Neurobiological correlates of religious coping among older adults with and without mood disorders: An exploratory study.

In this study, 32 older adults with and without mood disorders completed resting-state functional Magnetic Resonance Imaging and measures of demographics, spirituality/religion, positive and negative religious coping, and depression. Group Independent Component Analysis identified and selected three a priori resting state networks [cingulo-opercular salience (cSN), central executive (CEN) and Default Mode Networks (DMN)] within the Triple Network Mode. We investigated associations of religious coping with within- and between-network connectivity, controlling for age. Insular connectivity within the cSN was associated with negative religious coping. Religious coping was associated with anti-correlation between the DMN and CEN even when controlling for depression.

Spatiotemporal dynamics of hippocampal-cortical networks underlying the unique phenomenological properties of trauma-related intrusive memories.

Trauma-related intrusive memories (TR-IMs) possess unique phenomenological properties that contribute to adverse post-traumatic outcomes, positioning them as critical intervention targets. However, transdiagnostic treatments for TR-IMs are scarce, as their underlying mechanisms have been investigated separate from their unique phenomenological properties. Extant models of more general episodic memory highlight dynamic hippocampal-cortical interactions that vary along the anterior-posterior axis of the hippocampus (HPC) to support different cognitive-affective and sensory-perceptual features of memory. Extending this work into the unique properties of TR-IMs, we conducted a study of eighty-four trauma-exposed adults who completed daily ecological momentary assessments of TR-IM properties followed by resting-state functional magnetic resonance imaging (rs-fMRI). Spatiotemporal dynamics of anterior and posterior hippocampal (a/pHPC)-cortical networks were assessed using co-activation pattern analysis to investigate their associations with different properties of TR-IMs. Emotional intensity of TR-IMs was inversely associated with the frequency and persistence of an aHPC-default mode network co-activation pattern. Conversely, sensory features of TR-IMs were associated with more frequent co-activation of the HPC with sensory cortices and the ventral attention network, and the reliving of TR-IMs in the "here-and-now" was associated with more persistent co-activation of the pHPC and the visual cortex. Notably, no associations were found between HPC-cortical network dynamics and conventional symptom measures, including TR-IM frequency or retrospective recall, underscoring the utility of ecological assessments of memory properties in identifying their neural substrates. These findings provide novel insights into the neural correlates of the unique features of TR-IMs that are critical for the development of individualized, transdiagnostic treatments for this pervasive, difficult-to-treat symptom.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level.

Trauma-related intrusive memories and anterior hippocampus structural covariance: an ecological momentary assessment study in posttraumatic stress disorder.

Trauma-related intrusive memories (TR-IMs) are hallmark symptoms of posttraumatic stress disorder (PTSD), but their neural correlates remain partly unknown. Given its role in autobiographical memory, the hippocampus may play a critical role in TR-IM neurophysiology. The anterior and posterior hippocampi are known to have partially distinct functions, including during retrieval of autobiographical memories. This study aimed to investigate the relationship between TR-IM frequency and the anterior and posterior hippocampi morphology in PTSD. Ninety-three trauma-exposed adults completed daily ecological momentary assessments for fourteen days to capture their TR-IM frequency. Participants then underwent anatomical magnetic resonance imaging to obtain measures of anterior and posterior hippocampal volumes. Partial least squares analysis was applied to identify a structural covariance network that differentiated the anterior and posterior hippocampi. Poisson regression models examined the relationship of TR-IM frequency with anterior and posterior hippocampal volumes and the resulting structural covariance network. Results revealed no significant relationship of TR-IM frequency with hippocampal volumes. However, TR-IM frequency was significantly negatively correlated with the expression of a structural covariance pattern specifically associated with the anterior hippocampus volume. This association remained significant after accounting for the severity of PTSD symptoms other than intrusion symptoms. The network included the bilateral inferior temporal gyri, superior frontal gyri, precuneus, and fusiform gyri. These novel findings indicate that higher TR-IM frequency in individuals with PTSD is associated with lower structural covariance between the anterior hippocampus and other brain regions involved in autobiographical memory, shedding light on the neural correlates underlying this core symptom of PTSD.

