Karenia brevis Extract Induces Cellular Entry through Distinct Mechanisms in Phagocytic RAW 264.7 Macrophages versus Non-Phagocytic Vero Cells.

Marine algae extracts are an important area of potential drug discovery; however, nearly all studies to date have used non-fluorescent-based methods to determine changes in target cell activity. Many of the most robust immunological and cellular analyses rely on fluorescent probes and readouts, which can be problematic when the algae extract is fluorescent itself. In this study, we identified the fluorescent spectrum of an isolated extract from the marine dinoflagellate Karenia brevis, which included two fluorescing components: chlorophyll α and pheophytin α. When excited at 405 nm and 664 nm, the extract emitted fluorescence at 676 nm and 696 nm, respectively. The extract and its fluorescing components, chlorophyll α and pheophytin α, entered phagocytic RAW 264.7 macrophages and non-phagocytic Vero kidney cells through distinct mechanisms. When incubated with the extract and its main components, both the RAW 264.7 macrophages and the Vero cells accumulated fluorescence as early as 30 min and continued through 48 h. Vero kidney cells accumulated the K. brevis fluorescent extract through a dynamin-independent and acidified endosomal-dependent mechanism. RAW 264.7 macrophages accumulated fluorescent extract through a dynamin-independent, acidified endosomal-independent mechanism, which supports accumulation through phagocytosis. Furthermore, RAW 264.7 macrophages downregulated cell-surface expression of CD206 in response to extract stimulation indicating activation of phagocytic responses and potential immunosuppression of these immune cells. This study represents the first characterization of the cellular update of K. brevis extracts in phagocytic versus non-phagocytic cells. The data suggest the importance of understanding cellular uptake of fluorescing algae extracts and their mechanism of action for future drug discovery efforts.

Immune Modulating Brevetoxins: Monocyte Cytotoxicity, Apoptosis, and Activation of M1/M2 Response Elements Is Dependent on Reactive Groups.

Brevetoxins are a suite of marine neurotoxins that activate voltage-gated sodium channels (VGSCs) in cell membranes, with toxicity occurring from persistent activation of the channel at high doses. Lower doses, in contrast, have been shown to elicit neuroregeneration. Brevetoxins have thus been proposed as a novel treatment for patients after stroke, when neuron regrowth and repair is critical to recovery. However, findings from environmental exposures indicate that brevetoxins may cause inflammation, thus, there is concern for brevetoxins as a stroke therapy given the potential for neuroinflammation. In this study, we examined the inflammatory properties of several brevetoxin analogs, including those that do and do not bind strongly to VGSCs, as binding has classically indicated toxicity. We found that several analogs are toxic to monocytes, while others are not, and the degree of toxicity is not directly related to VGSC binding. Rather, results indicate that brevetoxins containing aldehyde groups were more likely to cause immunotoxicity, regardless of binding affinity to the VGSC. Our results demonstrate that different brevetoxin family members can elicit a spectrum of apoptosis and necrosis by multiple possible mechanisms of action in monocytes. As such, care should be taken in treating "brevetoxins" as a uniform group, particularly in stroke therapy research.

Integrating Community Health Workers into Safety-Net Primary Care for Diabetes Prevention: Qualitative Analysis of Clinicians' Perspectives.

