The Relationship between Neurobiological Function and Inflammation in Depressed Children and Adolescents: A Scoping Review.

INTRODUCTION: Neurobiological dysfunction is associated with depression in children and adolescents. While research in adult depression suggests that inflammation may underlie the association between depression and brain alterations, it is unclear if altered levels of inflammatory markers provoke neurobiological dysfunction in early-onset depression. The aim of this scoping review was to provide an overview of existing literature investigating the potential interaction between neurobiological function and inflammation in depressed children and adolescents. METHODS: Systematic searches were conducted in six databases. Primary research studies that included measures of both neurobiological functioning and inflammation among children (≤18 years) with a diagnosis of depression were included. RESULTS: Four studies (240 participants; mean age 16.0 ± 0.6 years, 62% female) meeting inclusion criteria were identified. Studies primarily examined the inflammatory markers interleukin 6, tumor necrosis factor alpha, C-reactive protein, and interleukin 1 beta. Exploratory whole brain imaging and analysis as well as region of interest approaches focused on the anterior cingulate cortex, basal ganglia, and white matter tracts were conducted. Most studies found correlations between neurobiological function and inflammatory markers; however, depressive symptoms were not observed to moderate these effects. CONCLUSIONS: A small number of highly heterogeneous studies indicate that depression may not modulate the association between altered inflammation and neurobiological dysfunction in children and adolescents. Replication in larger samples using consistent methodological approaches (focus on specific inflammatory markers, examine certain brain areas) is needed to advance the knowledge of potential neuro-immune interactions early in the course of depression.

Depression and emotional eating in children and adolescents: A systematic review and meta-analysis.

Major Depressive Disorder in youth is associated with obesity and adult cardiovascular disease (CVD) risk. Eating in response to emotions (emotional eating) is a potential contributing factor to this association. Although emotional eating is associated with Major Depressive Disorder in adults, findings in children and adolescents are mixed. This systematic review and meta-analysis aims to determine the association between depression and emotional eating in children and adolescents. Systematic searches were conducted in seven databases. Studies were included if the study population had a mean age of ≤18 years and assessed both depression and emotional eating using validated measures. The search generated 12,241 unique studies, of which 37 met inclusion criteria. Random-effects meta-analyses of study outcomes were performed. Thirty-seven studies (26,026 participants; mean age = 12.4 years, SD = 3.1) were included. The mean effect size was significant for both cross-sectional and longitudinal data (Hedges' g = 0.48, p < 0.0001; g = 0.37, p = 0.002, respectively), revealing a positive moderately strong association between depressive symptoms and emotional eating in youth. Among longitudinal studies, the association was stronger when depressive symptoms and emotional eating were assessed using child and adolescent self-report versus parent-report. No studies examined youth with a clinical diagnosis of depression. Meta-analyses revealed that depressive symptoms and emotional eating are positively associated in children and adolescents. However, further research in clinical samples is needed. Results raise the possibility for the importance of emotional eating in the link between depression and early CVD risk, though further examination is required to determine whether emotional eating is a potential treatment target to decrease CVD risk among adolescents with increased depression symptoms.

Ventral hippocampus inactivation enhances the extinction of active avoidance responses in the presence of safety signals but leaves discrete trial operant active avoidance performance intact.

The acquisition of active avoidance (AA) behavior is typically aided by the presence of two signals-the warning signal, which predicts the future occurrence of an aversive event (e.g., shocks), and the safety signal, which is presented upon successful avoidance of oncoming shocks. While the warning signal could be conceived to act as a Pavlovian fear cue, and is likely mediated by brain areas that underlie Pavlovian fear cue conditioning, the neural substrates underlying safety signaling are less clear, largely due to the unavailability of AA tasks that are devoid of an explicit warning signal. The present study sought to investigate the role of the ventral hippocampus (VH) in safety signaled AA performance acquired without an explicit warning signal, using a novel discrete trial paradigm. Adult male Long Evans rats were divided into two groups and trained to acquire AA responses with, or without a safety signal. Analysis of the acquisition and stable state performance data revealed that the availability of a safety signal alone did not improve the acquisition or performance of AA responses. Furthermore, post-training, reversible VH inactivation did not impact stable state avoidance behavior. However, extinction of avoidance responses was facilitated in the group trained with a safety signal, and this effect was further potentiated by VH inactivation. Additional elevated plus maze (EPM), light-dark box, and locomotor tests demonstrated that VH inactivation reduced anxiety without affecting locomotor activity. Taken together, these results demonstrate the importance of VH in the extinction of persistent pathological avoidance behavior when safety is signaled.

