Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebellar heterotopia (CH) is a neuroradiologic abnormality that is poorly reported and investigated in the literature. It can be observed as an isolated finding, but it has been mainly reported in the context of cerebellar dysgenesis and syndromic conditions. This study aims to provide a comprehensive neuroradiologic, clinical, and genetic characterization of a cohort of pediatric patients with CH. MATERIALS AND METHODS/METHODS:Patients with a diagnosis of CH were systematically selected from the neuroimaging databases of the 4 Italian centers participating in this retrospective study. For each patient, information regarding demographic, clinical, genetic, and neuroradiologic data was collected. RESULTS:= 14). Isolated CH consistently showed a peripheral subcortical localization in the inferior portion of cerebellar hemispheres, with either unilateral or bilateral distribution. Ten patients belonging to the second group had a diagnosis of CHARGE syndrome, and their nodules of CH were mainly but not exclusively bilateral, symmetric, located in the peripheral subcortical zone and the inferior portion of the cerebellar hemispheres. The remaining 4 patients of the second group showed either bilateral or unilateral CH, located in both the peripheral cortex and deep white matter and the superior and inferior portions of cerebellum. Patients with isolated CH showed a high prevalence of language development delay; neurodevelopmental disorders were the most represented clinical diagnoses. Recurring features were behavioral problems and motor difficulties. A conclusive genetic diagnosis was found in 18/32 patients. CONCLUSIONS:We found distinctive neuroradiologic patterns of CH. Genetic results raise the possibility of a correlation between cerebellar morphologic and functional developmental disruption, underscoring the importance of CH detection and reporting to orient the diagnostic path.

Cerebellar dysfunction affects socio-affective abilities beyond motor control. Recent studies suggest that non-invasive cerebellar neurostimulation can modulate social cognition networks, offering potential therapeutic benefits for children with autism, ADHD, and mood disorders. However, its application in pediatrics remains largely unexplored. This review summarizes emerging pediatric research on cerebellar transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We discuss their mechanisms, potential benefits, and safety considerations, highlighting preliminary findings that suggest feasibility and effectiveness. Ethical concerns and technical challenges related to pediatric neuroanatomy and stimulation parameters are also addressed. While early results are promising, further clinical trials and neurophysiological studies are essential to optimize protocols and confirm long-term efficacy. Advancing our understanding of cerebellar involvement in socio-affective functions could lead to innovative rehabilitation strategies for neurodevelopmental disorders.

INTRODUCTION/BACKGROUND:Children with septo-optic-pituitary dysplasia (SOD) may experience a range of visual impairments and hormonal dysfunctions beyond developmental delay/intellectual disability. The literature describes sleep fragmentation, circadian rhythm disruptions and reduced sleep efficiency. These manifestations are believed to be closely linked to both structural and functional abnormalities associated with SOD, potentially disrupting the natural circadian rhythm. Both anomalies in midline brain structures and decreased visual input could potentially impact melatonin secretion, although a distinct melatonin profile for SOD patients has yet to be identified. Furthermore, the specific contribution of these factors to sleep disturbances in SOD remains unexplored. The aim of this study is to evaluate the quality of sleep and its characteristics, along with the melatonin profile, among paediatric patients diagnosed with SOD. A comparison will be made between these findings and those of children with isolated bilateral visual impairment, as well as patients with agenesis of the corpus callosum. METHODS AND ANALYSIS/METHODS:Participants aged between 3 and 18 years previously diagnosed with SOD will be recruited prospectively. Each participant will be assessed at baseline and at each follow-up visit scheduled to evaluate the clinical course. Sleep quality and daytime sleepiness changes will be tracked using actigraphic assessment, standardised sleep questionnaires and a sleep EEG. Additionally, plasma and salivary melatonin profiles will be assessed for each participant. ETHICS AND DISSEMINATION/BACKGROUND:This study has been approved by local Ethics Committee (N°0049187/23). The study findings will be shared through publication in an international peer-reviewed journal and presented at both national and international conferences. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06262152.

