Pancreatic exocrine insufficiency following pancreatoduodenectomy: A prospective bi-center study.

BACKGROUND/OBJECTIVES: Pancreatic exocrine insufficiency (PEI) is a common complication following pancreatoduodenectomy (PD) leading to malnutrition. The course of PEI and related symptoms and vitamin deficiencies is unknown. This study aimed to assess the (long-term) incidence of PEI and vitamin deficiencies after PD. METHODS: A bi-centre prospective observational cohort study was performed, including patients who underwent PD for mainly pancreatic and periampullary (pre)malignancies (2014-2018). Two cohorts were formed to evaluate short and long-term results. Patients were followed for 18 months and clinical symptoms were evaluated by questionnaire. PEI was based on faecal elastase-1 (FE-1) levels and/or clinical symptoms. RESULTS: In total, 95 patients were included. After three months, all but three patients had developed PEI and 27/29 (93%) patients of whom stool samples were available showed abnormal FE-1 levels, which did not improve during follow-up. After six months, all patients had developed PEI. During follow-up, symptoms resolved in 35%-70% of patients. Vitamin D and K deficiencies were observed in 48%-79% of patients, depending on the moment of follow-up; 0%-50% of the patients with deficiencies received vitamin supplementation. DISCUSSION: This prospective study found a high incidence of PEI after PD with persisting symptoms in one-to two thirds of all patients. Limited attention was paid to vitamin deficiencies. Improved screening and treatment strategies for PEI and vitamins need to be designed.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Brain activity and connectivity changes in response to glucose ingestion.

Objectives: The regulatory role of the brain in directing eating behavior becomes increasingly recognized. Although many areas in the brain have been found to respond to food cues, very little data is available after actual caloric intake. The aim of this study was to determine normal whole brain functional responses to ingestion of glucose after an overnight fast.Methods: Twenty-five normal weight, adult males underwent functional MRI on two separate visits. In a single-blind randomized study setup, participants received either glucose solution (50 g/300 ml of water) or plain water. We studied changes in Blood Oxygen Level Dependent (BOLD) signal, voxel-based connectivity by Eigenvector Centrality Mapping, and functional network connectivity.Results: Ingestion of glucose led to increased centrality in the thalamus and to decreases in BOLD signal in various brain areas. Decreases in connectivity in the sensory-motor and dorsal visual stream networks were found. Ingestion of water resulted in increased centrality across the brain, and increases in connectivity in the medial and lateral visual cortex network. Increased BOLD intensity was found in the intracalcarine and cingulate cortex.Discussion: Our data show that ingestion of glucose leads to decreased activity and connectivity in brain areas and networks linked to energy seeking and satiation. In contrast, drinking plain water leads to increased connectivity probably associated with continued food seeking and unfulfilled reward.Trail registration: This study combines data of two studies registered at clinicaltrails.gov under numbers NCT03202342 and NCT03247114.

Effect of flavor on neuronal responses of the hypothalamus and ventral tegmental area.

Although it is well known that food intake is affected by the palatability of food, the actual effect of flavoring on regulation of energy-homeostasis and reward perception by the brain, remains unclear. We investigated the effect of ethyl-butyrate (EB), a common non-caloric food flavoring, on the blood oxygen level dependent (BOLD) response in the hypothalamus (important in regulating energy homeostasis) and ventral tegmental area (VTA; important in reward processes). The 16 study participants (18-25 years, BMI 20-23 kg/m2) drank four study stimuli on separate visits using a crossover design during an fMRI setup in a randomized order. The stimuli were; plain water, water with EB, glucose solution (50gram/300 ml) and glucose solution with EB. BOLD responses to ingestion of the stimuli were determined in the hypothalamus and VTA as a measure of changes in neuronal activity after ingestion. In the hypothalamus and VTA, glucose had a significant effect on the BOLD response but EB flavoring did not. Glucose with and without EB led to similar decrease in hypothalamic BOLD response and glucose with EB resulted in a decrease in VTA BOLD response. Our results suggest that the changes in neuronal activity in the hypothalamus are mainly driven by energy ingestion and EB does not influence the hypothalamic response. Significant changes in VTA neuronal activity are elicited by energy combined with flavor.

