceglia, Maurizio Vergari, Andrea Arighi, Alberto Priori and Roberta Ferrucci

Biomedicines 2026, 14(5), 1156; https://doi.org/10.3390/biomedicines14051156 - 20 May 2026

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Abstract

Introduction: Multiple Sclerosis (MS) is frequently associated with a range of neurological, cognitive and psychological issues, presenting significant challenges to patients’ Quality of Life (QoL). Among non-invasive neuromodulation techniques, transcutaneous spinal Direct Current Stimulation (tsDCS) is emerging as a potential approach for symptom management in neurological conditions. However, the effects of tsDCS on MS remain poorly explored. Thus, this preliminary study aimed to evaluate the effects of tsDCS on MS symptomatology, focusing on cognitive and psychological variables. Methods: Six patients with MS were recruited for a randomized, sham-controlled, double-blind crossover study, and received anodal tsDCS or sham stimulation in two separate sessions at least one month apart. Assessment outcomes included cognitive and attentional-executive functions, depressive symptoms, and several QoL components. The tests were administered at baseline (T0), immediately after treatment (T1), one week (T2) and one month (T3) post-treatment. Results: Although protocol-by-time interactions did not reach statistical significance across all measures, protocol-independent improvements over time were observed in various QoL subscales, including Physical Functioning, Role Limitations due to Physical Health, Vitality, Health Distress, and Overall QoL. Conclusions: Our findings indicate that tsDCS is a feasible and well-tolerated intervention in patients with MS, with possible implications for QoL. Given the small sample size and the exploratory nature of this study, further research is needed to clarify whether tsDCS may represent a potentially beneficial non-invasive neuromodulation approach for improving well-being in patients with MS across both physical and mental dimensions. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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