Structural and functional brain alterations in subthreshold depression: A multimodal coordinate-based meta-analysis.

Imaging studies of subthreshold depression (StD) have reported structural and functional abnormalities in a variety of spatially diverse brain regions. However, there is no consensus among different studies. In the present study, we applied a multimodal meta-analytic approach, the Activation Likelihood Estimation (ALE), to test the hypothesis that StD exhibits spatially convergent structural and functional brain abnormalities compared to healthy controls. A total of 31 articles with 25 experiments were included, collectively representing 1001 subjects with StD. We found consistent differences between StD and healthy controls mainly in the left insula across studies with various neuroimaging methods. Further exploratory analyses found structural atrophy and decreased functional activities in the right pallidum and thalamus in StD, and abnormal spontaneous activity converged to the middle frontal gyrus. Coordinate-based meta-analysis found spatially convergent structural and functional impairments in StD. These findings provide novel insights for understanding the neural underpinnings of subthreshold depression and enlighten the potential targets for its early screening and therapeutic interventions in the future.

Dissecting Genetic Mechanisms of Differential Locomotion, Depression, and Allodynia after Spinal Cord Injury in Three Mouse Strains.

Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or genomic contribution to this condition. Here, we evaluated neuropsychiatric behaviors in A/J, BALB/c, and C57BL/6 male mice and tested genetic or genomic alterations following SCI. A/J and BALB/c naive mice showed significantly less locomotor activity and greater anxiety-like behavior than C57BL/6 mice. Although SCI elicited locomotor dysfunction, C57BL/6 and A/J mice showed the best and the worst post-traumatic recovery, respectively. Mild (m)-SCI mice showed deficits in gait dynamics. All moderate/severe SCI mice exhibited similar degrees of anxiety/depression. mSCI in BALB/c and A/J mice resulted in depression, whereas C57BL/6 mice did not exhibit depression. mSCI mice had significantly lower mechanical thresholds than their controls, indicating high cutaneous hypersensitivity. C57BL/6, but not A/J and BLAB/c mice, showed significantly lower heat thresholds than their controls. C57BL/6 mice exhibited spontaneous pain. RNAseq showed that genes in immune responses and wound healing were upregulated, although A/J mice showed the largest increase. The cell cycle and the truncated isoform of trkB genes were robustly elevated in SCI mice. Thus, different genomics are associated with post-traumatic recovery, underscoring the likely importance of genetic factors in SCI.

Pesticide-Induced Alterations in Locomotor Activity, Anxiety, and Depression-like Behavior Are Mediated through Oxidative Stress-Related Autophagy: A Persistent Developmental Study in Mice.

Chlorpyrifos (CPF), dichlorvos (DDV), and cypermethrin (CP), as commonly used pesticides, have been implicated in inducing neuropsychiatric disorders, such as anxiety, depression-like behaviors, and locomotor activity impairment. However, the exact molecular mechanisms of these adverse effects, particularly in both sexes and their next-generation effects, remain unclear. In this study, we conducted behavioral analysis, along with cellular assays (monodansylcadaverine staining) and molecular investigations (qRT-PCR and western blotting of mTOR, P62, and Beclin-1) to clear the potential role of autophagy in pesticide-induced behavioral alterations. For this purpose, 42 adult female and 21 male inbred ICR mice (F0) were distributed into seven groups. Maternal mice (F0) and 112 F1 offspring were exposed to 0.5 and 1 ppm of CPF, DDV, and CP through drinking water. F1 male and female animals were studied to assess the sex-specific effects of pesticides on brain tissue. Our findings revealed pronounced anxiogenic effects and impaired locomotor activity in mice. F1 males exposed to CPF (1 ppm) exhibited significantly elevated depression-like behaviors compared to other groups. Moreover, pesticide exposure reduced mTOR and P62 levels, while enhancing the Beclin-1 gene and protein expression. These changes in autophagy signaling pathways, coupled with oxidative and neurogenic damage in the cerebral cortex and hippocampus, potentially contribute to heightened locomotor activity, anxiety, and depression-like behaviors following pesticide exposure. This study underscores the substantial impact of pesticides on both physiological and behavioral aspects, emphasizing the necessity for comprehensive assessments and regulatory considerations for pesticide use. Additionally, the identification of sex-specific responses presents a crucial dimension for pharmaceutical sciences, highlighting the need for tailored therapeutic interventions and further research in this field.