General psychopathology factor and unresolved-disorganized attachment uniquely correlated to white matter integrity using diffusion tensor imaging.

BACKGROUND: A dimensional approach of psychopathology focuses on features and risk factors that are shared across diagnoses. In support for this dimensional approach, studies point to a general psychopathology factor (GPF) associated with risk for multiple psychiatric disorders. It is, however, unknown how GPF relates to white matter integrity (WMI). In the current diffusion tensor imaging (DTI) study, we examined how GPF relates to abnormalities in a skeleton representation of white matter tracts, taking into account a trans-diagnostic risk factor: unresolved-disorganized attachment (Ud) resulting from loss or trauma. METHODS: Unique associations between GPF, Ud, and WMI were examined in a combined sample of adolescents (N = 63) with childhood sexual abuse-related posttraumatic stress disorder (N = 18), anxiety and depressive disorders (N = 26) and without psychiatric disorder (N = 19). WMI was measured using DTI. Ud was measured using the Adult Attachment Interview. We controlled for puberty stage, gender, age, and IQ. RESULTS: Controlling for GPF, Ud was associated with reduced fractional anisotropy (FA) in the splenium and inferior fronto-occipital fasciculus (IFOF). Controlling for Ud, GPF was associated with reduced FA in the genu and body of the corpus callosum. CONCLUSIONS: Decreasing WMI in the genu and body with increasing psychopathology across diagnoses suggests demyelinization in these areas and may underlie comorbidity and presence of symptoms that transcend psychopathological diagnoses. In contrast, trauma-related WMI reductions in the splenium and IFOF may account for heterogeneity within diagnostic categories as a function of childhood trauma. These findings support the importance of a dimensional approach in addition to traditional diagnostic classifications in clinical research and practice.

Dietary sugars and non-caloric sweeteners elicit different homeostatic and hedonic responses in the brain.

OBJECTIVE: The brain is essential in regulating intake of food and beverages by balancing energy homeostasis, which is regulated by the hypothalamus, with reward perception, which is regulated by the ventral tegmental area (VTA). The aim of this study was to investigate the effects of ingestion of glucose, fructose, sucrose, and sucralose (a non-caloric artificial sweetener) on the magnitude and trajectory of the hypothalamic and the VTA blood oxygen level-dependent (BOLD) responses. METHOD: In five visits, 16 healthy men between 18 to 25 y of age with a body mass index between 20 and 23 kg/m2 drank five interventions in a randomized order while a functional magnetic resonance imaging scan was taken. The interventions consisted of 50 g of glucose, fructose, or sucrose, or 0.33 g of sucralose dissolved in 300 mL tap water. The control condition consisted of 300 mL of plain tap water. BOLD signals were determined in the hypothalamus and the VTA within a manually drawn region of interest. Differences in changes in BOLD signal between stimuli were analyzed using mixed models. RESULTS: Compared with the control condition, a decrease in BOLD signal in the hypothalamus was found after ingestion of glucose (P = 0.0003), and a lesser but delayed BOLD response was found after ingestion of sucrose (P = 0.006) and fructose (P = 0.003). Sucralose led to a smaller and transient response from the hypothalamus (P = 0.026). In the VTA, sucralose led to a very similar response to the water control condition, leading to an increase in VTA BOLD activity that continued over the measured time period. The natural sugars appeared to only lead to a transient increase in VTA activity. CONCLUSIONS: Glucose induces a deactivation in the hypothalamus immediately after ingestion and continued over the next 12 min, which is correlated with satiety signaling by the brain. Fructose and sucrose are both associated with a delayed and lesser response from the hypothalamus, likely because the sugars first have to be metabolized by the body. Sucralose leads to the smallest and most transient decrease in BOLD in the hypothalamus and leads to a similar response as plain water in the VTA, which indicates that sucralose might not have a similar satiating effect on the brain as the natural sugars.