From Complexity to Precision-Charting Decision-Making Through Normative Modeling.

This Viewpoint synthesizes data-driven and theory-driven approaches to normative modeling.

Brain-based graph-theoretical predictive modeling to map the trajectory of transdiagnostic symptoms of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM's mean square error (MSE) to that of a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region for information spread) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders, highlighting transdiagnostic generalization. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level. ClinicalTrials.gov identifier: NCT01976975.

Distinct profiles of anhedonia and reward processing and their prospective associations with quality of life among individuals with mood disorders.

Leading professional health bodies have called for the wider adoption of Patient Reported Outcome Measures, such as quality of life, in research and clinical practice as a means for understanding why the global burden of depression continues to climb despite increased rates of treatment use. Here, we examined whether anhedonia-an often recalcitrant and impairing symptom of depression-along with its neural correlates, was associated with longitudinal changes in patient-reported quality of life among individuals seeking treatment for mood disorders. We recruited 112 participants, including n = 80 individuals with mood disorders (58 unipolar, 22 bipolar) and n = 32 healthy controls (63.4% female). We assessed anhedonia severity along with two electroencephalographic markers of neural reward responsiveness (scalp-level 'Reward Positivity' amplitude and source-localized reward-related activation in the dorsal anterior cingulate cortex), and assessed quality of life at baseline, 3- and 6-month follow-up. Anhedonia emerged as a robust correlate of quality of life cross-sectionally and longitudinally among individuals with mood disorders. Furthermore, increased neural reward responsiveness at baseline was associated with greater improvements in quality of life over time, and this improvement was mediated by longitudinal improvements in anhedonia severity. Finally, differences in quality of life observed between individuals with unipolar and bipolar mood disorders were mediated by differences in anhedonia severity. Our findings indicate that anhedonia and its reward-related neural correlates are linked to variability in quality of life over time in individuals with mood disorders. Treatments capable of improving anhedonia and normalizing brain reward function may be necessary for improving broader health outcomes for individuals seeking treatment for depression.ClinicalTrials.gov identifier: NCT01976975.

Depressive and anxiety symptoms, and neural correlates of reward and punishment anticipation in female athletes with amenorrhea.

Objective: Studies in estrogen deficiency states such as primary ovarian insufficiency and Turner syndrome suggest that estrogen status may be an important modulator of mood and emotions. In this study we compared depressive and anxiety symptoms between adolescent and young adult female oligo-amenorrheic athletes (AA) and eumenorrheic females (EM), and explored structural, and functional changes in related brain areas during reward processing, a behavioral construct that is altered in depression and anxiety. Methods: We included (i) 24 AA participating in ≥4 hours/week of aerobic exercise or running ≥20 miles/week for ≥6 months in the preceding year, with lack of menstrual cycles for ≥3 months within at least 6 preceding months of oligo-amenorrhea, OR in premenarchal girls, absence of menses at >15 years), and (ii) 27 EM aged 14-25 years. Participants completed the Beck Depression Inventory-II (BDI-II), State and Trait Anxiety Inventory (STAI), and Mood and Anxiety Symptoms Questionnaire (MASQ). Structural MRI and brain activation during a functional MRI (fMRI) task that probes reward and punishment processing was examined in a subset of 10 AA and 23 EM. Results: Median (IQR) age and BMI of AA and EM groups were 20.6 (19.0-22.6) vs. 20.6 (19.2-23.7) years, p=0.6 and v 20.3 (18.8-21.5) vs. 21.9 (19.6-23.5) kg/m2, p=0.005, respectively. While groups did not differ for BDI-II scores, AA had higher anhedonic depression MASQ scores (p=0.04), and STAI (p=0.03) scores vs. EM. In the fMRI subset, AA had higher caudate volumes vs. EM [F(1, 29)=9.930, p=0.004]. Lower activation observed in the right caudate during reward anticipation in AA compared with EM (p=0.036) suggests blunted reward processing in the striatum in estrogen deficient states. Conclusion: Athletes with amenorrhea had higher depressive and anxiety symptomatology compared to eumenorrheic young women. Exploratory analyses demonstrated increased caudate volumes and decreased caudate activation during reward processing in athletes with amenorrhea suggesting that estrogen may play a role in reward processing.