BACKGROUND: Evidence shows community health workers (CHWs) can effectively deliver proven behavior-change strategies to prevent type 2 diabetes mellitus (diabetes) and enhance preventive care efforts in primary care for minority and low-income populations. However, operational details to integrate CHWs into primary care practice remain less well known. OBJECTIVE: To examine clinicians' perceptions about working with CHWs for diabetes prevention in safety-net primary care. SETTING: Clinicians are primary care physicians and nurses at two New York City safety-net hospitals participating in CHORD (Community Health Outreach to Reduce Diabetes). CHORD is a cluster-randomized trial testing a CHW intervention to prevent diabetes. DESIGN: Guided by the Consolidated Framework for Implementation Research, we studied how features of the CHW model and organizational context of the primary care practices influenced clinicians' perspectives about the acceptability, appropriateness, and feasibility of a diabetes-prevention CHW program. Data were collected pre-intervention using semi-structured interviews (n = 18) and a 20-item survey (n = 54). APPROACH: Both survey and interview questions covered clinicians' perspectives on diabetes prevention, attitudes and beliefs about CHWs' role, expectations in working with CHWs, and use of clinic- and community-based diabetes- prevention resources. Survey responses were descriptively analyzed. Interviews were coded using a mix of deductive and inductive approaches for thematic analysis. KEY RESULTS: Eighty-seven percent of survey respondents agreed CHWs could help in preventing diabetes; 83% reported interest in working with CHWs. Ninety-one percent were aware of clinic-based prevention resources; only 11% were aware of community resources. Clinicians supported CHWs' cultural competency and neighborhood reach, but expressed concerns about the adequacy of CHWs' training; public and professional emphasis on diabetes treatment over prevention; and added workload and communication with CHWs. CONCLUSIONS: Clinicians found CHWs appropriate for diabetes prevention in safety-net settings. However, disseminating high-quality evidence about CHWs' effectiveness and operations is needed to overcome concerns about integrating CHWs in primary care.

Brain differences between persistent and remitted attention deficit hyperactivity disorder.

Previous resting state studies examining the brain basis of attention deficit hyperactivity disorder have not distinguished between patients who persist versus those who remit from the diagnosis as adults. To characterize the neurobiological differences and similarities of persistence and remittance, we performed resting state functional magnetic resonance imaging in individuals who had been longitudinally and uniformly characterized as having or not having attention deficit hyperactivity disorder in childhood and again in adulthood (16 years after baseline assessment). Intrinsic functional brain organization was measured in patients who had a persistent diagnosis in childhood and adulthood (n = 13), in patients who met diagnosis in childhood but not in adulthood (n = 22), and in control participants who never had attention deficit hyperactivity disorder (n = 17). A positive functional correlation between posterior cingulate and medial prefrontal cortices, major components of the default-mode network, was reduced only in patients whose diagnosis persisted into adulthood. A negative functional correlation between medial and dorsolateral prefrontal cortices was reduced in both persistent and remitted patients. The neurobiological dissociation between the persistence and remittance of attention deficit hyperactivity disorder may provide a framework for the relation between the clinical diagnosis, which indicates the need for treatment, and additional deficits that are common, such as executive dysfunctions.

Clinical Features and Outcomes of Black Patients With Melanoma.

Importance: Melanoma in Black individuals has an annual incidence of approximately 1 in 100 000 people. Most studies of melanoma in Black patients have used population databases, which lack important, precise clinical details. Objective: To identify patient-level and tumor-level characteristics of melanoma in Black patients. Design, Setting, and Participants: This case series included Black patients with melanoma at 2 tertiary care centers (University of Texas Southwestern [UTSW] Medical Center and Parkland Health), affiliated with a single institution, UTSW in Dallas, Texas. Self-reported Black patients with a histopathologic diagnosis of melanoma were identified between January 2006 and October 2022. Main Outcomes and Measures: The main variables were demographics, clinical characteristics, personal and family medical history, immunosuppression history, comorbidities, histopathology reports, molecular/genetic studies, imaging reports, melanoma treatments and responses, time to progression, metastatic sites, and survival rates. Results: A total of 48 Black patients with melanoma (median [range] age at diagnosis, 62 [23-86] years; 30 [63%] female) were included in the study. Of 40 primary cutaneous melanomas, 30 (75%) were located on acral skin, despite only 10 of 30 (33%) being histologically classified as acral lentiginous melanomas. Compared with those with acral disease, patients with nonacral cutaneous melanomas were more likely to be immunocompromised (4 of 10 [40%] vs 2 of 30 [7%]) or have a personal history of cancer (6 of 10 [60%] vs 5 of 30 [17%]), with all 3 patients with superficial spreading melanoma having a history of both. No patients had more than 1 confirmed primary melanoma. Overall, 13 Black patients (27%) with melanoma developed stage IV disease, of whom 12 died because of disease progression. Those diagnosed with advanced acral melanoma, mucosal/ocular melanoma, or melanoma of unknown primary lacked actionable sequence variations, were nonresponsive to immunotherapy, and had the poorest outcomes. No patients with nonacral cutaneous melanomas developed distant metastases or died of melanoma. Conclusions and Relevance: This single-institution case series highlights several features of melanoma in Black patients that have not been captured in existing population-level registries, including precise anatomic sites, immune status, family and personal cancer history, and genetics. Multi-institutional registries would improve understanding of melanoma in Black patients.