Long-term effects of stimulant exposure on cerebral blood flow response to methylphenidate and behavior in attention-deficit hyperactivity disorder.

Stimulant prescription rates for attention deficit hyperactivity disorder (ADHD) are increasing, even though potential long-term effects on the developing brain have not been well-studied. A previous randomized clinical trial showed short-term age-dependent effects of stimulants on the DA system. We here assessed the long-term modifying effects of age-of-first-stimulant treatment on the human brain and behavior. 81 male adult ADHD patients were stratified into three groups: 1) early stimulant treatment (EST; <16 years of age) 2) late stimulant treatment (LST: ≥23 years of age) and 3) stimulant treatment naive (STN; no history of stimulant treatment). We used pharmacological magnetic resonance imaging (phMRI) to assess the cerebral blood flow (CBF) response to an oral methylphenidate challenge (MPH, 0.5 mg/kg), as an indirect measure of dopamine function in fronto-striatal areas. In addition, mood and anxiety scores, and recreational drug use were assessed. Baseline ACC CBF was lower in the EST than the STN group (p = 0.03), although CBF response to MPH was similar between the three groups (p = 0.23). ADHD symptom severity was higher in the STN group compared to the other groups (p < 0.01). In addition, the EST group reported more depressive symptoms (p = 0.04), but not anxiety (p = 0.26), and less recreational drug use (p = 0.04). In line with extensive pre-clinical data, our data suggest that early, but not late, stimulant treatment long-lastingly affects the human brain and behavior, possibly indicating fundamental changes in the dopamine system.

Increased brain activation during motor imagery suggests central abnormality in Neonatal Brachial Plexus Palsy.

Neonatal Brachial Plexus Palsy (NBPP) may lead to permanent impairment of arm function. As NBPP occurs when central motor programs develop, these may be ill-formed. We studied elbow flexion and motor imagery with fMRI to search for abnormal motor programming. We compared the cortical activity of adults with conservatively treated NBPP to that of healthy individuals stratified for hand dominance, using fMRI BOLD tasks of elbow flexion and motor imagery of flexion. Additionally, resting-state networks and regional gray matter volume were studied. Sixteen adult NBPP patients (seven men; median age 29 years) and sixteen healthy subjects (seven men, median age 27 years) participated. Cortical activation was significantly higher in patients during flexion imagery compared to healthy individuals and it increased with lesion extent and muscle weakness. The contralateral and ipsilateral premotor cortex, and the contralateral motor cortex showed stronger activity during imagined flexion in the right-handed NBPP subjects compared to healthy individuals. Activity patterns during actual flexion did not differ between groups. No differences in resting-state network connectivity or gray matter amount were found between the groups. NBPP affected imagined but not actual elbow flexion, suggesting an impairment of motor planning which would indicate abnormal motor programming in NBPP.

White matter microstructure of patients with neurofibromatosis type 1 and its relation to inhibitory control.

Neurofibromatosis Type 1 (NF1) is commonly associated with deficits in executive functions such as working memory and inhibitory control. A valid biomarker to describe the pathological basis of these deficits in NF1 is not available. The aim of this study was to investigate whether any abnormalities in white matter integrity of the executive function related anterior thalamic radiation (ATR), cingulate bundle (CB), and superior longitudinal fasciculus (SLF) may be regarded as a pathological basis for inhibitory control deficits in adolescents with NF1. Sixteen NF1 patients and 32 healthy controls underwent 3 T DTI MRI scanning. Whole brain-, ATR-, CB-, and SLF-white matter integrity were studied using fractional anisotropy, mean (MD), radial, and axial (DA) diffusivity. Correlation analyses between white matter metrics and inhibitory control (as measured with a computerized task) were performed. Also, verbal and performance abilities (IQ-estimates) were assessed and correlated with white matter metrics. Patients showed significant whole brain- and local microstructural pathology when compared to healthy controls in all measures. In NF1-patients, whole-brain (MD: r = .646 and DA: r = .673) and ATR- (r-range: -.405-.771), but not the CB- (r-range: -.307-.472) and SLF- (r-range: -.187-.406) white matter integrity, were correlated with inhibitory control. Verbal and performance abilities were not associated with white matter pathology. In NF1, white matter abnormalities are observed throughout the brain, but damage to the ATR seems specifically, or at least most strongly related to inhibitory control. Future studies should examine whether reduced white matter integrity in other brain regions or tracts is (more strongly) associated with different aspects of the cognitive-behavioral phenotype associated with NF1.