Circulating PACAP levels are associated with increased amygdala-default mode network resting-state connectivity in posttraumatic stress disorder.

The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.

Antidepressant treatment-related brain activity changes in remitted major depressive disorder.

Recent evidence has shown that some brain regions are core hubs and play a key role in the treatment of depression. Twenty-five unmedicated patients with major depressive disorder (MDD) were included, and telephone follow-up was performed at 8, 24, and 48 weeks after enrollment. After reaching clinical remission, they were scheduled for a second magnetic resonance imaging scan and clinical evaluation. Thirty-one healthy controls were also investigated. The intrinsic functional connectivity (degree centrality) of each participant was mapped using a computationally efficient approach. Then, functional connectivity of patients was calculated between the identified regions of interest by degree centrality analysis and every voxel. Later, linear regression analysis was used to identify potential variables predictive of an improvement in disease severity. The prominent hubs identified by degree centrality analysis included the cerebellum, inferior temporal gyrus, lingual gyrus, dorsal medial prefrontal cortex (DMPFC), and dorsal lateral prefrontal cortex. We also found that the increased degree centrality of DMPFC was associated with improvement in depressive symptoms. The brain activity associated with antidepressant effects, especially brain connectivity changes in the left DMPFC, can potentially be used to monitor treatment response and predict treatment outcomes.

Neural sensitivity to peer feedback and depression symptoms in adolescents: a 2-year multiwave longitudinal study.

BACKGROUND: Depression risk increases during adolescent development, and individual differences in neural sensitivity to peer feedback (rejection vs. acceptance) may be a key diathesis in understanding stress-related depression risk. METHODS: At baseline, adolescents (12-14 years old; N = 124) completed clinical interviews and self-report symptom measures, and the Chatroom Task while MRI data were acquired. The majority of participants provided usable MRI data (N = 90; 76% female), which included adolescents with no maternal depression history (low risk n = 64) and those with a maternal depression history (high risk n = 26). Whole-brain regression models probed group differences in neural sensitivity following peer feedback, and whole-brain linear mixed-effects models examined neural sensitivity to peer feedback by peer stress interactions relating to depression symptoms at up to nine longitudinal assessments over 2 years. RESULTS: Whole-brain cluster-corrected results indicated brain activation moderating the strong positive association between peer interpersonal stress and depression over time. This included activation in the anterior insula, cingulate, amygdala, and striatum during anticipation and receipt of feedback (i.e., rejection vs. acceptance). Moderation effects were stronger when examining peer interpersonal (vs. non-interpersonal) stress and in relation to depression (vs. social anxiety) symptoms. CONCLUSIONS: Neural responses to peer feedback in key social and incentive processing brain regions may reflect core dispositional risk factors that interact with peer interpersonal stressors to predict adolescent depression symptom severity over time.

An Unusual Lesion of Epignathus with Duplicate Tongue and Ranula in a Neonate.

We report a rare case of epignathus (oropharyngeal teratoma) in a neonate, who presented with a midline mass covered with skin and multiple hairs protruding from the Palate and associated with bifid tongue and ranula. With the characteristic presentation, diagnosis of oro/oropharyngeal teratoma was made and a massive internet search revealed very few reported cases of "epignathus". It is unfortunate that the survival of such neonates is only moderate. Prenatal scans and follow up in an institution can prepare the multidisciplinary team to save the child. EXIT procedure to excise the mass or secure the airway, with future repair of the palate is the treatment option available. This case report emphasizes the rare clinical presentation of the disease and the prenatal diagnosis of such a condition can help in prompt decision making and management.

Deconstructing dissociation: a triple network model of trauma-related dissociation and its subtypes.

