Distinguishing between depression in bipolar disorder and unipolar depression using magnetic resonance imaging: a systematic review.

OBJECTIVES: Magnetic resonance imaging (MRI) studies comparing bipolar and unipolar depression characterize pathophysiological differences between these conditions. However, it is difficult to interpret the current literature due to differences in MRI modalities, analysis methods, and study designs. METHODS: We conducted a systematic review of publications using MRI to compare individuals with bipolar and unipolar depression. We grouped studies according to MRI modality and task design. Within the discussion, we critically evaluated and summarized the functional MRI research and then further complemented these findings by reviewing the structural MRI literature. RESULTS: We identified 88 MRI publications comparing participants with bipolar depression and unipolar depressive disorder. Compared to individuals with unipolar depression, participants with bipolar disorder exhibited heightened function, increased within network connectivity, and reduced grey matter volume in salience and central executive network brain regions. Group differences in default mode network function were less consistent but more closely associated with depressive symptoms in participants with unipolar depression but distractibility in bipolar depression. CONCLUSIONS: When comparing mood disorder groups, the neuroimaging evidence suggests that individuals with bipolar disorder are more influenced by emotional and sensory processing when responding to their environment. In contrast, depressive symptoms and neurofunctional response to emotional stimuli were more closely associated with reduced central executive function and less adaptive cognitive control of emotionally oriented brain regions in unipolar depression. Researchers now need to replicate and refine network-level trends in these heterogeneous mood disorders and further characterize MRI markers associated with early disease onset, progression, and recovery.

Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Longitudinal changes in brain activation during anticipation of monetary loss in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) show aberrant brain activation patterns during reward and loss anticipation. We examined for the first time longitudinal changes in brain activation during win and loss anticipation to identify trait markers of aberrant anticipatory processing in BD. METHODS: Thirty-four euthymic and depressed individuals with BD-I and 17 healthy controls (HC) were scanned using functional magnetic resonance imaging twice 6 months apart during a reward task. RESULTS: HC, but not individuals with BD, showed longitudinal reductions in the right lateral occipital cortex (RLOC) activation during processing of cues predicting possible money loss (p-corrected <0.05). This result was not affected by psychotropic medication, mood state or the changes in depression/mania severity between the two scans in BD. Elevated symptoms of subthreshold hypo/mania at baseline predicted more aberrant longitudinal patterns of RLOC activation explaining 12.5% of variance in individuals with BD. CONCLUSIONS: Increased activation in occipital cortex during negative outcome anticipation may be related to elevated negative emotional arousal during anticipatory cue processing. One interpretation is that, unlike HC, individuals with BD were not able to learn at baseline that monetary losses were smaller than monetary gains and were not able to reduce emotional arousal for negative cues 6 months later. Future research in BD should examine how modulating occipital cortical activation affects learning from experience in individuals with BD.

Efficacy of resin infiltration of proximal caries in primary molars: 1-year follow-up of a split-mouth randomized controlled clinical trial.

OBJECTIVE: The main purpose of this split month, randomized, controlled clinical trial was evaluate the efficacy of caries infiltration in controlling the progression of non-cavitated proximal lesions in primary molars. Anxiety and time required for the caries infiltration was also evaluated. MATERIALS AND METHODS: Fifty healthy children, 5 to 9 years, presenting two primary molars with proximal caries lesions (1/2 of the enamel or outer 1/3 of dentin), were included. Lesions were randomly allocated to the test group (fluoridated toothpaste + flossing + infiltration) or to the control group (fluoridated toothpaste + flossing). Caries risk was based on the Cariogram model. The main outcome after 1-year radiographic follow up was assessed by an independent blinded examiner A facial image scale (FIS) was applied to assess dental anxiety and time required to perform the infiltration was recorded. RESULTS: Of the sample, 92.9% corresponded to high or medium caries risk. In 42 patients (1-year follow up), caries progression was observed in 11.9% (5/42) of the test lesions compared with 33.3% (14/42) of the control lesions (p < 0.05). Five control and three test lesions progressed to the middle 1/3 of dentin and were restored. No side effects were observed. Anxiety was both low before and after the treatment, and mean time required for the infiltration was 11.29 min (± 1.16 min). CONCLUSIONS: Caries infiltration of proximal caries lesions in primary molars is significantly more efficacious than standard therapy alone (fluoride toothpaste + flossing). CLINICAL RELEVANCE: Caries infiltration is an applicable and well-accepted method be used in children, representing a promising micro-invasive approach.

