Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.

REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial.

BACKGROUND: Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS: Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS: From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS: Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02638766.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

Expression of Adenosine A2B Receptor and Adenosine Deaminase in Rabbit Gastric Mucosa ECL Cells.

Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal cells through A2B adenosine receptor (A2BR) binding. A functional link between surface A2BR and adenosine deaminase (ADA) was found in parietal cells, but whether this connection is a general feature of gastric mucosa cells is unknown. Here we examine whether A2BR is expressed at the membrane of histamine-producing enterochromaffin-like (ECL) cells, the major endocrine cell type in the oxyntic mucosa, and if so, whether it has a vicinity relationship with ADA. We used a highly homogeneous population of rabbit ECL cells (size 7.5-10 µm) after purification by elutriation centrifugation. The surface expression of A2BR and ADA proteins was assessed by flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are partially coexpressed at the gastric ECL cell surface and that A2BR is functional, with regard to binding of adenosine analogs and adenylate cyclase activation. The physiological relevance of A2BR and ADA association in regulating histamine release is yet to be explained.

Bidirectional synaptic plasticity can explain bidirectional retrograde effects of emotion on memory.

Emotional events can either impair or enhance memory for immediately preceding items. The GANE model explains this bidirectional effect as a glutamate "priority" signal that modulates noradrenaline release depending on arousal state. We argue for an alternative explanation: that priority itself evokes phasic noradrenaline release. Thus, contrasting E-1 memory effects are explained by a mechanism based on the Bienenstock-Cooper-Munro theory.

Stimulation of gastric acid secretion by rabbit parietal cell A(2B) adenosine receptor activation.

Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.

Patient Confidence and Information Preferences During the Treatment Decision-making Process: Results From a Large Multiple Myeloma Patient Survey Across 12 Countries in Europe and Israel.

BACKGROUND: The relapsing nature of multiple myeloma (MM) means that patients typically receive different and multiple lines of therapy, requiring many treatment decisions over the disease course. The aim of this study was to explore patient confidence and information preferences during the treatment decision-making process. PATIENTS AND METHODS: A multinational, cross-sectional survey enrolled patients with MM. It was co-developed and distributed by Myeloma Patients Europe across 12 countries in Europe and Israel from May 2019 to March 2020. Eligibility criteria included a self-reported diagnosis of MM and being able to recall the decision-making process at the start of their latest treatment line. RESULTS: A total of 1559 patients were included, with complete responses received from 1081 (69%) patients. The median age range was 54 to 64 years; there was an equal gender split and 57% had their latest treatment decision made within the past year. Overall, 54% of patients felt "very confident" in the latest treatment decision. Patients deemed the most important information to be safety/tolerability and treatment effectiveness, but the latter was among the least frequently received. Most patients reported that their primary physician treating MM was their main source for all types of information (range, 62%-94%), with 87% of patients reporting a "very good" or "good" relationship with them. CONCLUSION: Over half of patients felt very confident in their latest treatment decision; however, patients reported not routinely receiving important treatment effectiveness information. Addressing the discrepancies between information that patients receive and consider important may enhance confidence in decision-making.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

What matters most to patients with multiple myeloma? A Pan-European patient preference study.

Introduction: Given the rapid increase in novel treatments for patients with multiple myeloma (MM), this patient preference study aimed to establish which treatment attributes matter most to MM patients and evaluate discrete choice experiment (DCE) and swing weighting (SW) as two elicitation methods for quantifying patients' preferences. Methods: A survey incorporating DCE and SW was disseminated among European MM patients. The survey included attributes and levels informed by a previous qualitative study with 24 MM patients. Latent class and mixed logit models were used to estimate the DCE attribute weights and descriptive analyses were performed to derive SW weights. MM patients and patient organisations provided extensive feedback during survey development. Results: 393 MM patients across 21 countries completed the survey (M years since diagnosis=6; M previous therapies=3). Significant differences (p<.01) between participants' attribute weights were revealed depending on participants' prior therapy experience, and their experience with side-effects and symptoms. Multivariate analyses showed that participants across the three MM patient classes identified via the latent class model differed regarding their past number of therapies (F=4.772, p=.009). Patients with the most treatments (class 1) and those with the least treatments (class 3) attached more value to life expectancy versus quality of life-related attributes such as pain, mobility and thinking problems. Conversely, patients with intermediary treatment experience (class 2) attached more value to quality of life-related attributes versus life expectancy. Participants highlighted the difficulty of trading-off between life expectancy and quality of life and between physical and mental health. Participants expressed a need for greater psychological support to cope with their symptoms, treatment side-effects, and uncertainties. With respect to patients' preferences for the DCE or SW questions, 42% had no preference, 32% preferred DCE, and 25% preferred SW. Conclusions: Quality of life-related attributes affecting MM patients' physical, mental and psychological health such as pain, mobility and thinking problems were considered very important to MM patients, next to life expectancy. This underscores a need to include such attributes in decision-making by healthcare stakeholders involved in MM drug development, evidence generation, evaluation, and clinical practice. This study highlights DCE as the preferred methodology for understanding relative attribute weights from a patient's perspective.

