Neural activity and network analysis for understanding reasoning using the matrix reasoning task.

Reasoning requires the ability to manipulate mental representations and understand relationships between objects. There is a paucity of research regarding the functional connections between multiple brain areas that may interact during commonly used reasoning tasks. The present study aimed to examine functional activation and connectivity of frontoparietal regions during a Matrix Decision Making Task, completed by twenty-one right-handed healthy participants while undergoing fMRI. Voxel-wise whole brain analysis of neural response to the task revealed activation spanning dorsal and lateral prefrontal, occipital, and parietal regions. Utilizing Group Iterative Multiple Model Estimation, a data-driven approach that estimates the presence and direction of connectivity between specific ROIs, connectivity between prefrontal and sensory processing regions were revealed. Moreover, the magnitude of connectivity strength between the left precentral gyrus and left dorsal cingulate (dACC) was positively correlated with MR behavioral performance. Taken together, results are consistent with earlier work demonstrating involvement of regions comprising the central executive network in relational reasoning. These data expand existing knowledge regarding communication of key brain regions during the task and demonstrate that understanding how key brain regions are interconnected can effectively predict the quality of behavioral output.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Change in neural response during emotion regulation is associated with symptom reduction in cognitive behavioral therapy for anxiety disorders.

BACKGROUND: Anxiety disorders are debilitating conditions that can be treated with cognitive behavioral therapy (CBT). Increased understanding of the neurobiological correlates of CBT may inform treatment improvements and personalization. Prior neuroimaging studies point to treatment-related changes in anterior cingulate, insula, and other prefrontal regions during emotional processing, yet to date the impact of CBT on neural substrates of "top down" emotion regulation remains understudied. We examined the relationship between symptom changes assessed over the course of CBT treatment sessions and pre- to post-treatment neural change during an emotion regulation task. METHOD: In the current study, a sample of 30 participants with panic disorder or generalized anxiety disorder completed a reappraisal-based emotion regulation task while undergoing fMRI before and after completing CBT. RESULTS: Reduced activation in the parahippocampal gyrus was observed from pre- to post-treatment during periods of reducing versus maintaining emotion. Parahippocampal activation was associated with change in symptoms over the course of treatment and post-treatment responder status. Results suggest that, from pre- to post-CBT, participants demonstrated downregulation of neural responses during effortful cognitive emotion regulation. LIMITATIONS: Effects were not observed in frontoparietal systems as would be hypothesized based on prior literature, suggesting that treatment-related change could occur outside of fronto-parietal and limbic regions that are central to most models of neural functioning in anxiety disorders. CONCLUSIONS: Continued work is needed to better understand how CBT affects cognitive control and memory processes that are hypothesized to support reappraisal as a strategy for emotion regulation.

Attenuated prefrontal and temporal neural activity during working memory as a potential biomarker of suicidal ideation in veterans with PTSD.

BACKGROUND: Suicide is a significant health concern among veterans, and suicidal ideation is a common and functionally debilitating condition that frequently precedes suicidal behavior. Characterizing neurobiological substrates associated with suicidal ideation in veterans may inform evaluation of risk for this population. Associations between suicidal ideation and functional abnormalities in prefrontal, temporal, and striatal regions supporting cognitive task performance have been documented in individuals with mood and psychotic disorders, suggesting a potential role for neurocognitive vulnerabilities in this condition. To date, however, relatively little research has explored neural correlates of suicidal ideation, particularly among individuals with posttraumatic stress disorder (PTSD). METHODS: Twenty three combat veterans diagnosed with PTSD completed an adapted Reading Span (Rspan) working memory task during functional magnetic resonance imaging (fMRI). Participants were classified based on presence of current SI. We evaluated differences between these groups on neural activation in response to interference-based working memory demands within the task. Primary analyses were conducted using a voxel-wise between-group t-test. RESULTS: Task-based activations were observed in regions including the cingulate, middle frontal, parietal, and occipital cortex, striatum, and cerebellum. Relative to individuals without SI, individuals with SI demonstrated less activation in a large region spanning the lateral prefrontal cortex and cingulate cortex, as well as the inferior temporal cortex, in response to interference demands. CONCLUSIONS: Results are consistent with models proposing that prefrontal neural substrates involved in cognitive regulation are implicated in suicidal ideation. Involvement of temporal functioning may also exist based on current findings. Future research is needed to understand whether disturbances in prefrontal regulatory control reflect a specific profile subtype with distinct neural correlates, and how such neural patterns may be used to improve detection and treatment personalization.