Trauma-related pathological dissociation is characterized by disruptions in one's sense of self, perceptual, and affective experience. Dissociation and its trauma-related antecedents disproportionately impact women. However, despite the gender-related prevalence and high individual and societal costs, dissociation remains widely underappreciated in clinical practice. Moreover, dissociation lacks a synthesized neurobiological model across its subtypes. Leveraging the Triple Network Model of psychopathology, we sought to parse heterogeneity in dissociative experience by examining functional connectivity of three core neurocognitive networks as related to: (1) the dimensional dissociation subtypes of depersonalization/derealization and partially-dissociated intrusions; and, (2) the diagnostic category of dissociative identity disorder (DID). Participants were 91 women with and without: a history of childhood trauma, current posttraumatic stress disorder (PTSD), and varied levels of dissociation. Participants provided clinical data about dissociation, PTSD symptoms, childhood maltreatment history, and completed a resting-state functional magnetic resonance imaging scan. We used a novel statistical approach to assess both overlapping and unique contributions of dissociation subtypes. Covarying for age, childhood maltreatment and PTSD severity, we found dissociation was linked to hyperconnectivity within central executive (CEN), default (DN), and salience networks (SN), and decreased connectivity of CEN and SN with other areas. Moreover, we isolated unique connectivity markers associated with depersonalization/derealization in CEN and DN, to partially-dissociated intrusions in CEN, and to DID in CEN. This suggests dissociation subtypes have robust functional connectivity signatures that may serve as targets for PTSD/DID treatment engagement. Our findings underscore dissociation assessment as crucial in clinical care, in particular, to reduce gender-related health disparities.

Evolving Trends of Button Battery Ingestion in Indian Children at a Tertiary Care Hospital.

INTRODUCTION: Foreign body ingestion is a common problem encountered in the pediatric age group. Impaction of lithium batteries of greater than 20-mm diameter in the esophagus is associated with severe complications. This study aimed at analyzing the evolving trends of button battery ingestion in pediatric age groups at our tertiary care center in terms of clinical presentation, intraoperative findings, and the correlation of various clinical variables. METHODS: A retrospective observational study was done. All children younger than 18 years with impaction of a button battery of size greater than 20 mm in the esophagus between January 2015 and December 2018 were included in the study. All children underwent removal of the battery using direct laryngoscopy/rigid esophagoscopy under general anesthesia. RESULTS: There were 100 children included in the study with a mean age of 29.92 months having 93 children (93%) younger than 6 years. The mean duration of impaction was 34.7 hours. Increased duration of impaction was associated with an increased risk of complications and an increased difficulty in removal. There was a significant correlation between the site of impaction and the age of the patient. Complications were seen in 10% of cases with severe complications in 6 cases. No fatalities were reported in this study. CONCLUSIONS: Button batteries impacted in the esophagus can lead to severe complications including death. There has been an increasing trend in the ingestion of button batteries over the last 4 years. A prompt diagnosis and emergent removal of the battery are crucial to minimize the rate of complications. Symptoms of stridor and dysphagia must be given more attention, and these children are prioritized because they are more prone to have complications. Furthermore, primary prevention and caregiver education should be emphasized, and the need for a legislation to change the policies for securing the batteries in their products must be endorsed.

Treatment of COVID-19: a review of current and prospective pharmacotherapies.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and have grave health and socioeconomic consequences worldwide. Researchers have raced to understand the pathophysiological mechanisms underpinning the disease caused by SARS-CoV-2 so that effective therapeutic targets can be discovered. This review summarises the key pharmacotherapies that are being investigated for treatment of COVID-19, including antiviral, immunomodulator and anticoagulation strategies.

Mapping Disease Course Across the Mood Disorder Spectrum Through a Research Domain Criteria Framework.

