Attention Bias Modification Treatment Versus a Selective Serotonin Reuptake Inhibitor Or Waiting List Control for Social Anxiety Disorder: A Randomized Clinical Trial.

OBJECTIVE: Social anxiety disorder is common and impairing. The efficacy of pharmacotherapy is moderate, highlighting the need for alternative therapies. This study compared the efficacy of gaze-contingent music reward therapy (GC-MRT), an eye-tracking-based attention bias modification treatment, with a selective serotonin reuptake inhibitor (SSRI) treatment or a waiting list control condition in reducing social anxiety disorder symptoms. Superior clinical effects of similar magnitude were expected for the active treatments relative to the control condition. METHODS: Participants were 105 treatment-seeking adults with social anxiety disorder, randomly allocated to 12 weeks of GC-MRT, SSRI, or waiting list control. Mean changes in clinician-rated and self-reported social anxiety symptoms from baseline to mid- and posttreatment assessments were compared between groups using generalized estimating equations. Changes in attentional dwell time on threat were also examined. RESULTS: Analysis indicated a significant differential reduction in symptoms between groups. Patients in the GC-MRT and SSRI groups had lower social anxiety scores at the mid- and posttreatment assessments compared with patients in the waiting list group. The efficacy of the active treatments did not differ. Only patients in the GC-MRT group showed reduction in dwell time on threat from baseline to posttreatment assessment. CONCLUSIONS: Eye-tracking-based attention bias modification is an acceptable and effective treatment option for social anxiety disorder.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

The functional and structural neural correlates of dynamic balance impairment and recovery in persons with acquired brain injury.

Dynamic balance control is associated with the function of multiple brain networks and is impaired following Acquired Brain Injury (ABI). This study aims to characterize the functional and structural correlates of ABI-induced dynamic balance impairments and recovery following a rehabilitation treatment. Thirty-one chronic participants with ABI participated in a novel rehabilitation treatment composed of 22 sessions of a perturbation-based rehabilitation training. Dynamic balance was assessed using the Community Balance and Mobility scale (CB&M) and the 10-Meter Walking Test (10MWT). Brain function was estimated using resting-state fMRI imaging that was analysed using independent component analysis (ICA), and regions-of-interest analyses. Brain morphology was also assessed using structural MRI. ICA revealed a reduction in component-related activation within the sensorimotor and cerebellar networks post-intervention. Improvement in CB&M scale was associated with a reduction in FC within the cerebellar network and with baseline FC within the cerebellar-putamen and cerebellar-thalamic networks. Improvement in 10MWT was associated with baseline FC within the cerebellar-putamen and cerebellar-cortical networks. Brain volume analysis did not reveal structural correlates of dynamic balance, but dynamic balance was correlated with time since injury. Our results show that dynamic balance recovery is associated with FC reduction within and between the cerebellar and sensorimotor networks. The lack of global structural correlates of dynamic balance may point to the involvement of specific networks in balance control.

Zinc Status Index (ZSI) for Quantification of Zinc Physiological Status.

Zinc (Zn) deficiency is estimated to affect over one billion (17%) of the world's population. Zn plays a key role in various cellular processes such as differentiation, apoptosis, and proliferation, and is used for vital biochemical and structural processes in the body. Widely used biomarkers of Zn status include plasma, whole blood, and urine Zn, which decrease in severe Zn deficiency; however, accurate assessment of Zn status, especially in mild to moderate deficiency, is difficult, as studies with these biomarkers are often contradictory and inconsistent. Thus, sensitive and specific biological markers of Zn physiological status are still needed. In this communication, we provide the Zn status index (ZSI) concept, which consists of a three-pillar formula: (1) the LA:DGLA ratio, (2) mRNA gene expression of Zn-related proteins, and (3) gut microbiome profiling to provide a clear assessment of Zn physiological status and degree of Zn deficiency with respect to assessing dietary Zn manipulation. Analysis of five selected studies found that with lower dietary Zn intake, erythrocyte LA:DGLA ratio increased, mRNA gene expression of Zn-related proteins in duodenal and liver tissues was altered, and gut microbiota populations differed, where the ZSI, a statistical model trained on data from these studies, was built to give an accurate estimation of Zn physiological status. However, the ZSI needs to be tested and refined further to determine its full potential.