Parental depression is a risk factor for children's cognitive and psychological development. Literature has found reciprocal relations between parental depression and child psychopathology and effects of parental depression on children's cognition. The present study is the first to examine reciprocity among parental depression and child cognition, and pathways to child psychopathology. Structural equation models were conducted using data from the Early Head Start Research and Evaluation Project, a nationally representative sample of 3,001 economically marginalized families. Measures were collected in four waves from 14 months to 10-11 years. Reciprocal associations emerged between maternal and paternal depression at from 14 months to 5 years. Reciprocal parental depression was associated with greater psychopathology at age 10-11. Maternal depression predicted poorer child cognition, which indirectly predicted increased depression in mothers of children aged 3-5 through paternal depression, and in fathers at age 3, through earlier paternal depression. This study was unable to parse within- and between-person effects. Additionally, data for paternal depression was limited to ages 2 and 3. Findings emphasize the transactional nature of child cognition and child and parent psychopathology, supporting family focused intervention and prevention efforts that target parent psychopathology and child cognition.

The rapid development and clinical use of brain stimulation has renewed debates about whether to define and accredit a pathway for clinical subspecialty training. To address this, the Brain Stimulation Subspecialty Summits (BraSSS) were convened in 2023 and 2024, featuring international leaders in brain stimulation across psychiatry, neurology, neurosurgery, psychology, and neuroscience. Both meetings included two days of lectures and debates focused on clinical content, emerging science, and educational standards. The 2023 meeting was held at Brigham & Women's Hospital and Harvard University, where 54 attendees reached a consensus that the subspecialty is adequately developed to warrant formal recognition and initiated debates regarding the name and scope of the subspecialty. The 2024 meeting was held at Stanford University, where 56 attendees developed a content outline, organized committees, and reached a consensus to form an independent society focused on developing and maintaining unbiased accreditation standards. "Brain stimulation" was chosen democratically as the name of the subspecialty. Clinicians from multiple primary specialties may enter this subspecialty training track. While individual programs may have a specific area of focus (e.g. interventional psychiatry or epilepsy), our expectation is that accredited brain stimulation programs will provide training experiences that cross specialties and stimulation modalities. Several potential unintended consequences were discussed, and plans were developed to address them. Overall, subspecialty recognition was deemed to be beneficial to the brain stimulation field, with a goal to launch an associated society and start the process of accrediting existing US and Canadian programs in 2025.

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2^-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.

Chronic motor or vocal tic disorder (CMVTD) is a distressing neuropsychiatric condition. A subset of patients remains refractory to currently approved therapies. The present report describes a pediatric patient with CMVTD who had previously failed multiple pharmacological treatments, including two Food and Drug Administration (FDA)-approved agents (pimozide, aripiprazole), guanfacine, psychotherapy, and novel compounds (lumateperone, cariprazine). The patient was initiated on valbenazine, titrated to 80 mg daily. Clinical improvement was noted within 24-48 hours, with sustained benefit and good tolerability. Tic severity, measured by the Yale Global Tic Severity Scale-Revised (YGTSS-R), improved from 65 at baseline to five following treatment (net reduction of 60 points). This case illustrates a marked therapeutic response to valbenazine in a patient with CMVTD refractory to conventional and novel therapies. These observations highlight the potential role of vesicular monoamine transporter 2 (VMAT2) inhibition in tic disorders and also the need for further clinical study.

IMPORTANCE/UNASSIGNED:Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear. OBJECTIVE/UNASSIGNED:To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors. DATA SOURCES/UNASSIGNED:PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions. STUDY SELECTION/UNASSIGNED:Studies of any design with DSM or International Classification of Diseases-defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted. MAIN OUTCOMES AND MEASURES/UNASSIGNED:For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs. RESULTS/UNASSIGNED:Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I2 > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment.

Serotonergic psychedelics and 3,4-methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane's RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I²=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; SMD=-0.62 [-0.97; -0.28]; I²=55 %; GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMD_MDMA=-1.18 [-2.04; -0.32]; I²=0 %; k = 2; GRADE=low and SMD_serotonergic=-0.88 [-1.70; -0.06]; I²=54 %;k = 5; GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (k = 6; RR=1.42 [0.89; 2.26]; I²=7 %; GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k = 1; SMD=0.22 [-0.32; 0.76]; GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation (RR_MDMA=0.74 [0.32; 1.72]; RR_serotonergic=0.81 [0.56; 1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.