Alessandra Vergallito

Background/Objectives: Chronic primary pain (CPP) is a new diagnostic category including chronic pain conditions lacking clinical signs or a clear etiopathogenetic origin. These disorders may share a common neural mechanism known as central sensitization, where nociceptive neurons become hyper-responsive to standard or subthreshold pain stimuli, resulting in pain hyper-sensitivity. In this context, non-invasive brain stimulation (NIBS) appears to be a promising tool for improving CPP symptoms by targeting maladaptive brain activity and connectivity. To date, the effects of NIBS on CPP symptoms remain unexplored. To fill this gap, we conducted a meta-analysis, investigating the effect of NIBS in improving the three core symptoms of CPP, namely pain intensity, emotional distress, and functional disability. Methods: Following PRISMA guidelines, we screened four databases up to February 2025 for English-language, peer-reviewed randomized clinical trials that included CPP patients treated with NIBS and reported pre/post or follow-up scores on validated measures of at least one core symptom. Quality of life was examined as an additional outcome. Results: Fifty-four studies were included, with 1371 participants receiving real stimulation and 1103 sham. Findings highlighted that real stimulation improved CPP symptoms immediately after treatment and at one-month follow-up. Meta-regressions showed that longer CPP duration reduced short-term effects on emotional distress and diminished all outcomes at one-month follow-up. Conclusions: Further research is needed to establish standardized NIBS protocols for CPP management, to investigate the effectiveness at longer follow-up periods, and to test whether combining NIBS with other interventions enhances treatment effectiveness and durability.

Chronic Primary Pain (CPP) is a new diagnostic category including chronic pain conditions lacking clinical signs or a clear etiopathogenetic origin. These disorders may share a common neural mechanism known as central sensitization, where nociceptive neurons become hyper-responsive to standard or subthreshold pain stimuli, resulting in pain hypersensitivity. In this context, non-invasive brain stimulation (NIBS) seems a promising tool to improve CPP symptoms by targeting maladaptive brain activity and connectivity. To date, NIBS effects on CPP symptoms remain unexplored. To fill this gap, we conducted a meta-analysis, investigating the effect of NIBS in improving the three core symptoms of CPP, namely pain intensity, emotional distress, and functional disability. Following PRISMA guidelines, we screened four databases up to the end of January 2023. Thirty-five English-written randomized clinical trials were included, comprising 874 participants assigned to the real stimulation condition and 713 to the sham. Findings highlighted the effect of the real over the sham stimulation in improving CPP core symptoms immediately after the treatment. For pain intensity and functional disability, the improvement persisted also at the one-month follow-up. Meta-regression analyses highlighted that a longer CPP duration reduced the effects of NIBS, while an increased number of sessions was associated with greater pain relief at follow-up. Taken together, our results suggest that NIBS can effectively alleviate CPP symptoms in the short and medium term. Further research is needed to define standardized NIBS protocols for CPP management and explore whether combining NIBS with other therapeutic interventions can enhance effects duration and efficacy.

Background/Objectives: Stuttering is a speech disorder involving fluency disruptions like repetitions, prolongations, and blockages, often leading to emotional distress and social withdrawal. Here, we present Augmented Multisensory Feedback Stimulation (AMFS), a novel personalized intervention to improve speech fluency in people who stutter (PWS). AMFS includes a five-day intensive phase aiming at acquiring new skills, plus a reinforcement phase designed to facilitate the transfer of these skills across different contexts and their automatization into effortless behaviors. The concept of our intervention derives from the prediction of the neurocomputational model Directions into Velocities of Articulators (DIVA). The treatment applies dynamic multisensory stimulation to disrupt PWS’ maladaptive over-reliance on sensory feedback mechanisms, promoting the emergence of participants’ natural voices. Methods: Forty-six PWS and a control group, including twenty-four non-stuttering individuals, participated in this study. Stuttering severity and physiological measures, such as heart rate and electromyographic activity, were recorded before and after the intensive phase and during the reinforcement stage in the PWS but only once in the controls. Results: The results showed a significant reduction in stuttering severity at the end of the intensive phase, which was maintained during the reinforcement training. Crucially, worse performance was found in PWS than in the controls at baseline but not after the intervention. In the PWS, physiological signals showed a reduction in activity during the training phases compared to baseline. Conclusions: Our findings show that AMFS provides a promising approach to enhancing speech fluency. Future studies should clarify the mechanisms underlying such intervention and assess whether effects persist after the treatment conclusion.