Anticipation-related brain connectivity in bipolar and unipolar depression: a graph theory approach.

Bipolar disorder is often misdiagnosed as major depressive disorder, which leads to inadequate treatment. Depressed individuals versus healthy control subjects, show increased expectation of negative outcomes. Due to increased impulsivity and risk for mania, however, depressed individuals with bipolar disorder may differ from those with major depressive disorder in neural mechanisms underlying anticipation processes. Graph theory methods for neuroimaging data analysis allow the identification of connectivity between multiple brain regions without prior model specification, and may help to identify neurobiological markers differentiating these disorders, thereby facilitating development of better therapeutic interventions. This study aimed to compare brain connectivity among regions involved in win/loss anticipation in depressed individuals with bipolar disorder (BDD) versus depressed individuals with major depressive disorder (MDD) versus healthy control subjects using graph theory methods. The study was conducted at the University of Pittsburgh Medical Center and included 31 BDD, 39 MDD, and 36 healthy control subjects. Participants were scanned while performing a number guessing reward task that included the periods of win and loss anticipation. We first identified the anticipatory network across all 106 participants by contrasting brain activation during all anticipation periods (win anticipation + loss anticipation) versus baseline, and win anticipation versus loss anticipation. Brain connectivity within the identified network was determined using the Independent Multiple sample Greedy Equivalence Search (IMaGES) and Linear non-Gaussian Orientation, Fixed Structure (LOFS) algorithms. Density of connections (the number of connections in the network), path length, and the global connectivity direction ('top-down' versus 'bottom-up') were compared across groups (BDD/MDD/healthy control subjects) and conditions (win/loss anticipation). These analyses showed that loss anticipation was characterized by denser top-down fronto-striatal and fronto-parietal connectivity in healthy control subjects, by bottom-up striatal-frontal connectivity in MDD, and by sparse connectivity lacking fronto-striatal connections in BDD. Win anticipation was characterized by dense connectivity of medial frontal with striatal and lateral frontal cortical regions in BDD, by sparser bottom-up striatum-medial frontal cortex connectivity in MDD, and by sparse connectivity in healthy control subjects. In summary, this is the first study to demonstrate that BDD and MDD with comparable levels of current depression differed from each other and healthy control subjects in density of connections, connectivity path length, and connectivity direction as a function of win or loss anticipation. These findings suggest that different neurobiological mechanisms may underlie aberrant anticipation processes in BDD and MDD, and that distinct therapeutic strategies may be required for these individuals to improve coping strategies during expectation of positive and negative outcomes.

Ventral prefrontal network response to alcohol in young adults with bipolar disorder: a within-subject randomized placebo-controlled alcohol administration study.

Bipolar disorder co-occurs with alcohol use disorder at a rate 3-5 times higher than the general population. We recently reported that individuals with bipolar disorder differ in the positive stimulating and anxiolytic effects of alcohol compared with healthy peers. This study used a randomized, placebo-controlled, cross-over, within-subject alcohol administration design to investigate neurobiological mechanisms within ventral prefrontal cortical (vPFC) systems that may underlie altered sensitivity to alcohol in bipolar disorder (NCT04063384). Forty-seven young adults (n = 23 with bipolar disorder, 64% women) completed clinical assessment and two beverage administration sessions (alcohol and placebo, counter-balanced). Participants were dosed to 0.08 g% breath alcohol concentration during the alcohol condition and completed measures of subjective response to alcohol and an emotional processing fMRI task during the ascending limb. Timing during the placebo condition mirrored the alcohol session. Acute alcohol was associated with reduced functional connectivity between the insula - subcallosal cingulate cortex, and increased connectivity between the left nucleus accumbens - ventromedial PFC in bipolar disorder, but with no change in functional connectivity between these regions in healthy peers. Alcohol-related increases in nucleus accumbens - ventromedial PFC functional connectivity was associated with greater positive stimulating effects of alcohol in bipolar disorder and heavier recent alcohol use. Results suggest vPFC brain systems respond differently to acute alcohol during emotional processing in young adults with bipolar disorder compared with healthy peers, and that vPFC system responses relate to the subjective experience of intoxication and recent alcohol use.