Further understanding of the comorbidity between Attention-Deficit/Hyperactivity Disorder and bipolar disorder in adults: an MRI study of cortical thickness.

Although Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) frequently co-occur and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this comorbidity is scarce. Our aim was to evaluate cortical thickness in ADHD and BPD, testing the hypothesis that comorbid subjects (ADHD+BPD) would have neuroanatomical correlates of both disorders. Magnetic Resonance Imaging (MRI) findings were compared between 31 adults with ADHD+BPD, 18 with BPD, 26 with ADHD, and 23 healthy controls. Cortical thickness analysis of regions of interest was estimated as a function of ADHD and BPD status, using linear regression models. BPD was associated with significantly thicker cortices in 13 regions, independently of ADHD status and ADHD was associated with significantly thinner neocortical gray matter in 28 regions, independent of BPD. In the comorbid state of ADHD plus BPD, the profile of cortical abnormalities consisted of structures that are altered in both disorders individually. Results support the hypothesis that ADHD and BPD independently contribute to cortical thickness alterations of selective and distinct brain structures, and that the comorbid state represents a combinatory effect of the two. Attention to comorbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings.

OBJECTIVES: In this report, we seek to (i) identify a potential neuroimaging endophenotype for bipolar disorder (BD) in emotion regulatory and autonomic circuitry in young first-degree relatives of persons with BD; and (ii) replicate our previous work identifying the functional neuroanatomy of working memory (WM) in an older sample of relatives of persons with BD. METHODS: Ten adolescent and young adult (age 13-24) unmedicated, non-ill, first-degree relatives of persons with BD (RELS) and 10 demographically comparable healthy controls performed a 2-back WM task and a 0-back control task during functional magnetic resonance imaging (fMRI). fMRI data were collected on a 1.5 Tesla scanner and analyzed using SPM-2. Mood was assessed on the day of scanning. RESULTS: The groups did not differ on any demographic, neuropsychological, or in-scanner task performance variables. In contrast to controls, RELS showed (i) weak task-dependent modulation activity in the cerebellar vermis (CV), insula, and amygdala/parahippocampal region, and (ii) exaggerated modulation of activity in the frontopolar cortex and brainstem, even after controlling for potential confounders. Many of the group differences were driven by differences in activity in the low-level (0-back) baseline task. CONCLUSIONS: Young, unmedicated RELS exhibited altered task-dependent modulation of frontopolar, CV, and insula activity during WM, especially during the low-level (0-back) baseline task. Results are largely consistent with our initial study of older adult RELS, suggesting these alterations may represent biomarkers of genetic risk for BD.

Relationship of DAT1 and adult ADHD to task-positive and task-negative working memory networks.

