Emotional imagination of negative situations: Functional neuroimaging in anorexia and bulimia.

AIM: The present study aims to extend the knowledge of the neural correlates of emotion processing in first episode subjects affected by anorexia nervosa (AN) or bulimia nervosa (BN). We applied an emotional distress paradigm targeting negative emotions thought to be relevant for interpersonal difficulties and therapeutic resistance mechanisms. METHODS: The current study applied to 44 female participants with newly diagnosed AN or BN and 20 matched controls a neuroimaging paradigm eliciting affective responses. The measurements also included an extensive assessment comprising clinical scales, neuropsychological tests, measures of emotion processing and empathy. RESULTS: AN and BN did not differ from controls in terms of emotional response, emotion matching, self-reported empathy and cognitive performance. However, eating disorder and psychopathological clinical scores, as well as alexithymia levels, were increased in AN and BN. On a neural level, no significant group differences emerged, even when focusing on a region of interest selected a priori: the amygdala. Some interesting findings put in relation the hippocampal activity with the level of Body Dissatisfaction of the participants, the relative importance of the key nodes for the common network in the decoding of different emotions (BN = right amygdala, AN = anterior cingulate area), and the qualitative profile of the deactivations. CONCLUSIONS: Our data do not support the hypothesis that participants with AN or BN display reduced emotional responsiveness. However, peculiar characteristics in emotion processing could be associated to the three different groups. Therefore, relational difficulties in eating disorders, as well as therapeutic resistance, could be not secondary to a simple difficulty in feeling and identifying basic negative emotions in AN and BN participants.

Cambios cerebrales funcionales a nivel longitudinal, entre la manía y la eutimia en el trastorno bipolar / No disponible

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Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES: To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment. METHODS: We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits. RESULTS: The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63). CONCLUSION: IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus. .

Dysregulation between emotion and theory of mind networks in borderline personality disorder.

Individuals with borderline personality disorder (BPD) commonly display deficits in emotion regulation, but findings in the area of social cognitive (e.g., theory of mind, ToM) capacities have been heterogeneous. The aims of the current study were to investigate differences between patients with BPD and controls in functional connectivity (1) between the emotion and ToM network and (2) in the default mode network (DMN). Functional magnetic resonance imaging was used to investigate 19 healthy controls and 17 patients with BPD at rest and during ToM processing. Functional coupling was analysed. Significantly decreased functional connectivity was found for patients compared with controls between anterior cingulate cortex and three brain areas involved in ToM processes: the left superior temporal lobe, right supramarginal/inferior parietal lobes, and right middle cingulate cortex. Increased functional connectivity was found in patients compared with controls between the precuneus as the DMN seed and the left inferior frontal lobe, left precentral/middle frontal, and left middle occipital/superior parietal lobes during rest. Reduced functional coupling between the emotional and the ToM network during ToM processing is in line with emotion-regulation dysfunctions in BPD. The increased connectivity between precuneus and frontal regions during rest might be related to extensive processing of internal thoughts and self-referential information in BPD.

Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk.

IMPORTANCE: Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear. OBJECTIVES: To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues. DESIGN: Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group. SETTINGS: Inpatient treatment setting in a community mental health center and hospital-based research unit. PATIENTS: Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons. INTERVENTION: Twelve-step recovery-based addiction treatment for the patient group. MAIN OUTCOMES AND MEASURES: Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity). RESULTS: Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue-induced and stress-induced craving in early recovering AD patients (x = 6, y = 43, z = -6; P < .01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P < .01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F = 6.42; P < .01, whole-brain corrected). CONCLUSIONS AND RELEVANCE: Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.

Behavioral and neurophysiological correlates of autobiographical memory deficits in patients with depression and individuals at high risk for depression.