BACKGROUND: The National Institute of Mental Health Research Domain Criteria (RDoC) initiative aims to establish a neurobiologically valid framework for classifying mental illness. Here, we examined whether the RDoC construct of reward learning and three aspects of its underlying neurocircuitry predicted symptom trajectories in individuals with mood pathology. METHODS: Aligning with the RDoC approach, we recruited individuals (n = 80 with mood disorders [58 unipolar and 22 bipolar] and n = 32 control subjects; 63.4% female) based on their performance on a laboratory-based reward learning task rather than clinical diagnosis. We then assessed 1) anterior cingulate cortex prediction errors using electroencephalography, 2) striatal reward prediction errors using functional magnetic resonance imaging, and 3) medial prefrontal cortex glutamatergic function (mPFC Gln/Glu) using 1H magnetic resonance spectroscopy. Severity of anhedonia, (hypo)mania, and impulsivity were measured at baseline, 3 months, and 6 months. RESULTS: Greater homogeneity in aspects of brain function (mPFC Gln/Glu) was observed when individuals were classified according to reward learning ability rather than diagnosis. Furthermore, mPFC Gln/Glu levels predicted more severe (hypo)manic symptoms cross-sectionally, predicted worsening (hypo)manic symptoms longitudinally, and explained greater variance in future (hypo)manic symptoms than diagnostic information. However, rather than being transdiagnostic, this effect was specific to individuals with bipolar disorder. Prediction error indices were unrelated to symptom severity. CONCLUSIONS: Although findings are preliminary and require replication, they suggest that heightened mPFC Gln/Glu warrants further consideration as a predictor of future (hypo)mania. Importantly, this work highlights the value of an RDoC approach that works in tandem with, rather than independent of, traditional diagnostic frameworks.

Identifying Subgroups of Major Depressive Disorder Using Brain Structural Covariance Networks and Mapping of Associated Clinical and Cognitive Variables.

Background: Identifying data-driven subtypes of major depressive disorder (MDD) holds promise for parsing the heterogeneity of MDD in a neurobiologically informed way. However, limited studies have used brain structural covariance networks (SCNs) for subtyping MDD. Methods: This study included 145 unmedicated patients with MDD and 206 demographically matched healthy control subjects, who underwent a structural magnetic resonance imaging scan and a comprehensive neurocognitive battery. Patterns of structural covariance were identified using source-based morphometry across both patients with MDD and healthy control subjects. K-means clustering algorithms were applied on dysregulated structural networks in MDD to identify potential MDD subtypes. Finally, clinical and neurocognitive measures were compared between identified subgroups to elucidate the profile of these MDD subtypes. Results: Source-based morphometry across all individuals identified 28 whole-brain SCNs that encompassed the prefrontal, anterior cingulate, and orbitofrontal cortices; basal ganglia; and cerebellar, visual, and motor regions. Compared with healthy control subjects, individuals with MDD showed lower structural network integrity in three networks including default mode, ventromedial prefrontal cortical, and salience networks. Clustering analysis revealed two MDD subtypes based on the patterns of structural network abnormalities in these three networks. Further profiling revealed that patients in subtype 1 had younger age of onset and more symptom severity as well as greater deficits in cognitive performance than patients in subtype 2. Conclusions: Overall, we identified two MDD subtypes based on SCNs that differed in their clinical and cognitive profile. Our results represent a proof-of-concept framework for leveraging these large-scale SCNs to parse heterogeneity in MDD.

Cortical thickness abnormalities in patients with first episode psychosis: a meta-analysis of psychoradiologic studies and replication in an independent sample.

BACKGROUND: Abnormalities of cortical thickness (CTh) in patients with their first episode psychosis (FEP) have been frequently reported, but findings are inconsistent. OBJECTIVE: To define the most consistent CTh changes in patients with FEP by meta-analysis of published whole-brain studies. METHODS: The meta-analysis used seed-based d mapping (SDM) software to obtain the most prominent regional CTh changes in FEP, and meta-regression analyses to explore the effects of demographics and clinical characteristics. The meta-analysis results were verified in an independent sample of 142 FEP patients and 142 age- and sex-matched healthy controls (HCs), using both a vertex-wise and a region of interest analysis, with multiple comparisons correction. RESULTS: The meta-analysis identified lower CTh in the right middle temporal cortex (MTC) extending to superior temporal cortex (STC), insula, and anterior cingulate cortex (ACC) in FEP compared with HCs. No significant correlations were identified between CTh alterations and demographic or clinical variables. These results were replicated in the independent dataset analysis. CONCLUSION: This study identifies a robust pattern of cortical abnormalities in FEP and extends understanding of gray matter abnormalities and pathological mechanisms in FEP.