Current and emerging treatment strategies for hair loss in women of color.

Hair loss is common in women of color, and is associated with significant psychosocial complaints. Early clinical recognition and prompt initiation of intervention with medical treatment is critical to halt the disease process. In this article, we review the clinical presentations of nonscarring and scarring alopecias in women of color, use of dermoscopy for early recognition of the disease process, and medical, procedural, and surgical interventions. In conditions that result in scarring alopecia, such as late-stage traction, frontal fibrosing, or central centrifugal cicatricial alopecia, patients may benefit from procedural interventions, such as hair transplantation, platelet rich plasma injections, low-level laser therapy, or scalp therapy.

Altered fear processing in adolescents with a history of severe childhood maltreatment: an fMRI study.

BACKGROUND: Children with a history of maltreatment suffer from altered emotion processing but the neural basis of this phenomenon is unknown. This pioneering functional magnetic resonance imaging (fMRI) study investigated the effects of severe childhood maltreatment on emotion processing while controlling for psychiatric conditions, medication and substance abuse. METHOD: Twenty medication-naive, substance abuse-free adolescents with a history of childhood abuse, 20 psychiatric control adolescents matched on psychiatric diagnoses but with no maltreatment and 27 healthy controls underwent a fMRI emotion discrimination task comprising fearful, angry, sad happy and neutral dynamic facial expressions. RESULTS: Maltreated participants responded faster to fearful expressions and demonstrated hyper-activation compared to healthy controls of classical fear-processing regions of ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex, which survived at a more lenient threshold relative to psychiatric controls. Functional connectivity analysis, furthermore, demonstrated reduced connectivity between left vmPFC and insula for fear in maltreated participants compared to both healthy and psychiatric controls. CONCLUSIONS: The findings show that people who have experienced childhood maltreatment have enhanced fear perception, both at the behavioural and neurofunctional levels, associated with enhanced fear-related ventromedial fronto-cingulate activation and altered functional connectivity with associated limbic regions. Furthermore, the connectivity adaptations were specific to the maltreatment rather than to the developing psychiatric conditions, whilst the functional changes were only evident at trend level when compared to psychiatric controls, suggesting a continuum. The neurofunctional hypersensitivity of fear-processing networks may be due to childhood over-exposure to fear in people who have been abused.

Altered interoceptive activation before, during, and after aversive breathing load in women remitted from anorexia nervosa.

BACKGROUND: The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change. METHODS: Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm. RESULTS: During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices (PFC). The RAN group also showed increased activation in PFC, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation after breathing load was associated with markers of past AN severity. CONCLUSIONS: Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal state fluctuation. Because eating changes our interoceptive state, restriction may be one method of avoiding aversive, unpredictable internal change in AN.

Grey matter volume and thickness abnormalities in young people with a history of childhood abuse.

BACKGROUND: Childhood abuse is associated with abnormalities in brain structure and function. Few studies have investigated abuse-related brain abnormalities in medication-naïve, drug-free youth that also controlled for psychiatric comorbidities by inclusion of a psychiatric control group, which is crucial to disentangle the effects of abuse from those associated with the psychiatric conditions. METHODS: Cortical volume (CV), cortical thickness (CT) and surface area (SA) were measured in 22 age- and gender-matched medication-naïve youth (aged 13-20) exposed to childhood abuse, 19 psychiatric controls matched for psychiatric diagnoses and 27 healthy controls. Both region-of-interest (ROI) and whole-brain analyses were conducted. RESULTS: For the ROI analysis, the childhood abuse group compared with healthy controls only, had significantly reduced CV in bilateral cerebellum and reduced CT in left insula and right lateral orbitofrontal cortex (OFC). At the whole-brain level, relative to healthy controls, the childhood abuse group showed significantly reduced CV in left lingual, pericalcarine, precuneus and superior parietal gyri, and reduced CT in left pre-/postcentral and paracentral regions, which furthermore correlated with greater abuse severity. They also had increased CV in left inferior and middle temporal gyri relative to healthy controls. Abnormalities in the precuneus, temporal and precentral regions were abuse-specific relative to psychiatric controls, albeit at a more lenient level. Groups did not differ in SA. CONCLUSIONS: Childhood abuse is associated with widespread structural abnormalities in OFC-insular, cerebellar, occipital, parietal and temporal regions, which likely underlie the abnormal affective, motivational and cognitive functions typically observed in this population.