Subjective response to alcohol in young adults with bipolar disorder and recent alcohol use: a within-subject randomized placebo-controlled alcohol administration study.

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults.

Functional assessment short test (FAST): Self-administration in outpatient mental health settings.

The Functional Assessment Short Test (FAST) is a clinician-administered assessment scale of psychosocial dysfunction across various domains typically impacted in individuals with bipolar disorder. The FAST is formally validated as a clinician-administered measure, but support for self-administration would allow its wider use. Therefore, this study aimed to determine whether the FAST could reliably serve as a self-report measure in individuals seeking mental health treatment. Participants completed both the self-report and clinician-administered versions of the FAST as part of their routine outpatient clinical care at the Bipolar Disorders Clinic at The University of Texas Health Austin (UTHA). We investigated correlations between self-report and clinician-administered FAST scores. There were significant positive correlations between self-report and clinician-administered scores in a diverse group of 84 individuals undergoing outpatient mental health treatment (Total FAST scores rS = 0.75; p < .001). These findings support using the FAST as a self-report scale, further increasing its utility to measure functional disability in mental health conditions such as bipolar disorder. Self-report application will increase the utility of the FAST in busy clinical workflows and, therefore, contribute to a more comprehensive clinical assessment of recovery and spur interventions that improve psychosocial functioning and quality of life.

Amygdala activity and prefrontal cortex-amygdala effective connectivity to emerging emotional faces distinguish remitted and depressed mood states in bipolar disorder.

OBJECTIVES: Few studies have employed effective connectivity (EC) to examine the functional integrity of neural circuitry supporting abnormal emotion processing in bipolar disorder (BD), a key feature of the illness. We used Granger Causality Mapping (GCM) to map EC between the prefrontal cortex (PFC) and bilateral amygdala and a novel paradigm to assess emotion processing in adults with BD. METHODS: Thirty-one remitted adults with BD [(remitted BD), mean age = 32 years], 21 adults with BD in a depressed episode [(depressed BD), mean age = 33 years], and 25 healthy control participants [(HC), mean age = 31 years] performed a block-design emotion processing task requiring color-labeling of a color flash superimposed on a task-irrelevant face morphing from neutral to emotional (happy, sad, angry, or fearful). GCM measured EC preceding (top-down) and following (bottom-up) activity between the PFC and the left and right amygdalae. RESULTS: Our findings indicated patterns of abnormally elevated bilateral amygdala activity in response to emerging fearful, sad, and angry facial expressions in remitted-BD subjects versus HC, and abnormally elevated right amygdala activity to emerging fearful faces in depressed-BD subjects versus HC. We also showed distinguishable patterns of abnormal EC between the amygdala and dorsomedial and ventrolateral PFC, especially to emerging happy and sad facial expressions in remitted-BD and depressed-BD subjects. DISCUSSION: EC measures of neural system level functioning can further understanding of neural mechanisms associated with abnormal emotion processing and regulation in BD. Our findings suggest major differences in recruitment of amygdala-PFC circuitry, supporting implicit emotion processing between remitted-BD and depressed-BD subjects, which may underlie changes from remission to depression in BD.

Pattern recognition analyses of brain activation elicited by happy and neutral faces in unipolar and bipolar depression.