FOLFIRINOX in Locally Advanced and Metastatic Pancreatic Cancer: A Single Centre Cohort Study.

Introduction: FOLFIRINOX is emerging as new standard of care for fit patients with locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). However, some of the physicians are reluctant to use FOLFIRINOX due to high toxicity rates reported in earlier studies. We reviewed our experience with FOLFIRINOX in LAPC and MPC, focussing on dose adjustments, toxicity and efficacy. Methods: We reviewed all patients with LAPC or MPC treated with FOLFIRINOX in our institution between April 2011 and December 2015. Unresectability (stage III and IV) was determined by the institution's multidisciplinary team for pancreatic cancer. Results: Fifty patients (18 LAPC and 32 MPC) were enrolled, with a median age of 55 years (IQR 49-66) and WHO performance status of 0/1. FOLFIRINOX was given as first-line treatment in 82% of patients. Dose modifications were applied in 90% of patients. The median number of completed cycles was 8 (IQR 5-9). Grade 3-4 toxicity occurred in 52% and grade 5 toxicity in 2%. The response rate was 25% (12% in LAPC, 32% in MPC). Median overall survival and progression-free survival were 14.8 and 10.3 months in LAPC, and 9.0 and 5.9 months in MPC, respectively. Overall 1- and 2-year survival was 65% and 10% in LAPC and 40% and 5% in MPC. Within the LAPC group, 6 patients (33%) underwent local ablative therapy and 1 patient (6%) a resection, leading to a median survival of 21.8 months. Conclusion: FOLFIRINOX treatment with nearly routine dose modification was associated with acceptable toxicity rates, relatively high response rates and an encouraging overall survival.

Reduced functional connectivity within the primary motor cortex of patients with brachial plexus injury.

This study aims at the effects of traumatic brachial plexus lesion with root avulsions (BPA) upon the organization of the primary motor cortex (M1). Nine right-handed patients with a right BPA in whom an intercostal to musculocutaneous (ICN-MC) nerve transfer was performed had post-operative resting state fMRI scanning. The analysis of empirical functional correlations between neighboring voxels revealed faster correlation decay as a function of distance in the M1 region corresponding to the arm in BPA patients as compared to the control group. No differences between the two groups were found in the face area. We also investigated whether such larger decay in patients could be attributed to a gray matter diminution in M1. Structural imaging analysis showed no difference in gray matter density between groups. Our findings suggest that the faster decay in neighboring functional correlations without significant gray matter diminution in BPA patients could be related to a reduced activity in intrinsic horizontal connections in M1 responsible for upper limb motor synergies.

Is the brain of complex regional pain syndrome patients truly different?