Unveiling convergent and divergent intrinsic brain network alternations in depressed adolescents engaged in non-suicidal self-injurious behaviors with and without suicide attempts.

AIMS: Limited understanding exists regarding the neurobiological mechanisms underlying non-suicidal self-injury (NSSI) and suicide attempts (SA) in depressed adolescents. The maturation of brain network is crucial during adolescence, yet the abnormal alternations in depressed adolescents with NSSI or NSSI+SA remain poorly understood. METHODS: Resting-state functional magnetic resonance imaging data were collected from 114 depressed adolescents, classified into three groups: clinical control (non-self-harm), NSSI only, and NSSI+SA based on self-harm history. The alternations of resting-state functional connectivity (RSFC) were identified through support vector machine-based classification. RESULTS: Convergent alterations in NSSI and NSSI+SA predominantly centered on the inter-network RSFC between the Limbic network and the three core neurocognitive networks (SalVAttn, Control, and Default networks). Divergent alterations in the NSSI+SA group primarily focused on the Visual, Limbic, and Subcortical networks. Additionally, the severity of depressive symptoms only showed a significant correlation with altered RSFCs between Limbic and DorsAttn or Visual networks, strengthening the fact that increased depression severity alone does not fully explain observed FC alternations in the NSSI+SA group. CONCLUSION: Convergent alterations suggest a shared neurobiological mechanism along the self-destructiveness continuum. Divergent alterations may indicate biomarkers differentiating risk for SA, informing neurobiologically guided interventions.

The association of depressive symptoms with handgrip strength and gait speed in community-dwelling older adults: data from the baseline phase of Birjand Longitudinal Aging Study.

BACKGROUND: Depression is a multifaceted condition with a high prevalence and burden to society. Handgrip strength (HGS) and gait speed (GS) are indices of physical health, which is linked to mental health. Previous studies have shown heterogeneity among countries in the association of physical parameters and depression. In this study, we aimed to investigate the association of HGS and GS with depressive symptoms in older adults. METHODS: This is a cross-sectional study analyzing data from the Birjand Longitudinal Aging Study, a cohort of community-dwelling older adults (≥ 60 years old). Depressive symptoms were assessed by the nine-item Patient Health Questionnaire. HGS was measured with a hand dynamometer in a sitting position, and GS was estimated by a 15-foot walk test at usual pace. RESULTS: Compared to participants in the first quartile, those in the second quartile of HGS had significantly lower odds of suffering from depressive symptoms, while GS was not significantly associated with depressive symptoms. A higher HGS was associated with a lower risk of moderate depressive symptoms, while a higher GS was related to a lower risk of moderately severe and severe symptoms. CONCLUSIONS: Our findings suggest that older people residing in Birjand, Iran with a moderate HGS are less likely to suffer from depressive symptoms than those with lower HGS.

Characteristics of oxyhemoglobin during the verbal fluency task in subthreshold depression: A multi-channel near-infrared spectroscopy study.