Ventral, but not dorsal, hippocampus inactivation impairs reward memory expression and retrieval in contexts defined by proximal cues.

The hippocampus (HPC) has been widely implicated in the contextual control of appetitive and aversive conditioning. However, whole hippocampal lesions do not invariably impair all forms of contextual processing, as in the case of complex biconditional context discrimination, leading to contention over the exact nature of the contribution of the HPC in contextual processing. Moreover, the increasingly well-established functional dissociation between the dorsal (dHPC) and ventral (vHPC) subregions of the HPC has been largely overlooked in the existing literature on hippocampal-based contextual memory processing in appetitively motivated tasks. Thus, the present study sought to investigate the individual roles of the dHPC and the vHPC in contextual biconditional discrimination (CBD) performance and memory retrieval. To this end, we examined the effects of transient post-acquisition pharmacological inactivation (using a combination of GABAA and GABAB receptor agonists muscimol and baclofen) of functionally distinct subregions of the HPC (CA1/CA3 subfields of the dHPC and vHPC) on CBD memory retrieval. Additional behavioral assays including novelty preference, light-dark box and locomotor activity test were also performed to confirm that the respective sites of inactivation were functionally silent. We observed robust deficits in CBD performance and memory retrieval following inactivation of the vHPC, but not the dHPC. Our data provides novel insight into the differential roles of the ventral and dorsal HPC in reward contextual processing, under conditions in which the context is defined by proximal cues.

The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making.

The resolution of an approach-avoidance conflict induced by ambivalent information involves the appraisal of the incentive value of the outcomes and associated stimuli to orchestrate an appropriate behavioral response. Much research has been directed at delineating the neural circuitry underlying approach motivation and avoidance motivation separately. Very little research, however, has examined the neural substrates engaged at the point of decision making when opposing incentive motivations are experienced simultaneously. We hereby examine the role of the dorsal and ventral hippocampus (HPC) in a novel approach-avoidance decision making paradigm, revisiting a once popular theory of HPC function, which posited the HPC to be the driving force of a behavioral inhibition system that is activated in situations of imminent threat. Rats received pre-training excitotoxic lesions of the dorsal or ventral HPC, and were trained to associate different non-spatial cues with appetitive, aversive and neutral outcomes in three separate arms of the radial maze. On the final day of testing, a state of approach-avoidance conflict was induced by simultaneously presenting two cues of opposite valences, and comparing the time the rats spent interacting with the superimposed 'conflict' cue, and the neutral cue. The ventral HPC-lesioned group showed significant preference for the conflict cue over the neutral cue, compared to the dorsal HPC-lesioned, and control groups. Thus, we provide evidence that the ventral, but not dorsal HPC, is a crucial component of the neural circuitry concerned with exerting inhibitory control over approach tendencies under circumstances in which motivational conflict is experienced.

Cognitive functioning in children and adolescents with depression: A systematic review and meta-analysis.

Although cognitive dysfunction is associated with depression in adults, the link in children and adolescents is unclear. This systematic review and meta-analysis quantifies the association between depression and cognitive function in children and adolescents. Systematic searches were conducted in six databases: Child Development and Adolescent Studies, Ovid MEDLINE, Ovid Embase, Ovid APA PsycINFO, EBSCO CINAHL Plus, Scopus (last search: April 2023). Studies including measures of cognitive outcomes (memory, attention, executive function, processing speed, language) among children (≤18 years) with depression were included. The Joanna Briggs Institute Critical Appraisal Tools were used to determine study risk of bias. Random-effects meta-analyses of study outcomes were performed. Seventeen studies were included (15 were cross-sectional, 1 prospective, 1 randomized control trial). Participants (N = 13,567) were 10 to 17 years old (mean 13.8 ± 2.2 years; 60 % female). Compared with healthy controls, depressed participants had lower performance on tests of working memory (g = -0.40; 95 % CI: -0.67, -0.13), long-term memory (g = -0.48; 95 % CI: -0.72, -0.25), attention (g = -0.15; 95 % CI: -0.26, -0.04), executive function (g = -0.16; 95 % CI: -0.24, -0.08), and language (g = -0.23; 95 % CI: -0.36, -0.09). No performance differences were observed on tests of short-term memory or processing speed. Children and adolescents with depression demonstrated lower performance on tests of working and long-term memory, attention, executive function and language. These findings emphasize the importance of considering cognitive functioning among children with depression, and greater understanding of the effect of treatment on these outcomes. PROSPERO (CRD42022332064).

Evaluation of an automated matching system of children and families to virtual mental health resources during COVID-19.

