Faculty Bibliography

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.

INTRODUCTION/UNASSIGNED:Comorbidity between disorders is pervasive, and its relationship to the main conditions under investigation needs to be addressed for robust causal inference. However, many clinical etiologic studies still fail to capitalize on the theoretical advancements and improved recommendations regarding covariate adjustment in this context. Specifically, studies often lack explicit causal assumptions about the role of comorbidity in exposure-outcome relationships, potentially leading to inappropriate accounting for comorbid conditions and resulting in biased effect estimates. This study aims to explore common causal structures involving comorbidity and provide guidance for handling it in etiologic research. METHODS/UNASSIGNED:We use Directed Acyclic Graphs (DAGs) to depict six causal scenarios involving comorbidity as a confounder, mediator, collider, or consequence of the exposure or outcome, illustrated with real-world clinical examples. Simulations were conducted across 5,000 iterations for each scenario, assessing the impact of conditioning on comorbidity under four effect measures (risk difference, odds ratio, risk ratio, and mean difference). Bias was evaluated by comparing adjusted and unadjusted effect estimates to the true values. RESULTS/UNASSIGNED:The impact of conditioning on comorbidity varied by its causal role. Adjusting for comorbidity mitigated bias when it acted as a confounder but introduced bias when it was a mediator or collider. In instances where comorbidity was a consequence of either the exposure or outcome, the decision to adjust depended on the research objectives and could vary across effect measures. DISCUSSION/UNASSIGNED:Explicit causal assumptions are essential for selecting appropriate analytical strategies in etiologic research. This study provides practical guidance on analytical handling of the measures of comorbidity, highlighting the need for study design and analysis to align with research objectives. Future work should address more complex causal structures and other methodological challenges.

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.

Interoceptive accuracy, the ability to correctly perceive internal body signals such as heartbeats, has been empirically and theoretically linked to stress. However, issues with the measurement of both interoceptive accuracy and stress have led to lack of clarity regarding this relationship. This systematic review and meta-analysis aimed to clarify whether interoceptive accuracy is associated with different facets of stress, including - physical, cognitive and self-reported stressors and the physiological stress response. A systematic search identified 2014 abstracts. Twenty-eight authors were contacted to request data for eligible studies, which yielded a final sample of 20 studies. Results revealed a positive association between heartbeat counting task (HCT) performance and acute physical stressors, and a negative association between HCT performance and physiological stress responses. No significant relationships were observed between stress and interoceptive accuracy assessed by the heartbeat discrimination task. While these findings offer tentative support for stress-interoceptive accuracy associations, they must be interpreted with caution given substantial heterogeneity in stress measures, limited use of interoception tasks beyond the HCT, and ongoing concerns regarding task validity. Implications for future research and methodological recommendations are discussed.

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.