Background: Substance use disorders (SUDs) and Gambling Disorder (GD) are addictive disorders with a chronic course. Given the limited efficacy of conventional treatments, there is increasing interest in alternative strategies targeting the altered neural circuits associated with the disease. In this context, deep Transcranial Magnetic Stimulation (dTMS) has emerged as a novel neuromodulation technique capable of reaching deep brain regions. However, no definite recommendation for its use in addiction treatment exists. This study systematically reviewed and quantitatively analyzed dTMS effects in SUDs and GD populations. Methods: Following the PRISMA guidelines, we screened four electronic databases up to February 2024 and selected relevant English-written original research articles. 17 papers were included in the systematic review. As only a minority of studies employed a sham-controlled design, we ran the meta-analysis on a subset of 12 studies, computing the pre-post real stimulation standardized mean change (SMCC) as the effect size, using self-reported craving scores as the dependent variable. Results: The results showed a significant and large effect of active dTMS in reducing craving scores (SMCC = - 1.26, 95% CI [-1.67, - 0.86], p <.001). High heterogeneity at both quantitative and qualitative levels across studies was found, with research focusing on different types of SUDs and only one study on gambling behaviors. Conclusions: Results provide initial evidence of the feasibility of dTMS for SUDs care. However, further comprehensive research is needed to unveil several methodological challenges. The limitations of the available literature and future research directions are critically discussed.

The utilization of non-invasive neurostimulation techniques, such as transcranial magnetic stimulation (TMS), is increasingly prevalent in psychiatry due to their efficacy and safety. Although the precise therapeutic mechanisms remain partially unclear, repetitive TMS, particularly high-frequency stimulation, may enhance cognitive functions, contributing to therapeutic benefits. This within-subjects study examined the impact of TMS on cognitive and symptomatic outcomes in patients with obsessive–compulsive disorder (OCD), substance use disorder (SUD), and major depressive disorder (MDD). A total of 44 patients underwent cognitive tests and symptom assessments before and after an intensive four-week TMS treatment phase, followed by a four-week maintenance phase. Cognitive assessments included Raven’s matrices, verbal fluency, and digit span tests, while symptom severity was measured using the Italian version of the SCL-90-R. Decision-making performance was also evaluated by administering a delay discounting (DD) test. Principal component analysis was used to generate a dimensional characterization of subjects along cognitive and symptom-related axes before and after treatment. The results indicated that TMS significantly improved symptom scores, but no significant cognitive enhancement was observed. Statistical analysis based on linear mixed-effects models confirmed these findings, showing a significant fixed effect of TMS treatment on symptoms but not on cognitive performance. DD metrics remained unchanged. These findings suggest that while TMS effectively alleviates clinical symptoms, it does not produce consistent or appreciable enhancement of cognitive functions in these protocols. This study highlights the need for more personalized and combined therapeutic approaches to maximize the benefits of TMS, potentially incorporating cognitive enhancement strategies. Future studies will be useful to explore whether the results we obtained are valid for other pathologies, cognitive tests, and stimulation protocols.

Schizophrenia is a chronic psychiatric disorder severely affecting patients’ functioning and quality of life. Unlike positive symptoms, cognitive impairment and negative symptoms cannot be treated pharmacologically and represent consistent predictors of the illness’s prognosis. Cognitive remediation (CR) interventions have been applied to target these symptoms. Brain stimulation also provides promising yet preliminary results in reducing negative symptoms, whereas its effect on cognitive impairment remains heterogeneous. Here, we combined intermittent theta burst stimulation (iTBS) with CR to improve negative symptoms and cognitive impairment in schizophrenia spectrum patients. One hundred eligible patients were invited, and twenty-one participated. We randomized them into four groups, manipulating the stimulation condition (real vs. sham) and CR (no training vs. training). We delivered fifteen iTBS sessions over the left dorsolateral prefrontal cortex for three weeks, followed (or not) by 50 min of training. Consensus-based clinical and cognitive assessment was administered at baseline and after the treatment, plus at three follow-ups occurring one, three, and six months after the intervention. Mixed-model analyses were run on cognitive and negative symptom scores. The preliminary findings highlighted a marginal modulation of iTBS on negative symptoms, whereas CR improved isolated cognitive functions. We herein discuss the limitations and strengths of the methodological approach.