BACKGROUND: Children and their families often face obstacles in accessing mental health (MH) services. The purpose of this study was to develop and pilot test an electronic matching process to match children with virtual MH resources and increase access to treatment for children and their families during COVID-19. METHODS: Within a large observational child cohort, a random sample of 292 families with children ages 6-12 years were invited to participate. Latent profile analysis indicated five MH profiles using parent-reported symptom scores from validated depression, anxiety, hyperactivity, and inattention measures: (1) Average Symptoms, (2) Low Symptoms, (3) High Symptoms, (4) Internalizing, and (5) Externalizing. Children were matched with virtual MH resources according to their profile; parents received surveys at Time 1 (matching process explanation), Time 2 (match delivery) and Time 3 (resource uptake). Data on demographics, parent MH history, and process interest were collected. RESULTS: 128/292 families (44%) completed surveys at Time 1, 80/128 families (63%) at Time 2, and a final 67/80 families (84%) at Time 3, yielding an overall uptake of 67/292 (23%). Families of European-descent and those with children assigned to the Low Symptoms profile were most likely to express interest in the process. No other factors were associated with continued interest or uptake of the electronic matching process. Most participating parents were satisfied with the process. CONCLUSIONS: The electronic matching process delivered virtual MH resources to families in a time-efficient manner. Further research examining the effectiveness of electronically matched resources in improving children's MH symptoms is needed.

The gut microbiome in children with mood, anxiety, and neurodevelopmental disorders: An umbrella review.

Research on the gut microbiome and mental health among children and adolescents is growing. This umbrella review provides a high-level overview of current evidence syntheses to amalgamate current research and inform future directions. Searches were conducted across seven databases for peer-reviewed pediatric (<18 years) review literature. Studies reporting gut microbiome composition and/or biotic supplementation on depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), or obsessive-compulsive disorder (OCD) were included. Deduplication and screening took place in Covidence. A sensitivity analysis was conducted to assess the degree of primary study overlap. Among the 39 included review studies, 23 (59%) were observational and 16 (41%) were interventional. Most reviews (92%) focused on ASD. Over half (56%) of the observational and interventional reviews scored low or critically low for methodological quality. A higher abundance of Clostridium clusters and a lower abundance of Bifidobacterium were consistently observed in ASD studies. Biotic supplementation was associated with ASD symptom improvement. Gut microbiome-mental health evidence syntheses in child and youth depression, anxiety, bipolar disorder, and OCD are lacking. Preliminary evidence suggests an association between specific microbiota and ASD symptoms, with some evidence supporting a role for probiotic supplementation ASD therapy.

Electrical high frequency stimulation of the nucleus accumbens shell does not modulate depressive-like behavior in rats.

Deep brain stimulation (DBS) is an effective tool for treatment-resistant depression, though it is still unclear which brain area to target in order to get robust results. While research suggests that the nucleus accumbens (NAc) plays an important role in depression, studies using NAc DBS to improve depressive behavior have not been able to fully explain underlying molecular mechanisms. We therefore used unilateral high frequency stimulation of the NAc shell in rats to verify its effectiveness in treating depression and study involved neurotransmitter systems. Animals underwent social isolation and food deprivation to induce depressive-like symptoms, and performed the forced swim test (FST) to see possible changes in depressive behavior due to NAc shell stimulation. Neurotransmitter levels were measured using in-vivo microdialysis to detect DBS-induced changes. Non-treated control rats showed no significant difference between swimming and floating during FST, verifying that our depression model induced depressive-like symptoms in rats. Furthermore, stimulated and sham-operated animals showed a significant increase in mobility during FST compared to control rats, suggesting an improvement of depressive-like symptoms. However, stimulated rats did not differ from sham-operated rats in their behavior during FST, nor did neurotransmitter levels significantly changed in stimulated rats compared to control rats. Our data suggest that NAc shell stimulation did not alter depressive behavior in rats and had no effects on the molecular level. However, depressive behavior was positively altered when stimulation electrode and microdialysis probe were inserted simultaneously into the NAc shell, causing significant tissue damage and therefore possibly altering the glutamatergic system.

Ventral Hippocampal CA1 and CA3 Differentially Mediate Learned Approach-Avoidance Conflict Processing.