Neural differences underlying face processing in veterans with TBI and co-occurring TBI and PTSD.

BACKGROUND: Traumatic brain injury (TBI) is common in military personnel and associated with high rates of posttraumatic stress disorder (PTSD). TBI impacts widely-distributed neural patterns, some of which influence affective processing. Better understanding how TBI and PTSD/TBI alters affective neural activity may improve our understanding of comorbidity mechanisms, but to date the neural correlates of emotional processing in these groups has been relatively understudied. METHODS: Military controls, military personnel with a history of TBI, and military personnel with both TBI and PTSD (N = 53) completed an emotional face processing task during fMRI. Whole-brain activation and functional connectivity during task conditions were compared between groups. RESULTS: Few whole-brain group differences emerged in planned pairwise contrasts, though the TBI group showed some areas of hypoactivation relative to other groups during processing of faces versus shapes. The PTSD/TBI group compared to the control and TBI groups demonstrated greater connectivity between the amygdala and insula seed regions and a number of prefrontal and posterior cingulate regions. LIMITATIONS: Generalizability to other patient groups, including those with only PTSD, has not yet been established. CONCLUSION: TBI alone was associated with hypoactivation during a condition processing faces versus shapes, but PTSD with TBI was associated altered functional connectivity between amygdala and insula regions and cingulate and prefrontal areas. Altered connectivity patterns across groups suggests that individuals with PTSD/TBI may need to increase frontal connectivity with the insulae in order to achieve similar task-based activity.

Comparison of neural substrates of temporal discounting between youth with autism spectrum disorder and with obsessive-compulsive disorder.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share abnormalities in hot executive functions such as reward-based decision-making, as measured in the temporal discounting task (TD). No studies, however, have directly compared these disorders to investigate common/distinct neural profiles underlying such abnormalities. We wanted to test whether reward-based decision-making is a shared transdiagnostic feature of both disorders with similar neurofunctional substrates or whether it is a shared phenotype with disorder-differential neurofunctional underpinnings. METHODS: Age and IQ-matched boys with ASD (N = 20), with OCD (N = 20) and 20 healthy controls, performed an individually-adjusted functional magnetic resonance imaging (fMRI) TD task. Brain activation and performance were compared between groups. RESULTS: Boys with ASD showed greater choice-impulsivity than OCD and control boys. Whole-brain between-group comparison revealed shared reductions in ASD and OCD relative to control boys for delayed-immediate choices in right ventromedial/lateral orbitofrontal cortex extending into medial/inferior prefrontal cortex, and in cerebellum, posterior cingulate and precuneus. For immediate-delayed choices, patients relative to controls showed reduced activation in anterior cingulate/ventromedial prefrontal cortex reaching into left caudate, which, at a trend level, was more decreased in ASD than OCD patients, and in bilateral temporal and inferior parietal regions. CONCLUSIONS: This first fMRI comparison between youth with ASD and with OCD, using a reward-based decision-making task, shows predominantly shared neurofunctional abnormalities during TD in key ventromedial, orbital- and inferior fronto-striatal, temporo-parietal and cerebellar regions of temporal foresight and reward processing, suggesting trans-diagnostic neurofunctional deficits.

Brexit: what does it mean for the veterinary profession?

ALICK SIMMONS: , chair of the BVA's Brexit working group, discusses the implications of Brexit for the veterinary profession and the opportunities it might provide.

West Nile virus-infected human dendritic cells fail to fully activate invariant natural killer T cells.