OBJECTIVE: Subthreshold depression is an essential precursor and risk factor for major depressive disorder, and its accurate identification and timely intervention are important for reducing the prevalence of major depressive disorder. Therefore, we used functional near-infrared spectroscopic imaging (fNIRS) to explore the characteristics of the brain neural activity of college students with subthreshold depression in the verbal fluency task. METHODS: A total of 72 subthreshold depressed college students (SDs) and 67 healthy college students (HCs) were recruited, and all subjects were subjected to a verbal fluency task (VFT) while a 53-channel fNIRS device was used to collect the subjects' cerebral blood oxygenation signals. RESULTS: The results of the independent samples t-test showed that the mean oxyhemoglobin in the right dorsolateral prefrontal (ch34, ch42, ch45) and Broca's area (ch51, ch53) of SDs was lower than that of HCs. The peak oxygenated hemoglobin of SDs was lower in the right dorsolateral prefrontal (ch34) and Broca's area (ch51, ch53).The brain functional connectivity strength was lower than that of HCs. Correlation analysis showed that the left DLPFC and Broca's area were significantly negatively correlated with the depression level. CONCLUSION: SDs showed abnormally low, inadequate levels of brain activation and weak frontotemporal brain functional connectivity. The right DLPFC has a higher sensitivity for the differentiation of depressive symptoms and is suitable as a biomarker for the presence of depressive symptoms. Dysfunction in Broca's area can be used both as a marker of depressive symptoms and as a biomarker, indicating the severity of depressive symptoms.

Frontal Theta Asymmetry may be a new target for reducing the severity of depression and improving cognitive function in depressed patients.

BACKGROUND: The prevalence of depressive disorder is increasing due to a variety of factors, which brings a huge strain on individuals, families and society. This study aims to investigate whether there is Frontal Theta Asymmetry (FTA) in depressed patients, and whether FTAs are related to depression severity and cognitive function changes in depressed patients. METHODS: Participants who met the inclusion criteria were enrolled in this study. Socio-demographic data of each participant were recorded. Zung's self-rating Depression Scale was used to assess the depression status of participants. P300 was used to evaluate the cognitive function of participants. EEG data from participants were collected by the NeuroScan SynAmps RT EEG system. t-test, Wilcoxon rank-sum test and Chi-square test were used to detect the differences of different variables between the two groups. Multiple linear regression analysis and multiple logistic regression analysis were used to analyze relationships between FTAs in different regions and participants' depression status and cognitive function. RESULTS: A total of 66 depressed participants and 47 healthy control participants were included in this study. The theta spectral power of the left frontal lobe was slightly stronger than that of the right frontal lobe in the depression group, while the opposite was true in the healthy control group. The FTA in F3/F4 had certain effects on the emergence of depression in participants, the emergence of depression in participants and Changes in cognitive function. CONCLUSIONS: FTAs are helpful to assess the severity of depression and early identify cognitive impairment in patients with depression.

Static and dynamic functional connectivity of the habenula in late-life depression patient with suicidal ideation.

BACKGROUND: Suicide is one of the most lethal complications of late-life depression (LLD), and habenular dysfunction may be involved in depression-related suicidality and may serve as a potential target for alleviating suicidal ideation. This study aimed to investigate abnormal functional connectivity of the habenula in LLD patients with suicidal ideation. METHODS: One hundred twenty-seven patients with LLD (51 with suicidal ideation (LLD-S) and 76 without suicidal ideation (LLD-NS)) and 75 healthy controls (HCs) were recruited. The static functional connectivity (sFC) and dynamic functional connectivity (dFC) between the habenula and the whole brain were compared among the three groups, and correlation and moderation analyses were applied to investigate whether suicidal ideation moderated the relationships of habenular FC with depressive symptoms and cognitive impairment. RESULTS: The dFC between the right habenula and the left orbitofrontal cortex (OFC) increased in the following order: LLD-S > LLD-NS > control. No significant difference in the habenular sFC was found among the LLD-S, LLD-NS and control groups. The dFC between the right habenula and the left OFC was positively associated with global cognitive function and visuospatial skills, and the association between this dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD. CONCLUSION: The increased variability in dFC between the right habenula and left OFC was more pronounced in the LLD-S group than in the LLD-NS group, and the association between habenular-OFC dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD.