Approach-avoidance conflict arises when an animal encounters a stimulus that is associated simultaneously with positive and negative valences [1]. The effective resolution of approach-avoidance conflict is critical for survival and is believed to go awry in a number of mental disorders, such as anxiety and addiction. An accumulation of evidence from both rodents and humans suggests that the ventral hippocampus (anterior in humans) plays a key role in approach-avoidance conflict processing [2-8], with one influential model proposing that this structure modulates behavioral inhibition in the face of conflicting goals by increasing the influence of negative valences [9]. Very little is known, however, about the contributions of specific hippocampal subregions to this process-an important issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a conflict cue imbued with both learned positive and learned negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the conflict cue. In contrast, dorsal CA1- and CA3-inactivated rats showed no change in conflict behavior, and furthermore, additional behavioral tasks confirmed that the observed pattern of approach-avoidance findings could not be explained by other factors, such as differential alterations in novelty detection or locomotor activity. Our data demonstrate that ventral CA1 and CA3 subserve distinct and opposing roles in approach-avoidance conflict processing and provide important insight into the functions and circuitry of the ventral hippocampus.

Different dosing regimens of repeated ketamine administration have opposite effects on novelty processing in rats.

Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects.

Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure.

RATIONALE: Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of conflicting approach and avoidance motivational signals have yet to be thoroughly investigated. OBJECTIVE: The present study sought to investigate the effects of cocaine pre-exposure on conflict resolution using novel approach-avoidance paradigms. METHODS: We used a novel mixed-valence conditioning paradigm to condition cocaine-pre-exposed rats to associate visuo-tactile cues with either the delivery of sucrose reward or shock punishment in the arms in which the cues were presented. Following training, exploration of an arm containing a superimposition of the cues was assessed as a measure of conflict resolution behavior. We also used a mixed-valence runway paradigm wherein cocaine-pre-exposed rats traversed an alleyway toward a goal compartment to receive a pairing of sucrose reward and shock punishment. Latency to enter the goal compartment across trials was taken as a measure of motivational conflict. RESULTS: Our results reveal that cocaine pre-exposure attenuated learning for the aversive cue association in our conditioning paradigm and enhanced preference for mixed-valence stimuli in both paradigms. CONCLUSIONS: Repeated cocaine pre-exposure allows appetitive approach motivations to gain greater influence over behavioral output in the context of motivational conflict, due to aberrant positive and negative incentive motivational processing.

A simple implantation method for flexible, multisite microelectrodes into rat brains.

A long term functional and reliable coupling between neural tissue and implanted microelectrodes is the key issue in acquiring neural electrophysiological signals or therapeutically excite neural tissue. The currently often used rigid micro-electrodes are thought to cause a severe foreign body reaction resulting in a thick glial scar and consequently a poor tissue-electrode coupling in the chronic phase. We hypothesize, that this adverse effect might be remedied by probes compliant to the soft brain tissue, i.e., replacing rigid electrodes by flexible ones. Unfortunately, this flexibility comes at the price of a low stiffness, which makes targeted low trauma implantation very challenging. In this study, we demonstrate an adaptable and simple method to implant extremely flexible microprobes even to deep areas of rat's brain. Implantation of flexible probes is achieved by rod supported stereotactic insertion fostered by a hydrogel (2% agarose in PBS) cushion on the exposed skull. We were thus able to implant very flexible micro-probes in 70 rats as deep as the rodent's subthalamic nucleus. This work describes in detail the procedures and steps needed for minimal invasive, but reliable implantation of flexible probes.

Electrical high frequency stimulation in the dorsal striatum: Effects on response learning and on GABA levels in rats.

Electrical high frequency stimulation (HFS) has been used to treat various neurological and psychiatric diseases. The striatal area contributes to response learning and procedural memory. Therefore, we investigated the effect of striatal HFS application on procedural/declarative-like memory in rats. All rats were trained in a flooded Double-H maze for three days (4 trials/day) to swim to an escape platform hidden at a constant location. The starting place was the same for all trials. After each training session, HFS of the left dorsal striatum was performed over 4h in alternating 20 min periods (during rest time, 10a.m. to 3p.m.). Nineteen hours after the last HFS and right after a probe trial assessing the rats' strategy (procedural vs. declarative-like memory-based choice), animals were sacrificed and the dorsal striatum was quickly removed. Neurotransmitter levels were measured by HPLC. Stimulated rats did not differ from sham-operated and control rats in acquisition performance, but exhibited altered behavior during the probe trial (procedural memory responses being less frequent than in controls). In stimulated rats, GABA levels were significantly increased in the dorsal striatum on both sides. We suggest that HFS of the dorsal striatum does not alter learning behavior in rats but influences the strategy by which the rats solve the task. Given that the HFS-induced increase of GABA levels was found 19 h after stimulation, it can be assumed that HFS has consequences lasting for several hours and which are functionally significant at a behavioral level, at least under our stimulation (frequency, timing, location, side and strength of stimulation) and testing conditions.