Alterations in working memory, default-mode network (DMN), and dopamine transporter have all been proposed as endophenotypes for attention-deficit/hyperactivity disorder (ADHD). Despite evidence that these systems are interrelated, their relationship to each other has never been studied in the context of ADHD. In order to understand the potential mediating effects of task-positive and task-negative networks between DAT1 and diagnosis, we tested effects of genotype and diagnosis on regions of positive and negative BOLD signal change (as measured with fMRI) in 53 adults with ADHD and 38 control subjects during a working memory task. We also examined the relationship of these responses to ADHD symptoms. Our results yielded four principal findings: 1) association of the DAT1 9R allele with adult ADHD, 2) marginal DAT1 association with task-related suppression in left medial PFC, 3) marginal genotype×diagnosis interaction in the dorsal anterior cingulate cortex, and 4) correlation of DMN suppression to ADHD symptoms. These findings replicate the association of the 9R allele with adult ADHD. Further, we show that DMN suppression is likely linked to DAT1 and to severity of inattention in ADHD. DMN may therefore be a target of DAT1 effects, and lie on the path between the gene and inattention in ADHD.

Effect of dopamine transporter gene (SLC6A3) variation on dorsal anterior cingulate function in attention-deficit/hyperactivity disorder.

Although attention-deficit/hyperactivity disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3' untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the multi-source interference task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3' UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 9R allele. Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples.

Attention and executive systems abnormalities in adults with childhood ADHD: A DT-MRI study of connections.

Attention-deficit/hyperactivity disorder (ADHD) is hypothesized to be due, in part, to structural defects in brain networks influencing cognitive, affective, and motor behaviors. Although the current literature on fiber tracts is limited in ADHD, gray matter abnormalities suggest that white matter (WM) connections may be altered selectively in neural systems. A prior study (Ashtari et al. 2005), using diffusion tensor magnetic resonance imaging (DT-MRI), showed alterations within the frontal and cerebellar WM in children and adolescents with ADHD. In this study of adults with childhood ADHD, we hypothesized that fiber pathways subserving attention and executive functions (EFs) would be altered. To this end, the cingulum bundle (CB) and superior longitudinal fascicle II (SLF II) were investigated in vivo in 12 adults with childhood ADHD and 17 demographically comparable unaffected controls using DT-MRI. Relative to controls, the fractional anisotropy (FA) values were significantly smaller in both regions of interest in the right hemisphere, in contrast to a control region (the fornix), indicating an alteration of anatomical connections within the attention and EF cerebral systems in adults with childhood ADHD. The demonstration of FA abnormalities in the CB and SLF II in adults with childhood ADHD provides further support for persistent structural abnormalities into adulthood.

Intraoperative Pancreatic Ductoscopy for Ampullary Adenocarcinoma During Pancreatic Resection: A Case Report.

Background: Periampullary neoplasms can be challenging to work up and diagnose preoperatively. Herein, we report the case of a patient whose preoperative workup failed to detect a malignancy, yet, underwent a pylorus-preserving pancreaticoduodenectomy (PPPD) with intraoperative pancreatic ductoscopy (IPD) and was ultimately found to have an ampullary adenocarcinoma. Presentation: A 78-year-old woman presented with 4 weeks of nausea, weight loss, jaundice, and light-colored stools. She underwent outpatient diagnostic studies, including magnetic resonance cholangiopancreatography, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography with pancreatic duct (PD) stenting and papillotomy. These revealed common bile duct dilatation measuring 2 cm, PD dilatation measuring 7 mm, a 17 mm cyst in the head of the pancreas, and a firm nodule noted between the biliary and pancreatic orifices. Cytologic and pathologic analyses were initially nondiagnostic. A repeat ampullary biopsy was negative for dysplasia and malignancy. A computed tomography scan was then performed and showed cystic pancreatic lesions with pancreatic ductal dilation. Suspicion remained high for periampullary tumor or a main duct intraductal papillary mucinous neoplasm, and the patient underwent a PPPD with IPD and tolerated the procedure well. Her final specimen pathology revealed well-to-moderately differentiated ampullary adenocarcinoma, pancreaticobiliary type with positive nodal disease. Conclusions: Given the relatively poor prognosis of patients with node-positive pancreaticobiliary-type ampullary adenocarcinoma, clinical suspicion should remain high for malignancy in patients with lesions located in the periampullary region and a negative preoperative workup, as aggressive treatment approaches are warranted to maximize their chance for survival.