IMPORTANCE: Individuals with major depressive disorder (MDD) compared with healthy control subjects (HCs) consistently recall fewer specific and more categorical autobiographical memories (AMs). This effect is most pronounced for positive AMs and persists into remission. OBJECTIVES: To determine whether individuals at high familial risk for developing MDD (HR group) also show an AM overgenerality bias and to use functional magnetic resonance imaging to assess differences in functional correlates of AM recall across HR, currently depressed MDD, and HC groups. DESIGN: While recalling AMs in response to emotionally valenced cue words, study participants underwent functional magnetic resonance imaging. Control tasks involved generating examples from a given category and counting the number of risers in a letter string. SETTING: Testing was conducted at the Laureate Institute for Brain Research, Tulsa, Oklahoma. PARTICIPANTS: Participants included 16 unmedicated patients with MDD, 16 HR participants, and 16 HCs. MAIN OUTCOMES AND MEASURES: Percentage of specific and categorical AMs recalled and brain regions in which hemodynamic activity changed during specific and positive AM recall compared with example generation. RESULTS: Both the MDD and HR groups generated fewer specific, more categorical, and fewer positive AMs than the HC group (P ≤ .02 for all). During specific AM recall compared with example generation, neuroimaging results showed between-group differences in the left cuneus (Talairach space coordinates x, y, z = -7, -71, 18; F = 7.55), right medial frontal cortex (x, y, z = 7, 59, 12; F = 8.53), right frontal operculum (x, y, z = 23, 23, 12; F = 8.25), and right and left pregenual anterior cingulate cortex (x, y, z = 9, 37, 10 and x, y, z = -3, 43, 6; F = 6.84 and F = 7.13, respectively). CONCLUSIONS AND RELEVANCE: Autobiographic memory deficits exist in HR individuals, suggesting that these impairments constitute traitlike abnormalities in MDD. We also found distinct patterns of hemodynamic activity for each group as they recalled specific AMs. Specifically, the HR and MDD groups showed differential hemodynamic activity from HCs in medial prefrontal and occipital regions, suggesting that these groups may use different self-referential focus during successful retrieval of specific memories.

Cognitive neuroscience: targeting neuroplasticity with neural decoding and biofeedback.

New research combining neural decoding and biofeedback to target neuroplasticity causally links early visual cortical plasticity with improved perception. This is an exciting new approach to understanding brain function, one which may lead to new ways of treating neurological disorders by targeted intervention.

Amygdala activation in maltreated children during pre-attentive emotional processing.

BACKGROUND: Childhood adversity is associated with significantly increased risk of psychiatric disorder. To date, functional magnetic resonance imaging (fMRI) studies of children have mainly focused on institutionalisation and investigated conscious processing of affect. AIMS: To investigate neural response to pre-attentively presented affect cues in a community sample of children with documented experiences of maltreatment in the home. METHOD: A masked dot-probe paradigm involving pre-attentive presentation of angry, happy and neutral facial expressions was employed. Eighteen maltreated children were compared with 23 carefully matched non-maltreated peers. RESULTS: Increased neural response was observed in the right amygdala for pre-attentively presented angry and happy faces in maltreated v. non-maltreated children. Level of amygdala activation was negatively associated with age at onset for several abuse subtypes. CONCLUSIONS: Maltreatment is associated with heightened neural response to positive and negative facial affect, even to stimuli outside awareness. This may represent a latent neural risk factor for future psychiatric disorder.

Resisting the urge to smoke and craving during a smoking quit attempt on varenicline: results from a pilot fMRI study.