Implications of depressive mood in OSAHS patients: insights from event-related potential.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a chronic breathing disorder characterized by recurrent upper airway obstruction during sleep. Although previous studies have shown a link between OSAHS and depressive mood, the neurobiological mechanisms underlying mood disorders in OSAHS patients remain poorly understood. This study aims to investigate the emotion processing mechanism in OSAHS patients with depressive mood using event-related potentials (ERPs). METHODS: Seventy-four OSAHS patients were divided into the depressive mood and non-depressive mood groups according to their Self-rating Depression Scale (SDS) scores. Patients underwent overnight polysomnography and completed various cognitive and emotional questionnaires. The patients were shown facial images displaying positive, neutral, and negative emotions and tasked to identify the emotion category, while their visual evoked potential was simultaneously recorded. RESULTS: The two groups did not differ significantly in age, BMI, and years of education, but showed significant differences in their slow wave sleep ratio (P = 0.039), ESS (P = 0.006), MMSE (P < 0.001), and MOCA scores (P = 0.043). No significant difference was found in accuracy and response time on emotional face recognition between the two groups. N170 latency in the depressive group was significantly longer than the non-depressive group (P = 0.014 and 0.007) at the bilateral parieto-occipital lobe, while no significant difference in N170 amplitude was found. No significant difference in P300 amplitude or latency between the two groups. Furthermore, N170 amplitude at PO7 was positively correlated with the arousal index and negatively with MOCA scores (both P < 0.01). CONCLUSION: OSAHS patients with depressive mood exhibit increased N170 latency and impaired facial emotion recognition ability. Special attention towards the depressive mood among OSAHS patients is warranted for its implications for patient care.

Vulnerable at rest? A resting-state EEG study and psychosocial factors of young adult offspring of alcohol-dependent parents.

BACKGROUND: Offspring of parents with alcohol use disorder (AUD) are more susceptible to developing AUD, with an estimated heritability of around 50%. Vulnerability to AUD in first-degree relatives is influenced by biological factors, such as spontaneous brain activity, and high-risk psychosocial characteristics. However, existing resting-state EEG studies in AUD offspring have shown inconsistent findings regarding theta, alpha, and beta band frequencies. Additionally, research consistently demonstrates an increased risk of internalizing and externalizing disorders, self-regulation difficulties, and interpersonal issues among AUD offspring. METHODS: This study aimed to investigate the absolute power of theta, alpha, and beta frequencies in young adult offspring with a family history of AUD compared to individuals without family history. The psychosocial profiles of the offspring were also examined in relation to individuals without a family history of AUD. Furthermore, the study sought to explore the potential association between differences in frequency bands and psychosocial variables. Resting-state EEG recordings were obtained from 31 young adult healthy offspring of alcohol-dependent individuals and 43 participants with no family history of AUD (age range: 16-25 years). Participants also completed self-report questionnaires assessing anxiety and depressive symptoms, impulsivity, emotion regulation, and social involvement. RESULTS: The results revealed no significant differences in spontaneous brain activity between the offspring and participants without a family history of AUD. However, in terms of psychosocial factors, the offspring exhibited significantly lower social involvement than the control group. CONCLUSIONS: This study does not provide evidence suggesting vulnerability in offspring based on differences in spontaneous brain activity. Moreover, this investigation highlights the importance of interventions aimed at enhancing social connections in offspring. Such interventions can not only reduce the risk of developing AUD, given its strong association with increased feelings of loneliness but also improve the overall well-being of the offspring.

Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

Postictal psychiatric symptoms: A neurophysiological study.