A randomized controlled trial of gaze-contingent music reward therapy for major depressive disorder.

BACKGROUND: Heightened attention allocation toward negative-valanced information and reduced attention allocation toward positive-valanced information represent viable targets for attention bias modification in major depressive disorder. Accordingly, we conducted a randomized controlled trial testing the efficacy of a novel gaze-contingent attention bias modification procedure for major depressive disorder. METHOD: Sixty patients with major depressive disorder were randomly assigned to either eight training sessions of feedback-based gaze-contingent music reward therapy designed to divert patients' gaze toward positive over sad stimuli, or to a control condition which entailed eight sessions of gaze-noncontingent music. Clinician-rated and self-reported measures of depression, and proportion of dwell-time on sad faces, were assessed pretreatment, posttreatment, and at a 3-month follow-up. RESULTS: Gaze-contingent music reward therapy produced a greater reduction in dwell-time on sad faces compared with the control condition, but it failed to generalize to novel faces. Both groups manifested similarly significant reductions in depression symptoms from pre- to posttreatment that were maintained at follow-up. Exploratory analyses suggest that first-episode patients may benefit more from this therapy than patients with a history of multiple episodes. CONCLUSIONS: Gaze-contingent music reward therapy can modify attention biases in depression, but clear differential clinical effects did not emerge. Theoretical and practical implications are discussed.

Gaze-Contingent Music Reward Therapy for Clinically Anxious 7- to 10-Year-Olds: An Open Multiple Baseline Feasibility Study.

This multiple-baseline open pilot trial examined feasibility, compliance, acceptability, and preliminary indices of efficacy of Gaze-Contingent Music Reward Therapy (GC-MRT) for anxious 7- to 10-year-old children. GC-MRT is a novel therapy for anxiety disorders that relies on eye-tracking technology and operant conditioning principles to divert attention toward neutral over threat stimuli, with music serving as a reward. Using a multiple-baseline design, 12 children (M age = 8.3 years, SD = .72, range = 7-10; 4 girls) with social anxiety disorder, generalized anxiety disorder, or separation anxiety disorder received 8 therapy sessions. Clinical status was determined via semistructured interviews and questionnaires. Patients were randomized to wait 1, 3, or 5 weeks between initial assessment and beginning of therapy. Self-reported anxiety was recorded weekly, and comprehensive clinical assessments were obtained pre- and posttreatment. All 12 patients completed the full course of GC-MRT within the allocated therapy period. Therapy credibility rates were moderate to high as reported by both children and parents. Clinician-rated anxiety levels remained consistent during baseline measurement and decreased significantly following treatment. Parent-reports also yielded significant reductions in child anxiety symptoms from pre- to posttreatment. However, child-reported anxiety did not change significantly. The results provide preliminary evidence for feasibility, acceptability, and efficacy of GC-MRT for young children with anxiety disorders. Efficacy should now be tested in randomized controlled trials.

Complementary Features of Attention Bias Modification Therapy and Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders.

OBJECTIVE: In the treatment of anxiety disorders, attention bias modification therapy (ABMT) and cognitive-behavioral therapy (CBT) may have complementary effects by targeting different aspects of perturbed threat responses and behaviors. ABMT may target rapid, implicit threat reactions, whereas CBT may target slowly deployed threat responses. The authors used amygdala-based connectivity during a threat-attention task and a randomized controlled trial design to evaluate potential complementary features of these treatments in pediatric anxiety disorders. METHOD: Prior to treatment, youths (8-17 years old) with anxiety disorders (N=54), as well as healthy comparison youths (N=51), performed a threat-attention task during functional MRI acquisition. Task-related amygdala-based functional connectivity was assessed. Patients with and without imaging data (N=85) were then randomly assigned to receive CBT paired with either active or placebo ABMT. Clinical response was evaluated, and pretreatment amygdala-based connectivity profiles were compared among patients with varying levels of clinical response. RESULTS: Compared with the CBT plus placebo ABMT group, the CBT plus active ABMT group exhibited less severe anxiety after treatment. The patient and healthy comparison groups differed in amygdala-insula connectivity during the threat-attention task. Patients whose connectivity profiles were most different from those of the healthy comparison group exhibited the poorest response to treatment, particularly those who received CBT plus placebo ABMT. CONCLUSIONS: The study provides evidence of enhanced clinical effects for patients receiving active ABMT. Moreover, ABMT appears to be most effective for patients with abnormal amygdala-insula connectivity. ABMT may target specific threat processes associated with dysfunctional amygdala-insula connectivity that are not targeted by CBT alone. This may explain the observation of enhanced clinical response to CBT plus active ABMT.