BACKGROUND: Varenicline has been shown to reduce cigarette craving during a quit attempt. OBJECTIVES: Use BOLD fMRI to explore differences in smoking cue reactivity at baseline and after five weeks of varenicline smoking cessation treatment. METHODS: Treatment-seeking nicotine-dependent adult smokers underwent BOLD fMRI scans with block presentation of visual smoking, neutral, and rest cues under two conditions: craving or resisting the urge to smoke at baseline and following 5 weeks of standard varenicline therapy. Data were analyzed using FMRI Expert Analysis Tool, version 5.98 of Functional Magnetic Imaging of the Brain Software Library focused on the smoking vs. neutral cue contrast at the individual and group level, Z>2.3 with cluster threshold p=0.05. RESULTS: Twenty-one participants were scanned at baseline and 16 completed the study; 10 were abstinent at the 2(nd) session, confirmed with urinary cotinine. In the Crave Condition no significant differences were found between the abstinent and non-abstinent groups at either time point. During the baseline Resist Condition, the abstinent group compared to the non-abstinent group demonstrated activation in a distributed network involved in alertness, learning and memory. Additionally, within the abstinent group, increased activation of the superior frontal gyrus was found at baseline compared to week 5. CONCLUSION: Successful smoking cessation with varenicline is associated with increased activation, prior to a quit attempt, in brain areas related to attentiveness and memory while resisting the urge to smoke Scientific Significance: Varenicline may exert effects by both reducing craving and enhancing resistance to smoking urges during cue-elicited craving.

Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo.

BACKGROUND: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy ((1)H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect. OBJECTIVE: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo. METHODS: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo-inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership. RESULTS: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels. CONCLUSION: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD.

Emotional response inhibition in bipolar disorder: a functional magnetic resonance imaging study of trait- and state-related abnormalities.

BACKGROUND: Impaired response inhibition and poor impulse control are hallmarks of the manic phase of bipolar disorder but are also present during depressive and, to a lesser degree, euthymic periods. The neural mechanisms underlying these impairments are poorly understood, including how mechanisms are related to bipolar trait or state effects. METHODS: One-hundred four unmedicated participants with bipolar mania (BM) (n = 30), bipolar depression (BD) (n = 30), bipolar euthymia (BE) (n = 14), and healthy control subjects (n = 30) underwent functional magnetic resonance imaging during emotional and nonemotional go/no-go tasks. The go/no-go task requires participants to press a button for go stimuli, while inhibiting the response to no-go trials. In separate blocks, participants inhibited the response to happy faces, sad faces, or letters. RESULTS: The BE group had higher insula activity during happy face inhibition and greater activity in left inferior frontal gyrus during sad face inhibition, demonstrating bipolar trait effects. Relative to the BE group, BD and BM groups demonstrated lower insula activity during inhibition of happy faces, though the depressed sample had lower activity than manic patients. The BD and BM groups had a greater response to inhibiting sad faces in emotion processing and regulation regions, including putamen, insula, and lateral prefrontal cortex. The manic group also had higher activity in insula and putamen during neutral letter inhibition. CONCLUSIONS: These results suggest distinct trait- and state-related neural abnormalities during response inhibition in bipolar disorder, with implications for future research and treatment.

Frontal-amygdala connectivity alterations during emotion downregulation in bipolar I disorder.

BACKGROUND: The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, downregulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion downregulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects. METHODS: Thirty BPI and 26 control subjects underwent functional magnetic resonance imaging scanning while performing an emotion processing task with passive viewing and emotion downregulation conditions. Contrasts were made for each group comparing the downregulation and passive viewing conditions, and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological interaction analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC). RESULTS: Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion downregulation tasks. Between-group analyses revealed similar activation of BPI and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus, and bilateral dorsal lateral prefrontal cortex during emotion downregulation in subjects with BPI. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared with subjects with BPI. CONCLUSIONS: This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate, and subcortical structures, are present in BPI subjects, even while euthymic.

Degenerative jargon aphasia: unusual progression of logopenic/phonological progressive aphasia?

Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction.

Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology.

The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.

Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder.

BACKGROUND: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. METHODS: In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. RESULTS: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS-) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the "fear network" (amygdalae, insulae, anterior cingulate cortex) across time. CONCLUSIONS: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional ("fear network") processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.

Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep.