OBJECTIVE: Postictal psychiatric symptoms (PPS) are a relatively common but understudied phenomenon in epilepsy. The mechanisms by which seizures contribute to worsening in psychiatric symptoms are unclear. We aimed to identify PPS prospectively during and after admission to the epilepsy monitoring unit (EMU) in order to characterize the postictal physiologic changes leading to PPS. METHODS: We prospectively enrolled patients admitted to the EMU and administered repeat psychometric questionnaires during and after their hospital stay in order to assess for postictal exacerbations in four symptom complexes: anger/hostility, anxiety, depression, and paranoia. Electroclinical and electrographic seizures were identified from the EEG recordings, and seizure durations were measured. The severity of postictal slowing was calculated as the proportion of postictal theta/delta activity in the postictal EEG relative to the preictal EEG using the Hilbert transform. RESULTS: Among 33 participants, 8 demonstrated significant increases in at least one of the four symptoms (the PPS+ group) within three days following the first seizure. The most common PPS was anger/hostility, experienced by 7/8 participants with PPS. Among the 8 PPS+ participants, four experienced more than one PPS. As compared to those without PPS (the PPS- group), the PPS+ group demonstrated a greater degree of postictal EEG slowing at 10 min (p = 0.022) and 20 min (p = 0.05) following seizure termination. They also experienced significantly more seizures during the study period (p = 0.005). There was no difference in seizure duration between groups. SIGNIFICANCE: Postictal psychiatric symptoms including anger/hostility, anxiety, depression, and paranoia may be more common than recognized. In particular, postictal increases in anger and irritability may be particularly common. We provide physiological evidence of a biological mechanism as well as a demonstration of the use of quantitative electroencephalography toward a better understanding of postictal neurophysiology.

Distinct global brain connectivity alterations in depressed adolescents with subthreshold mania and the relationship with processing speed: Evidence from sBEAD Cohort.

BACKGROUND: Bipolar disorder (BD) is a progressive condition. Investigating the neuroimaging mechanisms in depressed adolescents with subthreshold mania (SubMD) facilitates the early identification of BD. However, the global brain connectivity (GBC) patterns in SubMD patients, as well as the relationship with processing speed before the onset of full-blown BD, remain unclear. METHODS: The study involved 72 SubMD, 77 depressed adolescents without subthreshold mania (nSubMD), and 69 gender- and age-matched healthy adolescents (HCs). All patients underwent a clinical follow-up ranging from six to twelve months. We calculated the voxel-based graph theory analysis of the GBC map and conducted the TMT-A test to measure the processing speed. RESULTS: Compared to HCs and nSubMD, SubMD patients displayed distinctive GBC index patterns: GBC index decreased in the right Medial Superior Frontal Gyrus (SFGmed.R)/Superior Frontal Gyrus (SFG) while increased in the right Precuneus and left Postcentral Gyrus. Both patient groups showed increased GBC index in the right Inferior Temporal Gyrus. An increased GBC value in the right Supplementary Motor Area was exclusively observed in the nSubMD-group. There were opposite changes in the GBC index in SFGmed.R/SFG between two patient groups, with an AUC of 0.727. Additionally, GBC values in SFGmed.R/SFG exhibited a positive correlation with TMT-A scores in SubMD-group. LIMITATIONS: Relatively shorter follow-up duration, medications confounding, and modest sample size. CONCLUSION: These findings suggest that adolescents with subthreshold BD have specific impairments patterns at the whole brain connectivity level associated with processing speed impairments, providing insights into early identification and intervention strategies for BD.

Insula-cortico-subcortical networks predict interoceptive awareness and stress resilience.

BACKGROUND: Interoception, the neural sensing of visceral signals, and interoceptive awareness (IA), the conscious perception of interoception, are crucial for life survival functions and mental health. Resilience, the capacity to overcome adversity, has been associated with reduced interoceptive disturbances. Here, we sought evidence for our Insula Modular Active Control (IMAC) model that suggest that the insula, a brain region specialized in the processing of interoceptive information, realizes IA and contributes to resilience and mental health via cortico-subcortical connections. METHODS: 64 healthy participants (32 females; ages 18-34 years) answered questionnaires that assess IA and resilience. Mental health was evaluated with the Beck Depression Inventory II that assesses depressive mood. Participants also underwent a 15 minute resting-state functional resonance imaging session. Pearson correlations and mediation analyses were used to investigate the relationship between IA and resilience and their contributions to depressive mood. We then performed insula seed-based functional connectivity analyzes to identify insula networks involved in IA, resilience and depressive mood. RESULTS: We first demonstrated that resilience mediates the relationship between IA and depressive mood. Second, shared and distinct intra-insula, insula-cortical and insula-subcortical networks were associated with IA, resilience and also predicted the degree of experienced depressive mood. Third, while resilience was associated with stronger insula-precuneus, insula-cerebellum and insula-prefrontal networks, IA was linked with stronger intra-insula, insula-striatum and insula-motor networks. CONCLUSIONS: Our findings help understand the roles of insula-cortico-subcortical networks in IA and resilience. These results also highlight the potential use of insula networks as biomarkers for depression prediction.