OBJECTIVES: Recently, pattern recognition approaches have been used to classify patterns of brain activity elicited by sensory or cognitive processes. In the clinical context, these approaches have been mainly applied to classify groups of individuals based on structural magnetic resonance imaging (MRI) data. Only a few studies have applied similar methods to functional MRI (fMRI) data. METHODS: We used a novel analytic framework to examine the extent to which unipolar and bipolar depressed individuals differed on discrimination between patterns of neural activity for happy and neutral faces. We used data from 18 currently depressed individuals with bipolar I disorder (BD) and 18 currently depressed individuals with recurrent unipolar depression (UD), matched on depression severity, age, and illness duration, and 18 age- and gender ratio-matched healthy comparison subjects (HC). fMRI data were analyzed using a general linear model and Gaussian process classifiers. RESULTS: The accuracy for discriminating between patterns of neural activity for happy versus neutral faces overall was lower in both patient groups relative to HC. The predictive probabilities for intense and mild happy faces were higher in HC than in BD, and for mild happy faces were higher in HC than UD (all p < 0.001). Interestingly, the predictive probability for intense happy faces was significantly higher in UD than BD (p = 0.03). CONCLUSIONS: These results indicate that patterns of whole-brain neural activity to intense happy faces were significantly less distinct from those for neutral faces in BD than in either HC or UD. These findings indicate that pattern recognition approaches can be used to identify abnormal brain activity patterns in patient populations and have promising clinical utility as techniques that can help to discriminate between patients with different psychiatric illnesses.

An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder.

Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information.

Long-Term Healthcare Utilization and the Cost of Bipolar Disorder Among Participants in a Large Employer's Health Benefit Plan.

OBJECTIVE: Bipolar disorder (BD) is a chronic illness with recurrent exacerbations. The objective was to evaluate longitudinal costs related to BD in an employer-sponsored medical plan. METHODS: This analysis utilized 5 years of administrative claims data. Claimants with a diagnosis of BD were matched to plan members (1:5) based on age, sex, and years of follow-up. RESULTS: Medical costs for hospitalized BD members were 3.5 times more expensive than the general population (BDhosp = $92.2K vs General population = $26.8K). Average 5-year paid costs among hospitalized members with BD was $107K, $105.4K with cancer, and $103.3K with myocardial infarction (MI). CONCLUSIONS: Hospitalized BD plan members consumed more than 3.5 times the medical resources and were similar in longitudinal costs when compared with members with other costly conditions. These findings highlight the need for novel employer-sponsored programs to help manage BD.

Cognitive control associated with irritability induction: an autobiographical recall fMRI study.

OBJECTIVE: Despite the relevance of irritability emotions to the treatment, prognosis and classification of psychiatric disorders, the neurobiological basis of this emotional state has been rarely investigated to date. We assessed the brain circuitry underlying personal script-driven irritability in healthy subjects (n = 11) using functional magnetic resonance imaging. METHOD: Blood oxygen level-dependent signal changes were recorded during auditory presentation of personal scripts of irritability in contrast to scripts of happiness or neutral emotional content. Self-rated emotional measurements and skin conductance recordings were also obtained. Images were acquired using a 1,5T magnetic resonance scanner. Brain activation maps were constructed from individual images, and between-condition differences in the mean power of experimental response were identified by using cluster-wise nonparametric tests. RESULTS: Compared to neutral scripts, increased blood oxygen level-dependent signal during irritability scripts was detected in the left subgenual anterior cingulate cortex, and in the left medial, anterolateral and posterolateral dorsal prefrontal cortex (cluster-wise p-value < 0.05). While the involvement of the subgenual cingulate and dorsal anterolateral prefrontal cortices was unique to the irritability state, increased blood oxygen level-dependent signal in dorsomedial and dorsal posterolateral prefrontal regions were also present during happiness induction. CONCLUSION: Irritability induction is associated with functional changes in a limited set of brain regions previously implicated in the mediation of emotional states. Changes in prefrontal and cingulate areas may be related to effortful cognitive control aspects that gain salience during the emergence of irritability.

Esthetic Management of Incisors with Diffuse and Demarcated Opacities: 24 Month Follow-up Case Report.