Patient Preferences for Multiple Myeloma Treatments: A Multinational Qualitative Study.

Background: Investigational and marketed drugs for the treatment of multiple myeloma (MM) are associated with a range of characteristics and uncertainties regarding long term side-effects and efficacy. This raises questions about what matters most to patients living with this disease. This study aimed to understand which characteristics MM patients find most important, and hence should be included as attributes and levels in a subsequent quantitative preference survey among MM patients. Methods: This qualitative study involved: (i) a scoping literature review, (ii) discussions with MM patients (n = 24) in Belgium, Finland, Romania, and Spain using Nominal Group Technique, (iii) a qualitative thematic analysis including multi-stakeholder discussions. Results: MM patients voiced significant expectations and hopes that treatments would extend their lives and reduce their cancer signs and symptoms. Participants however raised concerns about life-threatening side-effects that could cause permanent organ damage. Bone fractures and debilitating neuropathic effects (such as chronic tingling sensations) were highlighted as major issues reducing patients' independence and mobility. Patients discussed the negative impact of the following symptoms and side-effects on their daily activities: thinking problems, increased susceptibility to infections, reduced energy, pain, emotional problems, and vision problems. MM patients were concerned with uncertainties regarding the durability of positive treatment outcomes, and the cause, severity, and duration of their symptoms and side-effects. Patients feared short-term positive treatment responses complicated by permanent, severe side-effects and symptoms. Conclusions: This study gained an in-depth understanding of the treatment and disease-related characteristics and types of attribute levels (severity, duration) that are most important to MM patients. Results from this study argue in favor of MM drug development and individual treatment decision-making that focuses not only on extending patients' lives but also on addressing those symptoms and side-effects that significantly impact MM patients' quality of life. This study underscores a need for transparent communication toward MM patients about MM treatment outcomes and uncertainties regarding their long-term efficacy and safety. Finally, this study may help drug developers and decision-makers understand which treatment outcomes and uncertainties are most important to MM patients and therefore should be incorporated in MM drug development, evaluation, and clinical practice.

Using RIFLE criteria to evaluate acute kidney injury in brain-deceased kidney donors.

BACKGROUND: The limited supply of deceased donors for renal transplantation led to considering alternative strategies for making more organs available. One of these strategies is the use of donors with renal dysfunction, as this is usually a reversible condition. RIFLE (risk, injury, failure, loss and end-stage renal failure) criteria were developed to standardize the definition and severity of acute kidney injury (AKI) but have not been previously used in brain-deceased donors. We applied the RIFLE classification to evaluate renal function changes in our donor pool, in an attempt to know its influence in transplant outcome. METHODS: Data were collected from the renal transplant patient and the intensive care unit brain-dead donors prospectively maintained databases of our hospital. Risk was defined when creatinine increased x1.5, injury when it increased x2 and failure when last creatinine increased x3 with respect to admission-day creatinine. RESULTS: From 176 donors, 10.8% suffered AKI and 7.9% were included in 'risk', 2.3% in 'injury' and 0.6% in 'failure' categories. There were no significant differences between AKI and non-AKI groups in donor and intensive care management variables, except in last-day creatinine. First-day urine volumes were lower (P = 0.043) and delayed graft function rates were higher (P = 0.013) in the AKI group than in the non-AKI group recipients. Graft survival and other outcome variables were not different between AKI and non-AKI recipients. CONCLUSIONS: The RIFLE classification system offers us an opportunity to standardize and quantify renal injury in donors. Although >10% of brain-deceased donors can suffer AKI, these grafts can perform adequately. Hence, the development of AKI in donors cannot be an isolated criterion to discard kidney donation.

Impact of restrictive fluid balance focused to increase lung procurement on renal function after kidney transplantation.