A preliminary study of dopamine D4 receptor genotype and structural brain alterations in adults with ADHD.

An emerging literature has demonstrated an association between the dopamine D4 receptor (DRD4) gene and volumetric brain abnormalities in children with ADHD. However, these results have not been extended to adults and have not addressed the impact of comorbidity. Our objective was to examine the DRD4 7R gene and volumetric brain abnormalities in adults with ADHD while accounting for comorbidity with bipolar disorder (BPD). Subjects were male and female adult outpatient referrals stratified into two diagnostic groups: 24 with ADHD, 19 with ADHD and BPD, as well as 20 male and female adult community controls without ADHD or BPD. We measured volumes (cm(3)) of a priori selected brain regions (superior frontal, middle frontal, anterior cingulate, and cerebellum cortices) by structural magnetic resonance imaging. Among adults with ADHD, subjects with the 7-repeat allele of the DRD4 gene had a significantly smaller mean volume in the superior frontal cortex and cerebellum cortex compared to subjects without this allele. In contrast, no such effects were detected in the adults with ADHD + BPD or controls. Our findings suggest that volumetric abnormalities in the dorsolateral prefrontal cortex and cerebellum may represent an intermediate neuroanatomical phenotype between DRD4 genotype and the clinical expression of ADHD in adults, but only in ADHD subjects without comorbid BPD. These result support the heterogeneity of ADHD and provides insights as to its underlying pathophysiology.

Hypoxic Stress Decreases c-Myc Protein Stability in Cardiac Progenitor Cells Inducing Quiescence and Compromising Their Proliferative and Vasculogenic Potential.

Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, evidence suggests that their regenerative capacity may be limited in conditions of severe hypoxia. Elucidating the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential. We investigated the effects of hypoxic stress on CPCs and found significant reduction in proliferation and impairment of vasculogenesis, which were associated with induction of quiescence, as indicated by accumulation of cells in the G0-phase of the cell cycle and growth recovery when cells were returned to normoxia. Induction of quiescence was associated with a decrease in the expression of c-Myc through mechanisms involving protein degradation and upregulation of p21. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, also triggering quiescence. Surprisingly, these effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions.

Dissociation of working memory impairments and attention-deficit/hyperactivity disorder in the brain.

Prevailing neuropsychological models of attention-deficit/hyperactivity disorder (ADHD) propose that ADHD arises from deficits in executive functions such as working memory, but accumulating clinical evidence suggests a dissociation between ADHD and executive dysfunctions. This study examined whether ADHD and working memory capacity are behaviorally and neurobiologically separable using functional magnetic resonance imaging (fMRI). Participants diagnosed with ADHD in childhood who subsequently remitted or persisted in their diagnosis as adults were characterized at follow-up in adulthood as either impaired or unimpaired in spatial working memory relative to controls who never had ADHD. ADHD participants with impaired spatial working memory performed worse than controls and ADHD participants with unimpaired working memory during an n-back working memory task while being scanned. Both controls and ADHD participants with unimpaired working memory exhibited significant linearly increasing activation in the inferior frontal junction, precuneus, lingual gyrus, and cerebellum as a function of working-memory load, and these activations did not differ significantly between these groups. ADHD participants with impaired working memory exhibited significant hypoactivation in the same regions, which was significantly different than both control participants and ADHD participants with unimpaired working memory. These findings support both a behavioral and neurobiological dissociation between ADHD and working memory capacity.

Altered Intrinsic Functional Brain Architecture in Children at Familial Risk of Major Depression.