West Nile virus (WNV) infection is a mosquito-borne zoonosis with increasing prevalence in the United States. WNV infection begins in the skin, and the virus replicates initially in keratinocytes and dendritic cells (DCs). In the skin and cutaneous lymph nodes, infected DCs are likely to interact with invariant natural killer T cells (iNKTs). Bidirectional interactions between DCs and iNKTs amplify the innate immune response to viral infections, thus controlling viral load and regulating adaptive immunity. iNKTs are stimulated by CD1d-bound lipid antigens or activated indirectly by inflammatory cytokines. We exposed human monocyte-derived DCs to WNV Kunjin and determined their ability to activate isolated blood iNKTs. DCs became infected as judged by synthesis of viral mRNA and Envelope and NS-1 proteins, but did not undergo significant apoptosis. Infected DCs up-regulated the co-stimulatory molecules CD86 and CD40, but showed decreased expression of CD1d. WNV infection induced DC secretion of type I interferon (IFN), but no or minimal interleukin (IL)-12, IL-23, IL-18 or IL-10. Unexpectedly, we found that the WNV-infected DCs stimulated human iNKTs to up-regulate CD69 and produce low amounts of IL-10, but not proinflammatory cytokines such as IFN-γ or tumour necrosis factor (TNF)-α. Both CD1d and IFNAR blockade partially abrogated this iNKT response, suggesting involvement of a T cell receptor (TCR)-CD1d interaction and type I interferon receptor (IFNAR) signalling. Thus, WNV infection interferes with DC-iNKT interactions by preventing the production of proinflammatory cytokines. iNKTs may be a source of IL-10 observed in human flavivirus infections and initiate an anti-inflammatory innate response that limits adaptive immunity and immune pathology upon WNV infection.

TAK1 regulates Paneth cell integrity partly through blocking necroptosis.

Paneth cells reside at the base of crypts of the small intestine and secrete antimicrobial factors to control gut microbiota. Paneth cell loss is observed in the chronically inflamed intestine, which is often associated with increased reactive oxygen species (ROS). However, the relationship between Paneth cell loss and ROS is not yet clear. Intestinal epithelial-specific deletion of a protein kinase Tak1 depletes Paneth cells and highly upregulates ROS in the mouse model. We found that depletion of gut bacteria or myeloid differentiation factor 88 (Myd88), a mediator of bacteria-derived cell signaling, reduced ROS but did not block Paneth cell loss, suggesting that gut bacteria are the cause of ROS accumulation but bacteria-induced ROS are not the cause of Paneth cell loss. In contrast, deletion of the necroptotic cell death signaling intermediate, receptor-interacting protein kinase 3 (Ripk3), partially blocked Paneth cell loss. Thus, Tak1 deletion causes Paneth cell loss in part through necroptotic cell death. These results suggest that TAK1 participates in intestinal integrity through separately modulating bacteria-derived ROS and RIPK3-dependent Paneth cell loss.

Early life stress and the anxious brain: evidence for a neural mechanism linking childhood emotional maltreatment to anxiety in adulthood.

BACKGROUND: Childhood emotional maltreatment (CEM) increases the likelihood of developing an anxiety disorder in adulthood, but the neural processes underlying conferment of this risk have not been established. Here, we test the potential for neuroimaging the adult brain to inform understanding of the mechanism linking CEM to adult anxiety symptoms. METHOD: One hundred eighty-two adults (148 females, 34 males) with a normal-to-clinical range of anxiety symptoms underwent structural and functional magnetic resonance imaging while completing an emotion-processing paradigm with facial expressions of fear, anger, and happiness. Participants completed self-report measures of CEM and current anxiety symptoms. Voxelwise mediation analyses on gray-matter volumes and activation to each emotion condition were used to identify candidate brain mechanisms relating CEM to anxiety in adulthood. RESULTS: During processing of fear and anger faces, greater amygdala and less right dorsolateral prefrontal (dlPFC) activation partially mediated the positive relationship between CEM and anxiety symptoms. Greater right posterior insula activation to fear also partially mediated this relationship, as did greater ventral anterior cingulate (ACC) and less dorsal ACC activation to anger. Responses to happy faces in these regions did not mediate the CEM-anxiety relationship. Smaller right dlPFC gray-matter volumes also partially mediated the CEM-anxiety relationship. CONCLUSIONS: Activation patterns of the adult brain demonstrate the potential to inform mechanistic accounts of the CEM conferment of anxiety symptoms. Results support the hypothesis that exaggerated limbic activation to negative valence facial emotions links CEM to anxiety symptoms, which may be consequent to a breakdown of cortical regulatory processes.

Effect of high-potency cannabis on corpus callosum microstructure.

BACKGROUND: The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. METHOD: The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. RESULTS: Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. CONCLUSIONS: Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.

Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI.

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD.

BACKGROUND: Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. METHOD: Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. RESULTS: Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. CONCLUSIONS: The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.

Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.

Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.