CLINICAL RELEVANCE: A minimally invasive esthetic treatment can provide longevity and color stability. SUMMARY: This clinical case report describes a minimally invasive approach to mask diffuse and demarcated opacities in permanent anterior teeth in an eight-year-old child who was upset with the appearance of her incisors. Clinical examination showed diffuse opacities in teeth 7, 8, 9, and 10, diagnosed as dental fluorosis associated with yellow demarcated opacity in tooth 9 related to molar-incisor hypomineralization. The treatment was based on conservative dentistry using the low-viscosity resin infiltration technique and resin composite restoration in an attempt to mask the lesions. The follow-up time was 24 months.

Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder.

Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18-56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG-sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG-sgCG signaling in BD than HC. There was no between-group difference in sgCG-DLPFC effective connectivity. In BD, abnormally increased right PHG-sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD.

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: significant effects of gender and trait anxiety.

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV. Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high- versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation.

State-dependent microstructural white matter changes in bipolar I depression.

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

Randomized controlled clinical trial of resin infiltration in primary molars: 2 years follow-up.

OBJECTIVE: The aim of this split-mouth, randomized, controlled clinical trial was to evaluate the efficacy of resin infiltration in controlling the progression of non-cavitated proximal lesions in primary molars after two-years follow-up. METHODS: Fifty healthy children presenting at least two primary molars with proximal lesion detected radiographically (in the inner half of enamel or the outer third of dentin) were included in the study. The proximal lesions were randomly allocated into resin infltration + flossing (test group) or flossing (control group). All patients received oral hygiene instructions for daily brushing with fluoride toothpaste (1100 ppmF) and flossing. The proportion of caries progression was compared using the McNemar test. The main outcome after 2-years, caries progression in the radiography was assessed by pair-wise reading by an independent examiner who was blind regarding the treatment. RESULTS: The sample comprised 28 (56%) girls and 22 (44%) boys with a defs of 7,3 (SD = 6,5), mainly of moderate (46%) to high (48%) caries risk. Results after one year were published previously. After 2-years, 29 (58%) patients were assessed. Caries progression was observed in 24.1% (7/29) of the test lesions, compared with 55.2% (16/29) of the control lesions (p = 0.012). The therapeutic effect was 31.1% and the relative risk reduction (RRR) was 56.3%. Eigth lesions from the control group and two lesions from the test group progressed to the inner third of dentin and were restored. CONCLUSIONS: In conclusion, resin infiltration was more efficacious in controlling proximal caries lesions in primary molars than non-invasive approach alone. CLINICAL SIGNIFICANCE: The results indicate that resin infiltration was an efficacious method in controlling proximal caries lesions in primary molars after 2 years, even in patients with high caries risk, reaffirming the results of 1-year follow-up.

Do bipolar disorder soft signs impact outcomes following Transcranial Magnetic Stimulation (TMS) therapy for depression?

BACKGROUND: Transcranial Magnetic Stimulation (TMS) is not currently FDA approved for depressed patients with bipolar disorder (BD), but many unipolar depressed patients presenting for TMS have soft signs of bipolarity. It is not known whether or not these soft signs portend differential outcomes. OBJECTIVE: To investigate the relationship between BD soft signs and TMS treatment outcomes in a naturalistic treatment setting. METHODS: We conducted a retrospective chart review of MDD patients (n = 105) treated with TMS. BD diathesis was defined by responses to a modified version of the Mood Disorder Questionnaire and family history. RESULTS: TMS response rates for the group with BD diathesis and the group without were equivalent using two self-report depression severity scales. Remission rate was significantly lower for the bipolar soft signs group (13.5% versus 30.2%; p = 0.04) on one scale. This result does not hold when corrected for multiple comparisons. We did not observe switch to mania. LIMITATIONS: These data are limited to patients diagnosed with unipolar depression with "soft" bipolar features defined by subthreshold symptoms. The results cannot be extrapolated to patients with a full bipolar diagnosis. CONCLUSION: Bipolar diathesis in MDD is not a safety concern but may lead to somewhat lower remission rates when considering TMS treatment.

Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial.

BACKGROUND: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could "accurately" identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. METHODS: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the "preferred" treatment. Remission rates were calculated for participants "accurately" treated based on the composite moderator (lucky) versus "inaccurately" treated (unlucky). FINDINGS: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. INTERPRETATION: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. FUNDING: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center.Trial Registration.Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).