BACKGROUND: Restrictive management of fluid status has been proposed to increase the rates of lung grafts available for transplant. However, no studies have supported the effect of this negative fluid balance in the kidney graft recipients. METHODS: We evaluated the effect of restrictive fluid balance in brain-dead donors and their impact in 404 kidney recipients using Kaplan-Meier curves and Cox regression for long-term effects, and logistic regression for short-term effects. Our primary interest was graft survival and the second was occurrence of delayed graft function (DGF). RESULTS: A negative or equalized fluid balance with a central venous pressure (CVP) <6 mm Hg affects neither graft survival in kidney recipients (P = 0.983) nor the development of DGF (P = 0.573). A positive fluid balance between brain death and organ retrieval does not reduce either the risk of graft survival or the risk of DGF. CONCLUSION: We concluded that restrictive management of fluid balance in a multiorgan donor supports adequate perfusion to vital organ systems even with a CVP <6 mm Hg. A strict fluid balance could avoid volume overload and lung neurogenic oedema, increasing the rate of lung grafts available for transplant without impacting either kidney graft survival or DGF development.

SARS-CoV-2 in Spanish Intensive Care Units: Early experience with 15-day survival in Vitoria.

PURPOSE: Community transmission of SARS-CoV-2 was detected in Spain in February 2020, with 216% intensive care unit (ICU) capacity expanded in Vitoria by March 18th, 2020. METHODS: We identified patients from the two public hospitals in Vitoria who were admitted to ICU with confirmed infection by SARS-CoV-2. Data reported here were available in April 6th, 2020. Mortality was assessed in those who completed 15-days of ICU stay. RESULTS: We identified 48 patients (27 males) with confirmed SARS-CoV-2. Median [interquartile range (IQR)] age of patients was 63 [51-75] years. Symptoms began a median of 7 [5-12] days before ICU admission. The most common comorbidities identified were obesity (48%), arterial hypertension (44%) and chronic lung disease (37%). All patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. Forty-five (94%) underwent intubation, 3 (6%) high flow nasal therapy (HFNT), 1 (2%) extracorporeal membrane oxygenation (ECMO) and 22 (46%) required prone position. After 15 days, 14/45 (31%) intubated patients died (13% within one week), 10/45 (22%) were extubated, and 21/45 (47%) underwent mechanical ventilation. Six patients had documented super-infection. Procalcitonin plasma above 0.5µg/L was associated with 16% vs. 19% (p=0.78) risk of death after 7 days. CONCLUSION: This early experience with SARS-CoV-2 in Spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. Seven-day mortality in SARS-CoV-2 requiring intubation was lower than 15%, with 80% of patients still requiring mechanical ventilation. After 15 days of ICU admission, half of patients remained intubated, whereas one third died.

Propofol-induced deep sedation reduces emotional episodic memory reconsolidation in humans.

The adjustment of maladaptive thoughts and behaviors associated with emotional memories is central to treating psychiatric disorders. Recent research, predominantly with laboratory animals, indicates that memories can become temporarily sensitive to modification following reactivation, before undergoing reconsolidation. A method to selectively impair reconsolidation of specific emotional or traumatic memories in humans could translate to an effective treatment for conditions such as posttraumatic stress disorder. We tested whether deep sedation could impair emotional memory reconsolidation in 50 human participants. Administering the intravenous anesthetic propofol following memory reactivation disrupted memory for the reactivated, but not for a non-reactivated, slideshow story. Propofol impaired memory for the reactivated story after 24 hours, but not immediately after propofol recovery. Critically, memory impairment occurred selectively for the emotionally negative phase of the reactivated story. One dose of propofol following memory reactivation selectively impaired subsequent emotional episodic memory retrieval in a time-dependent manner, consistent with reconsolidation impairment.

Action boosts episodic memory encoding in humans via engagement of a noradrenergic system.

We are constantly interacting with our environment whilst we encode memories. However, how actions influence memory formation remains poorly understood. Goal-directed movement engages the locus coeruleus (LC), the main source of noradrenaline in the brain. Noradrenaline is also known to enhance episodic encoding, suggesting that action could improve memory via LC engagement. Here we demonstrate, across seven experiments, that action (Go-response) enhances episodic encoding for stimuli unrelated to the action itself, compared to action inhibition (NoGo). Functional magnetic resonance imaging, and pupil diameter as a proxy measure for LC-noradrenaline transmission, indicate increased encoding-related LC activity during action. A final experiment, replicated in two independent samples, confirmed a novel prediction derived from these data that emotionally aversive stimuli, which recruit the noradrenergic system, modulate the mnemonic advantage conferred by Go-responses relative to neutral stimuli. We therefore provide converging evidence that action boosts episodic memory encoding via a noradrenergic mechanism.

Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

CONTEXT: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. OBJECTIVE: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. DESIGN: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. RESULTS: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. CONCLUSIONS: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

[Feasibility and results of the short Diet Quality Screener in Primary Care: EMAP study]. / Viabilidad y resultados de un cuestionario breve de calidad dietética en atención primaria: estudio EMAP.

