Faculty Bibliography

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK⁺) interneurons and a functional impairment of CCK⁺ interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model.SIGNIFICANCE STATEMENT Impaired synaptic inhibition in hippocampal circuits has been identified as a key feature that contributes to the emergence and propagation of seizure activity in human patients and animal models of temporal lobe epilepsy (TLE). Among the hippocampal subfields, the CA2 region is particularly resilient to seizure-associated neurodegeneration and has been suggested to play a key role in seizure activity in TLE. Here we report that perisomatic inhibition of CA2 pyramidal neurons mediated by cholecystokinin-expressing interneurons is selectively reduced in acute hippocampal slices from epileptic mice. Parvalbumin-expressing interneurons, in contrast, appear relatively conserved in epileptic mice. These findings advance our understanding of the cellular mechanisms underlying inhibitory disruption in hippocampal circuits in a mouse model of spontaneous recurring seizures.

School-based mental health clinics are the ideal venue to provide mental health services for youth due to their accessibility and lack of stigma compared with other community treatment centers. There were challenges associated with the abrupt shift to remote education and clinic services caused by COVID-19, but some school-based mental health clinics excelled in their implementation of telehealth services. This study of New York schools found four main facilitators to implementing telehealth services among school-based mental health clinics: (1) strong collaborative relationships between the clinic and school setting, (2) active and responsive leadership, (3) provider experience in conducting telehealth, and (4) provider flexibility to accommodate the needs of children and families. Factors were identified at every level of the school-based mental health clinic and system that helped to facilitate exemplary telehealth service delivery and implementation.

BACKGROUND:Sleep difficulties are common in children with attention-deficit/hyperactivity disorder (ADHD). However, sleep problems are multifaceted and little is known about the variation in sleep difficulties across children with ADHD. We examined the profiles of sleep difficulties in children with ADHD and associated clinical factors (e.g. co-occurring mental health conditions, stimulant use and parent mental health). METHODS:Data from two harmonised studies of children with ADHD (total: N = 392, ages 5-13 years) were used. Parents completed measures of children's sleep, co-occurring mental health conditions and their own mental health. Both parents and teachers completed measures of child ADHD symptoms and emotional and conduct symptoms. Latent profile analysis was used to identify sleep profiles, and multinomial logistic regression assessed clinical correlates of the groups. RESULTS:Five sleep profiles were identified: (a) insomnia/delayed sleep phase (36%), (b) generalised sleep difficulties at sleep onset and overnight (25%), (c) high anxious/bedtime resistance difficulties (11%), (d) overnight sleep difficulties including obstructive sleep apnoea and parasomnias (5%) and (e) no sleep difficulties (22%). Compared with the group without sleep difficulties, the generalised, anxious/bedtime resistance and insomnia/delayed sleep phase sleep had greater parent-reported emotional and conduct symptoms, co-occurring anxiety and increased parent mental health difficulties. The generalised and anxious/bedtime resistance groups also had greater parent-reported ADHD symptoms, with the anxious/bedtime resistance sleep group also having more frequent co-occurring depression and teacher-reported emotional symptoms. CONCLUSIONS:The sleep difficulties experienced by children with ADHD are varied. Supports to help children with ADHD need to consider the particular profiles of sleep difficulties experienced and broader clinical characteristics. Tailored intervention approaches are likely needed (including a need to address parent mental health).

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I² statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.

This pre-registered (CRD42022322038) systematic review and meta-analysis investigated clinical and cognitive outcomes of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders. PubMed, OVID, Web of Science, Chinese National Knowledge Infrastructure, Wanfang, and VIP database for Chinese technical periodicals were searched (until 16/03/2022) to identify trials investigating cognitive and clinical outcomes of eTNS in neurological or psychiatric disorders. The Cochrane Risk of Bias 2.0 tool assessed randomized controlled trials (RCTs), while the Risk of Bias of Non-Randomized Studies (ROBINS-I) assessed single-arm trials. Fifty-five peer-reviewed articles based on 48 (27 RCTs; 21 single-arm) trials were included, of which 12 trials were meta-analyzed (N participants = 1048; of which ~3% ADHD, ~3% Epilepsy, ~94% Migraine; age range: 10-49 years). The meta-analyses showed that migraine pain intensity (K trials = 4, N = 485; SMD = 1.03, 95% CI[0.84-1.23]) and quality of life (K = 2, N = 304; SMD = 1.88, 95% CI[1.22-2.53]) significantly improved with eTNS combined with anti-migraine medication. Dimensional measures of depression improved with eTNS across 3 different disorders (K = 3, N = 111; SMD = 0.45, 95% CI[0.01-0.88]). eTNS was well-tolerated, with a good adverse event profile across disorders. eTNS is potentially clinically relevant in other disorders, but well-blinded, adequately powered RCTs must replicate findings and support optimal dosage guidance.

Theories of posttraumatic stress disorder (PTSD) highlight the role of cognitive and behavioral factors in its development, maintenance, and treatment. This study investigated the relationship between changes in factors specified in Ehlers and Clark's (2000) model of PTSD and PTSD symptom change in 217 patients with PTSD who were treated with cognitive therapy for PTSD (CT-PTSD) in routine clinical care. Bivariate latent change score models (LCSM) of session-by-session changes in self-report measures showed that changes in PTSD symptoms were preceded by changes in negative appraisals, flashback characteristics of unwanted memories, safety behaviours, and unhelpful responses to intrusions, but not vice versa. For changes in trauma memory disorganization and PTSD symptoms we found a bidirectional association. This study provides evidence that cognitive and behavioral processes proposed in theoretical models of PTSD play a key role in driving symptom improvement during CT-PTSD.

BACKGROUND/UNASSIGNED:Aggression is a major public health concern that emerges early in development and lacks optimized treatment, highlighting need for improved mechanistic understanding regarding the etiology of aggression. The present study leveraged fetal resting-state functional magnetic resonance imaging to identify candidate neurocircuitry for the onset of aggressive behaviors before symptom emergence. METHODS/UNASSIGNED: = 79). Independent component analysis was used to define frontal and limbic regions of interest. RESULTS/UNASSIGNED:Child aggression was not related to within-network connectivity of subcortical limbic regions or within-medial prefrontal network connectivity in fetuses. However, weaker functional coupling between the subcortical limbic network and medial prefrontal network in fetuses was prospectively associated with greater maternal-rated child aggression at 3 years of age even after controlling for maternal emotion dysregulation and toddler language ability. We observed similar, but weaker, associations between fetal frontolimbic functional connectivity and toddler internalizing symptoms. CONCLUSIONS/UNASSIGNED:Neural correlates of aggressive behavior may be detectable in utero, well before the onset of aggression symptoms. These preliminary results highlight frontolimbic connections as potential candidate neurocircuitry that should be further investigated in relation to the unfolding of child behavior and psychiatric risk.