BACKGROUND: In recent years, changes in brain structure and function have been studied extensively in patients with complex regional pain syndrome (CRPS) following clinical observations of altered central processing of sensory stimuli and motor control. However, concerning MRI data, the evidence is complex to interpret due to heterogeneity in statistical methods and results. METHOD: The aim of this study was to determine if CRPS patients exhibit specific, clinically relevant changes in brain structure and function in rest. We do this by presenting MRI data on brain structure and function in 19 chronic, female CRPS patients and age- and sex-matched healthy controls (HCs). In addition, we analyse and report the data in multiple ways to make comparison with previous studies possible and to demonstrate the effect of different statistical methods, in particular, concerning the correction for multiple testing. RESULTS: Using family-wise error (FWE) correction for multiple testing, in our group of CRPS patients, we find no specific difference in brain structure or function in rest in comparison to HCs. In addition, we argue that previously found MRI results in the literature are inconsistent in terms of localization, quantity and directionality of the reported changes in brain structure and function. CONCLUSION: Previously published MRI-based evidence for altered brain structure and function in rest in CRPS patients is not consistent and our data suggests that no such phenomenon exists. WHAT DOES THIS STUDY ADD?: This article does not replicate the previous found results. The reported evidence in MRI literature of aberrant neuroplasticity in CRPS patients is inconsistent in terms of localization, quantity and directionality of changes in brain structure and function.

Investigating distinct and common abnormalities of resting-state functional connectivity in depression, anxiety, and their comorbid states.

Depression and anxiety disorders are highly comorbid and share neurobiological characteristics. However, this is usually not explicitly addressed in studies on intrinsic brain functioning in these disorders. Contrary to previous resting-state reports on small, monodiagnostic subsets of the current sample, we investigated resting-state functional connectivity (RSFC) in medication-free patients with depression, anxiety, comorbid depression and anxiety, and a healthy control group. RSFC was investigated in 140 medication-free subjects: 37 major depressive disorder patients (MDD), 30 patients with one or more anxiety disorders (ANX), 25 patients with MDD and one or more anxiety disorders (COM), and 48 healthy controls (HC). RSFC networks were calculated using a probabilistic independent component analysis. Using a dual regression approach, individuals׳ timecourses were extracted and regressed to obtain subjects-specific spatial maps, which were used for group comparisons in four networks of interest (limbic, default mode, salience and sensory-motor networks). When compared to HC, the COM group showed increased RSFC of the limbic network with a cluster containing the bilateral precuneus, intracalcarine cortex, lingual gyrus, and posterior cingulate, and with a cluster including the right precentral gyrus, inferior frontal gyrus, and middle frontal gyrus. This effect was specific for comorbid depression and anxiety. No abnormal RSFC of other networks or in the MDD and ANX groups was observed. No association was found between strength of RSFC and symptom severity. These results indicate that altered RSFC of cortical regions with a limbic network could be specific for comorbid depression and anxiety.

Obesity is marked by distinct functional connectivity in brain networks involved in food reward and salience.

We hypothesized that brain circuits involved in reward and salience respond differently to fasting in obese versus lean individuals. We compared functional connectivity networks related to food reward and saliency after an overnight fast (baseline) and after a prolonged fast of 48 h in lean versus obese subjects. We included 13 obese (2 males, 11 females, BMI 35.4 ± 1.2 kg/m(2), age 31 ± 3 years) and 11 lean subjects (2 males, 9 females, BMI 23.2 ± 0.5 kg/m(2), age 28 ± 3 years). Resting-state functional magnetic resonance imaging scans were made after an overnight fast (baseline) and after a prolonged 48 h fast. Functional connectivity of the amygdala, hypothalamus and posterior cingulate cortex (default-mode) networks was assessed using seed-based correlations. At baseline, we found a stronger connectivity between hypothalamus and left insula in the obese subjects. This effect diminished upon the prolonged fast. After prolonged fasting, connectivity of the hypothalamus with the dorsal anterior cingulate cortex (dACC) increased in lean subjects and decreased in obese subjects. Amygdala connectivity with the ventromedial prefrontal cortex was stronger in lean subjects at baseline, which did not change upon the prolonged fast. No differences in posterior cingulate cortex connectivity were observed. In conclusion, obesity is marked by alterations in functional connectivity networks involved in food reward and salience. Prolonged fasting differentially affected hypothalamic connections with the dACC and the insula between obese and lean subjects. Our data support the idea that food reward and nutrient deprivation are differently perceived and/or processed in obesity.

Altered cortical-amygdala coupling in social anxiety disorder during the anticipation of giving a public speech.