Real-time heart rate variability biofeedback amplitude during a large-scale digital mental health intervention differed by age, gender, and mental and physical health.

Heart rate variability biofeedback (HRVB) is an efficacious treatment for depression and anxiety. However, translation to digital mental health interventions (DMHI) requires computing and providing real-time HRVB metrics in a personalized and user-friendly fashion. To address these gaps, this study validates a real-time HRVB feedback algorithm and characterizes the association of the main algorithmic summary metric-HRVB amplitude-with demographic, psychological, and health factors. We analyzed HRVB data from 5158 participants in a therapist-supported DMHI incorporating slow-paced breathing to treat depression or anxiety symptoms. A real-time feedback metric of HRVB amplitude and a gold-standard research metric of low-frequency (LF) power were computed for each session and then averaged within-participants over 2 weeks. We provide HRVB amplitude values, stratified by age and gender, and we characterize the multivariate associations of HRVB amplitude with demographic, psychological, and health factors. Real-time HRVB amplitude correlated strongly (r = .93, p < .001) with the LF power around the respiratory frequency (~0.1 Hz). Age was associated with a significant decline in HRVB (ß = -0.46, p < .001), which was steeper among men than women, adjusting for demographic, psychological, and health factors. Resting high- and low-frequency power, body mass index, hypertension, Asian race, depression symptoms, and trauma history were significantly associated with HRVB amplitude in multivariate analyses (p's < .01). Real-time HRVB amplitude correlates highly with a research gold-standard spectral metric, enabling automated biofeedback delivery as a potential treatment component of DMHIs. Moreover, we identify demographic, psychological, and health factors relevant to building an equitable, accurate, and personalized biofeedback user experience.

Maternal prenatal depressive symptoms and child brain responses to affective touch at two years of age.

BACKGROUND: Touch is an essential form of mother-child interaction, instigating better social bonding and emotional stability. METHODS: We used diffuse optical tomography to explore the relationship between total haemoglobin (HbT) responses to affective touch in the child's brain at two years of age and maternal self-reported prenatal depressive symptoms (EPDS). Affective touch was implemented via slow brushing of the child's right forearm at 3 cm/s and non-affective touch via fast brushing at 30 cm/s and HbT responses were recorded on the left hemisphere. RESULTS: We discovered a cluster in the postcentral gyrus exhibiting a negative correlation (Pearson's r = -0.84, p = 0.015 corrected for multiple comparisons) between child HbT response to affective touch and EPDS at gestational week 34. Based on region of interest (ROI) analysis, we found negative correlations between child responses to affective touch and maternal prenatal EPDS at gestational week 14 in the precentral gyrus, Rolandic operculum and secondary somatosensory cortex. The responses to non-affective touch did not correlate with EPDS in these regions. LIMITATIONS: The number of mother-child dyads was 16. However, by utilising high-density optode arrangements, individualised anatomical models, and video and accelerometry to monitor movement, we were able to minimize methodological sources of variability in the data. CONCLUSIONS: The results show that maternal depressive symptoms during pregnancy may be associated with reduced child responses to affective touch in the temporoparietal cortex. Responses to affective touch may be considered as potential biomarkers for psychosocial development in children. Early identification of and intervention in maternal depression may be important already during early pregnancy.

The Predictive Potential of Heart Rate Variability for Depression.