Formation of Long-Term Locomotor Memories Is Associated with Functional Connectivity Changes in the Cerebellar-Thalamic-Cortical Network.

Although motor adaptation is typically rapid, accumulating evidence shows that it is also associated with long-lasting behavioral and neuronal changes. Two processes were suggested to explain the formation of long-term motor memories: recall, reflecting a retrieval of previous motor actions, and faster relearning, reflecting an increased sensitivity to errors. Although these manifestations of motor memories were initially demonstrated in the context of adaptation experiments in reaching, indications of long-term motor memories were also demonstrated recently in other kinds of adaptation such as in locomotor adaptation. Little is known about the neural processes that underlie these distinct aspects of memory. We hypothesize that recall and faster relearning reflect different learning processes that operate at the same time and depend on different neuronal networks. Seventeen subjects performed a multisession locomotor adaptation experiment in the laboratory, together with resting-state and localizer fMRI scans, after the baseline and the locomotor adaptation sessions. We report a modulation of the cerebellar-thalamic-cortical and cerebellar-basal ganglia networks after locomotor adaptation. Interestingly, whereas thalamic-cortical baseline connectivity was correlated with recall, cerebellar-thalamic baseline connectivity was correlated with faster relearning. Our results suggest that separate neuronal networks underlie error sensitivity and retrieval components. Individual differences in baseline resting-state connectivity can predict idiosyncratic combination of these components. SIGNIFICANCE STATEMENT: The ability to shape our motor behavior rapidly in everyday activity, such as when walking on sand, suggests the existence of long-term motor memories. It was suggested recently that this ability is achieved by the retrieval of previous motor actions and by enhanced relearning capacity. Little is known about the neural mechanisms that underlie these memory processes. We studied the modularity in long-term motor memories in the context of locomotor adaptation using resting-state fMRI. We show that retrieval and relearning effects are associated with separate locomotor control networks and that intersubject variability in learning and in the generation of motor memories could be predicted from baseline resting-state connectivity in locomotor-related networks.

Gaze-Contingent Music Reward Therapy for Social Anxiety Disorder: A Randomized Controlled Trial.

OBJECTIVE: Patients with social anxiety disorder exhibit increased attentional dwelling on social threats, providing a viable target for therapeutics. This randomized controlled trial examined the efficacy of a novel gaze-contingent music reward therapy for social anxiety disorder designed to reduce attention dwelling on threats. METHOD: Forty patients with social anxiety disorder were randomly assigned to eight sessions of either gaze-contingent music reward therapy, designed to divert patients' gaze toward neutral stimuli rather than threat stimuli, or to a control condition. Clinician and self-report measures of social anxiety were acquired pretreatment, posttreatment, and at 3-month follow-up. Dwell time on socially threatening faces was assessed during the training sessions and at pre- and posttreatment. RESULTS: Gaze-contingent music reward therapy yielded greater reductions of symptoms of social anxiety disorder than the control condition on both clinician-rated and self-reported measures. Therapeutic effects were maintained at follow-up. Gaze-contingent music reward therapy, but not the control condition, also reduced dwell time on threat, which partially mediated clinical effects. Finally, gaze-contingent music reward therapy, but not the control condition, also altered dwell time on socially threatening faces not used in training, reflecting near-transfer training generalization. CONCLUSIONS: This is the first randomized controlled trial to examine a gaze-contingent intervention in social anxiety disorder. The results demonstrate target engagement and clinical effects. This study sets the stage for larger randomized controlled trials and testing in other emotional disorders.

The Combined Application of the Caco-2 Cell Bioassay Coupled with In Vivo (Gallus gallus) Feeding Trial Represents an Effective Approach to Predicting Fe Bioavailability in Humans.