BACKGROUND: Severe stress in social situations is a core symptom of social anxiety disorder (SAD). Connectivity between the amygdala and cortical regions is thought to be important for emotion regulation, a function that is compromised in SAD. However, it has never been tested if and how this connectivity pattern changes under conditions of stress-inducing social evaluative threat. Here we investigate changes in cortical-amygdala coupling in SAD during the anticipation of giving a public speech. METHOD: Twenty individuals with SAD and age-, gender- and education-matched controls (n = 20) participated in this study. During the functional magnetic resonance imaging (fMRI) session, participants underwent three 'resting-state' fMRI scans: one before, one during, and one after the anticipation of giving a public speech. Functional connectivity between cortical emotion regulation regions and the amygdala was investigated. RESULTS: Compared to controls, SAD participants showed reduced functional integration between cortical emotion regulation regions and the amygdala during the public speech anticipation. Moreover, in SAD participants cortical-amygdala connectivity changes correlated with social anxiety symptom severity. CONCLUSIONS: The distinctive pattern of cortical-amygdala connectivity suggests less effective cortical-subcortical communication during social stress-provoking situations in SAD.

Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with a very poor prognosis. Current palliative (radio)chemotherapy provides only a marginal survival benefit of 2-3 months. Several innovative local ablative therapies have been explored as new treatment options. This systematic review aims to provide an overview of the clinical outcomes of these ablative therapies. METHODS: A systematic search in PubMed, Embase and the Cochrane Library was performed to identify clinical studies, published before 1 June 2014, involving ablative therapies in LAPC. Outcomes of interest were safety, survival, quality of life and pain. RESULTS: After screening 1037 articles, 38 clinical studies involving 1164 patients with LAPC, treated with ablative therapies, were included. These studies concerned radiofrequency ablation (RFA) (7 studies), irreversible electroporation (IRE) (4), stereotactic body radiation therapy (SBRT) (16), high-intensity focused ultrasound (HIFU) (5), iodine-125 (2), iodine-125-cryosurgery (2), photodynamic therapy (1) and microwave ablation (1). All strategies appeared to be feasible and safe. Outcomes for postoperative, procedure-related morbidity and mortality were reported only for RFA (4-22 and 0-11 per cent respectively), IRE (9-15 and 0-4 per cent) and SBRT (0-25 and 0 per cent). Median survival of up to 25·6, 20·2, 24·0 and 12·6 months was reported for RFA, IRE, SBRT and HIFU respectively. Pain relief was demonstrated for RFA, IRE, SBRT and HIFU. Quality-of-life outcomes were reported only for SBRT, and showed promising results. CONCLUSION: Ablative therapies in patients with LAPC appear to be feasible and safe.

Composite fermion-boson mapping for fermionic lattice models.

We present a mapping of elementary fermion operators onto a quadratic form of composite fermionic and bosonic cluster operators. The mapping is an exact isomorphism as long as the physical constraint of one composite particle per cluster is satisfied. This condition is treated on average in a composite particle mean-field approach, which consists of an ansatz that decouples the composite fermionic and bosonic sectors. The theory is tested on the 1D and 2D Hubbard models. Using a Bogoliubov determinant for the composite fermions and either a coherent or Bogoliubov state for the bosons, we obtain a simple and accurate procedure for treating the Mott insulating phase of the Hubbard model with mean-field computational cost.

Amygdala and anterior cingulate resting-state functional connectivity in borderline personality disorder patients with a history of interpersonal trauma.