Previous evidence suggested that chronic pain is characterized by cognitive deficits, particularly in the social cognition domain. Recently, a new chronic pain classification has been proposed distinguishing chronic primary pain (CPP), in which pain is the primary cause of patients’ disease, and chronic secondary pain (CSP), in which pain is secondary to an underlying illness. The present study aimed at investigating social cognition profiles in the two disorders. We included 38 CPP, 43 CSP patients, and 41 healthy controls (HC). Social cognition was assessed with the Ekman-60 faces test (Ekman-60F) and the Story-Based Empathy Task (SET), whereas global cognitive functioning was measured with the Montreal Cognitive Assessment (MoCA). Pain and mood symptoms, coping strategies, and alexithymia were also evaluated. Correlations among clinical pain-related measures, cognitive performance, and psychopathological features were investigated. Results suggested that CSP patients were impaired compared to CPP and HC in social cognition abilities, while CPP and HC performance was not statistically different. Pain intensity and illness duration did not correlate with cognitive performance or psychopathological measures. These findings confirmed the presence of social cognition deficits in chronic pain patients, suggesting for the first time that such impairment mainly affects CSP patients, but not CPP. We also highlighted the importance of measuring global cognitive functioning when targeting chronic pain disorders. Future research should further investigate the cognitive and psychopathological profile of CPP and CSP patients to clarify whether present findings can be generalized as disorder characteristics.

The phenomenon of neural plasticity pertains to the intrinsic capacity of neurons to undergo structural and functional reconfiguration through learning and experiential interaction with the environment. These changes could manifest themselves not only as a consequence of various life experiences but also following therapeutic interventions, including the application of noninvasive brain stimulation (NIBS) and psychotherapy. As standalone therapies, both NIBS and psychotherapy have demonstrated their efficacy in the amelioration of psychiatric disorders’ symptoms, with a certain variability in terms of effect sizes and duration. Consequently, scholars suggested the convenience of integrating the two interventions into a multimodal treatment to boost and prolong the therapeutic outcomes. Such an approach is still in its infancy, and the physiological underpinnings substantiating the effectiveness and utility of combined interventions are still to be clarified. Therefore, this opinion paper aims to provide a theoretical framework consisting of compelling arguments as to why adding NIBS to psychotherapy can promote therapeutic change. Namely, we will discuss the physiological effects of the two interventions, thus providing a rationale to explain the potential advantages of a combined approach.

Gambling disorder (GD) is a behavioral addiction that severely impacts individuals’ functioning, leading to high socioeconomic costs. Non-invasive brain stimulation (NiBS) has received attention for treating psychiatric and neurological conditions in recent decades, but there is no recommendation for its use for GD. Therefore, this study aimed to systematically review and analyze the available literature to determine the effectiveness of NiBS in treating GD. Following the PRISMA guidelines, we screened four electronic databases up to July 2022 and selected relevant English-written original articles. We included ten papers in the systematic review and seven in the meta-analysis. As only two studies employed a sham-controlled design, the pre–post standardized mean change (SMCC) was computed as effect size only for real stimulation. The results showed a significant effect of NiBS in reducing craving scores (SMCC = −0.69; 95% CI = [−1.2, −0.2], p = 0.010). Moreover, considering the GD’s frequent comorbidity with mood disorders, we ran an exploratory analysis of the effects of NiBS on depressive symptoms, which showed significant decreases in post-treatment scores (SMCC = −0.71; 95% CI = [−1.1, −0.3], p < 0.001). These results provide initial evidence for developing NiBS as a feasible therapy for GD symptoms but further comprehensive research is needed to validate these findings. The limitations of the available literature are critically discussed.