Research methods that predict Fe bioavailability for humans can be extremely useful in evaluating food fortification strategies, developing Fe-biofortified enhanced staple food crops and assessing the Fe bioavailability of meal plans that include such crops. In this review, research from four recent poultry (Gallus gallus) feeding trials coupled with in vitro analyses of Fe-biofortified crops will be compared to the parallel human efficacy studies which used the same varieties and harvests of the Fe-biofortified crops. Similar to the human studies, these trials were aimed to assess the potential effects of regular consumption of these enhanced staple crops on maintenance or improvement of iron status. The results demonstrate a strong agreement between the in vitro/in vivo screening approach and the parallel human studies. These observations therefore indicate that the in vitro/Caco-2 cell and Gallus gallus models can be integral tools to develop varieties of staple food crops and predict their effect on iron status in humans. The cost-effectiveness of this approach also means that it can be used to monitor the nutritional stability of the Fe-biofortified crop once a variety has released and integrated into the food system. These screening tools therefore represent a significant advancement to the field for crop development and can be applied to ensure the sustainability of the biofortification approach.

A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1).

This study investigated the influence of maternal choline intake on the human placental transcriptome, with a special interest in its role in modulating placental vascular function. Healthy pregnant women (n=26, wk 26-29 gestation) were randomized to 480 mg choline/d, an intake level approximating the adequate intake of 450 mg/d, or 930 mg/d for 12 wk. Maternal blood and placental samples were retrieved at delivery. Whole genome expression microarrays were used to identify placental genes and biological processes impacted by maternal choline intake. Maternal choline intake influenced a wide array of genes (n=166) and biological processes (n=197), including those related to vascular function. Of special interest was the 30% down-regulation (P=0.05) of the antiangiogenic factor and preeclampsia risk marker fms-like tyrosine kinase-1 (sFLT1) in the placenta tissues obtained from the 930 vs. 480 mg/d choline intake group. Similar decreases (P=0.04) were detected in maternal blood sFLT1 protein concentrations. The down-regulation of sFLT1 by choline treatment was confirmed in a human trophoblast cell culture model and may be related to enhanced acetylcholine signaling. These findings indicate that supplementing the maternal diet with extra choline may improve placental angiogenesis and mitigate some of the pathological antecedents of preeclampsia.

Consequences of delayed ciprofloxacin and doxycycline treatment regimens against Francisella tularensis airway infection.

This study examines the efficacy, bacterial load, and humoral response of extensively delayed ciprofloxacin or doxycycline treatments following airway exposure of mice to Francisella tularensis subsp. holarctica (strain LVS) or to the highly virulent F. tularensis subsp. tularensis (strain SchuS4). A delay in onset of both antibiotic treatments allowed the rescue of all LVS-infected animals. However, for animals infected with SchuS4, only ciprofloxacin was efficacious and prolongation of treatment rescued all animals.

Hyperbaric oxygen treatment reduces mortality in acute iron intoxication in rats.

Acute iron intoxication is one of the leading causes of overdose morbidity and mortality in children. The toxicity of iron has been postulated to be related to free radical formation and subsequent lipid peroxidation. Hyperbaric oxygen treatment can result in a number of beneficial biochemical, cellular and physiological effects, and has recently been shown to induce cellular protection against ischaemia, and in some cases against free radical formation. In the current study, we aimed to investigate the effects of hyperbaric oxygen treatment on mortality in acute iron intoxication in rats. After iron administration, 57 animals were divided into two groups: a treatment group receiving hyperbaric oxygen treatment (n = 30) and a control group (n = 27), and followed for 48 hr for signs of severe intoxication. In the second part of the study, 21 animals were divided into a treatment group receiving hyperbaric oxygen treatment (n = 10) and a control group (n = 11), and markers of oxidative stress were evaluated. We showed a significant reduction in mortality in hyperbaric oxygen-treated animals from 17 of 27 (62.9%) among untreated rats to 6 of 30 (20%). Surprisingly, in the treatment group, levels of oxidative stress markers were higher. We postulate that hyperbaric oxygen has a potentially beneficial effect in acute iron intoxication.

Effect of a 24+ hour fast on breast milk composition.