BACKGROUND: Studies in borderline personality disorder (BPD) have consistently revealed abnormalities in fronto-limbic brain regions during emotional, somatosensory and cognitive challenges. Here we investigated changes in resting-state functional connectivity (RSFC) of three fronto-limbic core regions of specific importance to BPD. METHOD: Functional magnetic resonance imaging data were acquired in 20 unmedicated female BPD patients and 17 healthy controls (HC, matched for age, sex and education) during rest. The amygdala, and the dorsal and ventral anterior cingulate cortex (ACC) were defined as seeds to investigate RSFC patterns of a medial temporal lobe network, the salience network and default mode network. The Dissociation Experience Scale (DES), a measure of trait dissociation, was additionally used as a predictor of RSFC with these seed regions. RESULTS: Compared with HC, BPD patients showed a trend towards increased RSFC between the amygdala and the insula, orbitofrontal cortex and putamen. Compared with controls, patients furthermore exhibited diminished negative RSFC between the dorsal ACC and posterior cingulate cortex, a core region of the default mode network, and regions of the dorsomedial prefrontal cortex. Last, increased negative RSFC between the ventral ACC and medial occipital regions was observed in BPD patients. DES scores were correlated with amygdala connectivity with the dorsolateral prefrontal cortex and fusiform gyrus. CONCLUSIONS: Our findings suggest alterations in resting-state networks associated with processing of negative emotions, encoding of salient events, and self-referential processing in individuals with BPD compared with HC. These results shed more light on the role of abnormal brain connectivity in BPD.

Altered white-matter architecture in treatment-naive adolescents with clinical depression.

BACKGROUND: Depressive disorders are highly prevalent in adolescence and confer a heightened risk of recurrence in adulthood. Insight into the developmental neurocircuitry of depression could advance our understanding of depression and aid the development of effective treatment strategies. Whereas white-matter (WM) abnormalities are strongly implicated in adult depression, we still lack a firm understanding of WM architecture in adolescent depression. Using diffusion tensor imaging (DTI), we set out to investigate WM microstructure in a sample of clinically depressed adolescents relative to matched controls. METHOD: We employed tract-based spatial statistics (TBSS) to examine WM microstructure in 25 treatment-naive adolescents with clinical depression relative to 21 matched controls. Using TBSS, we examined fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD). Threshold-free cluster enhancement (TFCE) with family-wise error (FWE) correction was used to control for multiple comparisons. RESULTS: Our analysis revealed abnormal WM microstructure in clinically depressed adolescents. More specifically, whole-brain analysis revealed that patients had lower FA values in the body of the corpus callosum (CC), coupled with elevated RD and MD, and preserved AD. Conversely, region-of-interest analysis revealed that patients had higher FA values in the uncinate fasciculus (UF), coupled with elevated AD, reduced RD and preserved MD. CONCLUSIONS: In line with neurocircuitry models of depression, our findings suggest that WM abnormalities within pathways facilitating cognitive and emotional functioning are involved in the pathophysiology of depression. Importantly, our findings show that these WM abnormalities are already present early in the course of the disorder.

Resting-state functional connectivity in adults with childhood emotional maltreatment.

BACKGROUND: Childhood emotional maltreatment (CEM) has been associated with disturbances in emotional and behavioral functioning, and with changes in regional brain morphology. However, whether CEM has any effect on the intrinsic organization of the brain is not known. In this study, we investigated the effects of CEM on resting-state functional connectivity (RSFC) using seeds in the limbic network, the default-mode network (DMN) and the salience network, and the left dorsomedial prefrontal cortex (dmPFC). Method Using 3-T magnetic resonance imaging (MRI), resting-state functional MRI (RS-fMRI) scans were obtained. We defined seeds in the bilateral amygdala, the dorsal anterior cingulate cortex (dACC), the posterior cingulate cortex (PCC) and the left dmPFC, and used these to examine whether individuals reporting CEM (n=44) differed from individuals reporting no CEM (n=44) in RSFC with other brain regions. The two groups were matched for age, gender, handedness and the presence of psychopathology. RESULTS: CEM was associated with decreased RSFC between the right amygdala and the bilateral precuneus and a cluster extending from the left insula to the hippocampus and putamen. In addition, CEM was associated with decreased RSFC between the dACC and the precuneus and also frontal regions of the brain. CONCLUSIONS: We found that CEM has a profound effect on RSFC in the limbic network and the salience network. Regions that show aberrant connectivity are related to episodic memory encoding, retrieval and self-processing operations.