Heart rate variability (HRV),a measure of the fluctuations in the intervals between consecutive heartbeats, is an indicator of changes in the autonomic nervous system. A chronic reduction in HRV has been repeatedly linked to clinical depression. However, the chronological and mechanistic aspects of this relationship, between the neural, physiological, and psychopathological levels, remain unclear. In this review we present evidence by which changes in HRV might precede the onset of depression. We describe several pathways that can facilitate this relationship. First, we examine a theoretical model of the impact of autonomic imbalance on HRV and its role in contributing to mood dysregulation and depression. We then highlight brain regions that are regulating both HRV and emotion, suggesting these neural regions, and the Insula in particular, as potential mediators of this relationship. We also present additional possible mediating mechanisms involving the immune system and inflammation processes. Lastly, we support this model by showing evidence that modification of HRV with biofeedback leads to an improvement in some symptoms of depression. The possibility that changes in HRV precede the onset of depression is critical to put to the test, not only because it could provide insights into the mechanisms of the illness but also because it may offer a predictive anddiagnosticphysiological marker for depression. Importantly, it could also help to develop new effective clinical interventions for treating depression.

Neural and affective responses to prolonged eye contact with parents in depressed and nondepressed adolescents.

Eye contact improves mood, facilitates connectedness, and is assumed to strengthen the parent-child bond. Adolescent depression is linked to difficulties in social interactions, the parent-child bond included. Our goal was to elucidate adolescents' affective and neural responses to prolonged eye contact with one's parent in nondepressed adolescents (HC) and how these responses are affected in depressed adolescents. While in the scanner, 59 nondepressed and 19 depressed adolescents were asked to make eye contact with their parent, an unfamiliar peer, an unfamiliar adult, and themselves by using videos of prolonged direct and averted gaze, as an approximation of eye contact. After each trial, adolescents reported on their mood and feelings of connectedness, and eye movements and BOLD-responses were assessed. In HCs, eye contact boosted mood and feelings of connectedness and increased activity in inferior frontal gyrus (IFG), temporal pole, and superior frontal gyrus. Unlike HCs, eye contact did not boost the mood of depressed adolescents. While HCs reported increased mood and feelings of connectedness to the sight of their parent versus others, depressed adolescents did not. Depressed adolescents exhibited blunted overall IFG activity. These findings show that adolescents are particularly sensitive to eye contact and respond strongly to the sight of their parents. This sensitivity seems to be blunted in depressed adolescents. For clinical purposes, it is important to gain a better understanding of how the responsivity to eye contact in general and with their parents in particular, can be restored in adolescents with depression.

Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.

OBJECTIVE: In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. METHODS: In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. RESULTS: Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). INTERPRETATION: Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

Reduced reward responsiveness and depression vulnerability: Consideration of social contexts and implications for intervention.

Depression is a prevalent, heterogeneous, and debilitating disorder that often emerges in adolescence, and there is a need to better understand vulnerability processes to inform more targeted intervention efforts. Psychophysiological methods, like event-related potentials (ERPs), can offer unique insights into the cognitive and emotional processes underlying depression vulnerability. I review my and others' research examining ERP measures of reward responsiveness in youth depression and present a conceptual model of the development of low reward responsiveness, its role in depression vulnerability, and potential windows for targeted intervention. There is evidence that a blunted reward positivity (RewP) is observable in children at risk for depression, appears to be shaped in part by early social experiences, and predicts later depressive symptoms in combination with other risk factors like stress exposure. Further, a component consistent with RewP is reliably elicited in response to social acceptance feedback in computerized peer interaction tasks and demonstrates unique associations with social contextual factors and depressive symptoms, supporting the utility of developing psychophysiological tasks that may better capture youths' real-world experiences and social risk processes. In addition, I address the translational implications of clinical psychophysiological research and describe a series of studies showing that a reduced RewP predicts greater reductions in depressive symptoms with treatment but is not modifiable by current treatments like cognitive behavioral therapy. Finally, I describe our preliminary efforts to develop a positive emotion-focused intervention for the offspring of depressed mothers, informed by the RewP literature, and describe future directions for translating psychophysiological research to intervention and prevention.