In this preliminary prospective study, breast milk is sampled surrounding 4 religious fast days to determine the effect of a more than 24-hour fast on breast milk composition. The participants are 48 healthy women nursing healthy babies between 1 and 6 months of age. Samples are collected within 2 days before the fast (baseline), immediately after the fast, and 24 hours after fast completion. Samples are tested for sodium, calcium, phosphorus, triglycerides, total protein, and lactose. From baseline to immediately after fast, mean sodium, calcium, and protein levels increase (P = .013, P < .0001, and P < .0001, respectively) and mean phosphorus and lactose levels decrease (P < .0001 and P = .003, respectively). Mean triglycerides are unchanged. Twenty-four hours after fast, parameters are no longer significantly different from baseline except for elevated mean protein levels (P = .022) and lactose that is still reduced (P = .017). A fast of this nature is statistically associated with certain biochemical changes in breast milk.

Comorbidity between balance and anxiety disorders: verification in a normal population.

Comorbidity between balance and anxiety disorders has been documented in clinical psychiatric and neurological samples. The authors aimed to determine whether the comorbidity of balance and anxiety disorders has an analogous representation in the normal population. Participants were 20 undergraduate students ages 22-29 years. The authors assigned them to high or low trait anxiety groups and performed a balance task in 3 experimental stages: baseline, training, and test. The baseline and test stages consisted of 4 wobbly and 4 stable trials each. The authors measured state anxiety in the form of auditory startle responses (ASRs) during the stable trials. In the baseline stage, the ASR amplitudes were higher in the high trait anxiety participants. In the test stage, the low trait anxiety participants performed the balance task better than the high trait anxiety participants did. These data suggest that the clinical entity designated as a comorbidity of balance and anxiety disorders has an analogous representation in the normal population.

Reduced auditory efferent activity in childhood selective mutism.

BACKGROUND: Selective mutism is a psychiatric disorder of childhood characterized by consistent inability to speak in specific situations despite the ability to speak normally in others. The objective of this study was to test whether reduced auditory efferent activity, which may have direct bearings on speaking behavior, is compromised in selectively mute children. METHODS: Participants were 16 children with selective mutism and 16 normally developing control children matched for age and gender. All children were tested for pure-tone audiometry, speech reception thresholds, speech discrimination, middle-ear acoustic reflex thresholds and decay function, transient evoked otoacoustic emission, suppression of transient evoked otoacoustic emission, and auditory brainstem response. RESULTS: Compared with control children, selectively mute children displayed specific deficiencies in auditory efferent activity. These aberrations in efferent activity appear along with normal pure-tone and speech audiometry and normal brainstem transmission as indicated by auditory brainstem response latencies. CONCLUSIONS: The diminished auditory efferent activity detected in some children with SM may result in desensitization of their auditory pathways by self-vocalization and in reduced control of masking and distortion of incoming speech sounds. These children may gradually learn to restrict vocalization to the minimal amount possible in contexts that require complex auditory processing.

The development of P50 suppression in the auditory event-related potential.

The development of P50 suppression in the auditory event-related potential was examined in 32 participants aged 7-13 years and the relation of P50 suppression to individual differences in social withdrawal was investigated. Auditory click pairs were presented binaurally and the amplitude of the P50 component was measured for the two clicks. Across the whole sample, P50 amplitude to the second click was significantly smaller than P50 amplitude to the first click, although around one third of participants showed augmentation of the P50 to the second click. For the children who showed P50 suppression, the magnitude of P50 suppression increased with age and reached adult levels in the oldest participants. P50 suppression did not vary with the extent of social withdrawal behaviors.

Mismatch negativity in socially withdrawn children.

BACKGROUND: Individual differences in auditory processing have been associated with social withdrawal, introversion, and other forms of dysfunction in social engagement. The goal of this study was to investigate the characteristics of an electrophysiologic response that is seen to index early cortical auditory processing (mismatch negativity, MMN) among socially withdrawn and more sociable control children. METHODS: Auditory event-related potentials to standard and deviant tone stimuli were computed for 23 socially withdrawn children and 22 control subjects. We calculated MMN difference waveforms for frontal, central, and parietal electrode sites. RESULTS: Socially withdrawn children had smaller MMN amplitude and longer MMN latencies compared with more sociable control children. CONCLUSION: The findings point to the involvement of individual differences in early cortical auditory processing in childhood social withdrawal. Reduced MMN amplitude and delayed latency may index a component of social withdrawal seen in socially withdrawn children and in depressed and schizophrenic patients. The existence of a secondary MMN generator in the frontal cortex may provide a link between the hypothesized frontal lobe involvement in childhood social withdrawal, schizophrenia, and depression and the MMN reductions seen in these conditions.