BACKGROUND: Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain. METHODS: Metabotropic glutamate receptor subtype 5 binding was quantified with positron emission tomography in 22 young healthy men who completed two experimental blocks separated by 1 week. Two positron emission tomography examinations were conducted in randomized, crossover fashion with the highly selective radioligand, ¹¹C-ABP688, once after 9 hours (sleep control) and once after 33 hours (sleep deprivation) of controlled wakefulness. ¹¹C-ABP688 uptake was quantified in 13 volumes of interest with high mGluR5 expression and presumed involvement in sleep-wake regulation. RESULTS: Sleep deprivation induced a global increase in mGluR5 binding when compared with sleep control (p<.006). In anterior cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala, this increase correlated significantly with the sleep deprivation-induced increase in subjective sleepiness. CONCLUSIONS: This molecular imaging study demonstrates that cerebral functional mGluR5 availability is increased after a single night without sleep. Given that mGluR5 density is reduced in MDD, further research is warranted to examine whether this mechanism is involved in the potent antidepressant effect of wake therapy.

Cingulate biochemistry in heroin users on substitution pharmacotherapy.

OBJECTIVE: High doses of opiate substitution pharmacotherapy are associated with greater treatment retention and lower illicit drug consumption, although the neurobiological bases of these benefits are poorly understood. Dysfunction of the anterior cingulate cortex (ACC) is associated with greater addiction severity and mood dysregulation in opiate users, such that the beneficial effects of substitution pharmacotherapy may relate to normalisation of ACC function. This study aimed to investigate the differential impact of methadone compared with buprenorphine on dorsal ACC biochemistry. A secondary aim was to explore the differential effects of methadone and buprenorphine on dorsal ACC biochemistry in relation to depressive symptoms. METHODS: Twenty-four heroin-dependent individuals stabilised on methadone (n=10) or buprenorphine (n=14) and 24 healthy controls were scanned using proton Magnetic Resonance Spectroscopy and compared for metabolite concentrations of N-acetylaspartate, glutamate/glutamine, and myo-inositol. RESULTS: (1) Methadone was associated with normalisation of dorsal ACC biochemistry (increased N-acetylaspartate and glutamate/glutamine levels, and decreased myo-inositol levels) in a dose-dependent manner; (2) buprenorphine-treated individuals had higher myo-inositol and glutamate/glutamine levels than methadone-treated patients in the right dorsal ACC; and (3) myo-inositol levels were positively correlated with depressive symptoms in participants stabilised on buprenorphine. CONCLUSIONS: These findings point to a beneficial role of high-dose methadone on dorsal ACC biochemistry, and suggest a link between elevated myo-inositol levels and depressive symptoms in the context of buprenorphine treatment.

The biological and psychological basis of neuroticism: current status and future directions.

Neuroticism (N) is believed to reflect a stable disposition involving specific biological and psychological mechanisms that produce its robust association with psychopathology. The nature of these mechanisms remains unclear, however. Based on an extensive review of published evidence, we argue that three interesting leads are emerging. First, N may reflect individual differences in brain circuits involved in perception of and cognitive control over negative stimuli. More specifically, reduced connectivity between the left amygdala and ACC may impair extinction of the amygdala response to anxiety-eliciting stimuli. Second, the neural evidence matches the psychological findings, which associate N with a negative bias in attention, interpretation and recall of information, increased reactivity, and ineffective coping, and is consistent with findings of decreased cardiovascular flexibility. Third, current studies suggest that HPA-axis influences mood independently of N. Strong claims on N's biological basis, however, are not yet justified due to inconsistencies and lack of replication which are in part due to methodological limitations and N's heterogeneity. We discuss potential methodological improvements and substantive directions for future research.

Distinguishing between unipolar depression and bipolar depression: current and future clinical and neuroimaging perspectives.

Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date have directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward, and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a call to action to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at-risk individuals, and more novel neuroimaging approaches, such as connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD and biological targets for more personalized treatment and new treatment developments for BD and UD depression.