OBJECTIVE: To study the feasibility and results of the self-reported short diet quality screener (sDQS) in Primary Care. The variables associated with difficulty and inadequate diet are also determined. METHOD: Cross-sectional descriptive study conducted with 196 participants aged >18 years with diabetes mellitus, hypertension, or hypercholesterolaemia, consecutively included from 4 Primary Health Care Centres in Barcelona. The main variables collected were, age, sex, educational level, cardiovascular risk factors, body mass index, time to complete the sDQS, degree of difficulty, and diet score: inadequate diet ≤18, adequate in some aspects 19-27, adequate >27. RESULTS: The mean age was 48.8 years (52% males). The analysis of the variables showed that the prevalence of having higher than a primary education level, hypertension, diabetes, hypercholesterolemia, and obesity was 50%, 54.6%, 23.5%, 56.6%, and 27.5%, respectively. The mean time to complete the questionnaire was 2.3min. More than 80% considered it easy or very easy. An inadequate diet was reported by 21.4%, adequate in some aspects by 76.5%, and an adequate diet only by 2%. To be older than 49 years and a low diet quality increased the risk of needing ≥2min to complete the sDQS (OR 2.0, 95% CI; 1.0-4.3, and OR 2.3, 95% CI; 1.1-5.1, respectively). Not following a low cholesterol diet and age less than 49 years increased the risk of a low diet quality (OR 2.2; 95% CI: 1.1-4.5, and OR 2.9; 95% CI: 1.2-6.8, respectively). CONCLUSIONS: The completion of the sDQS is easy and was not a significant time-burden in Primary Care. A significant proportion of participants with cardiovascular risk reported a low diet quality.

The neural correlates of emotional face-processing in adolescent depression: a dimensional approach focusing on anhedonia and illness severity.

Deficits in emotion processing, a known clinical feature of major depressive disorder (MDD), have been widely investigated using emotional face paradigms and neuroimaging. However, most studies have not accounted for the high inter-subject variability of symptom severity. Similarly, only sparse research has focused on MDD in adolescence, early in the course of the illness. Here we sought to investigate neural responses to emotional faces using both categorical and dimensional analyses with a focus on anhedonia, a core symptom of MDD associated with poor outcomes. Nineteen medication-free depressed adolescents and 18 healthy controls (HC) were scanned during presentation of happy, sad, fearful, and neutral faces. ANCOVAs and regressions assessed group differences and relationships with illness and anhedonia severity, respectively. Findings included a group by valence interaction with depressed adolescents exhibiting decreased activity in the superior temporal gyrus (STG), putamen and premotor cortex. Post-hoc analyses confirmed decreased STG activity in MDD adolescents. Dimensional analyses revealed associations between illness severity and altered responses to negative faces in prefrontal, cingulate, striatal, and limbic regions. However, anhedonia severity was uniquely correlated with responses to happy faces in the prefrontal, cingulate, and insular regions. Our work highlights the need for studying specific symptoms dimensionally in psychiatric research.

A preliminary study of white matter in adolescent depression: relationships with illness severity, anhedonia, and irritability.

Major depressive disorder (MDD) during adolescence is a common and disabling psychiatric condition; yet, little is known about its neurobiological underpinning. Evidence indicates that MDD in adults involves alterations in white and gray matter; however, sparse research has focused on adolescent MDD. Similarly, little research has accounted for the wide variability of symptom severity among depressed teens. Here, we aimed to investigate white matter (WM) microstructure between 17 adolescents with MDD and 16 matched healthy controls (HC) using diffusion tensor imaging. We further assessed within the MDD group relationships between WM integrity and depression severity, as well as anhedonia and irritability - two core symptoms of adolescent MDD. As expected, adolescents with MDD manifested decreased WM integrity compared to HC in the anterior cingulum and anterior corona radiata. Within the MDD group, greater depression severity was correlated with reduced WM integrity in the genu of corpus callosum, anterior thalamic radiation, anterior cingulum, and sagittal stratum. However, anhedonia and irritability were associated with alterations in distinct WM tracts. Specifically, anhedonia was associated with disturbances in tracts related to reward processing, including the anterior limb of the internal capsule and projection fibers to the orbitofrontal cortex. Irritability was associated with decreased integrity in the sagittal stratum, anterior corona radiata, and tracts leading to prefrontal and temporal cortices. Overall, these preliminary findings provide further support for the hypotheses that there is a disconnect between prefrontal and limbic emotional regions in depression, and that specific clinical symptoms involve distinct alterations in WM tracts.