BACKGROUND: Neuroimaging studies of patients with major depression have revealed abnormal intrinsic functional connectivity measured during the resting state in multiple distributed networks. However, it is unclear whether these findings reflect the state of major depression or reflect trait neurobiological underpinnings of risk for major depression. METHODS: We compared resting-state functional connectivity, measured with functional magnetic resonance imaging, between unaffected children of parents who had documented histories of major depression (at-risk, n = 27; 8-14 years of age) and age-matched children of parents with no lifetime history of depression (control subjects, n = 16). RESULTS: At-risk children exhibited hyperconnectivity between the default mode network and subgenual anterior cingulate cortex/orbital frontal cortex, and the magnitude of connectivity positively correlated with individual symptom scores. At-risk children also exhibited 1) hypoconnectivity within the cognitive control network, which also lacked the typical anticorrelation with the default mode network; 2) hypoconnectivity between left dorsolateral prefrontal cortex and subgenual anterior cingulate cortex; and 3) hyperconnectivity between the right amygdala and right inferior frontal gyrus, a key region for top-down modulation of emotion. Classification between at-risk children and control subjects based on resting-state connectivity yielded high accuracy with high sensitivity and specificity that was superior to clinical rating scales. CONCLUSIONS: Children at familial risk for depression exhibited atypical functional connectivity in the default mode, cognitive control, and affective networks. Such task-independent functional brain measures of risk for depression in children could be used to promote early intervention to reduce the likelihood of developing depression.

Correlates of excessive daytime sleepiness in Parkinson's disease.

Measures of excessive daytime sleepiness, neuropsychologic function, and mood were assessed in twenty-two persons with mid-stage Parkinson's disease (PD) and sixteen age-matched healthy controls. Levodopa dose equivalents (LDE) were computed for the patients. While Epworth sleepiness score (ESS), Mini Mental State Exam, logical memory, Stroop, and the mood scales, reliably distinguished patients from controls, only the mood scales (especially anxiety) were reliably associated with ESS. LDE was not significantly associated with ESS. Excessive daytime sleepiness in patients with mid-stage PD may be more strongly related to anxiety than to other neuropsychologic dysfunction or dopaminergic dosing levels.

Emotion regulation ability varies in relation to intrinsic functional brain architecture.

This study investigated the neural basis of individual variation in emotion regulation, specifically the ability to reappraise negative stimuli so as to down-regulate negative affect. Brain functions in young adults were measured with functional Magnetic Resonance Imaging during three conditions: (i) attending to neutral pictures; (ii) attending to negative pictures and (iii) reappraising negative pictures. Resting-state functional connectivity was measured with amygdala and dorsolateral prefrontal cortical (DLPFC) seed regions frequently associated with emotion regulation. Participants reported more negative affect after attending to negative than neutral pictures, and less negative affect following reappraisal. Both attending to negative vs neutral pictures and reappraising vs attending to negative pictures yielded widespread activations that were significantly right-lateralized for attending to negative pictures and left-lateralized for reappraising negative pictures. Across participants, more successful reappraisal correlated with less trait anxiety and more positive daily emotion, greater activation in medial and lateral prefrontal regions, and lesser resting-state functional connectivity between (a) right amygdala and both medial prefrontal and posterior cingulate cortices, and (b) bilateral DLPFC and posterior visual cortices. The ability to regulate emotion, a source of resilience or of risk for distress, appears to vary in relation to differences in intrinsic functional brain architecture.

Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naïve Adults.

OBJECTIVE: We assessed the neural correlates of adult ADHD in treatment-naïve participants, an approach necessary for identifying neural substrates unconfounded by medication effects. METHOD: The sample consisted of 24 medication-naïve adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. RESULTS: VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. CONCLUSION: These results support the notion that medication-naïve ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings.

Functional and structural brain correlates of risk for major depression in children with familial depression.

Despite growing evidence for atypical amygdala function and structure in major depression, it remains uncertain as to whether these brain differences reflect the clinical state of depression or neurobiological traits that predispose individuals to major depression. We examined function and structure of the amygdala and associated areas in a group of unaffected children of depressed parents (at-risk group) and a group of children of parents without a history of major depression (control group). Compared to the control group, the at-risk group showed increased activation to fearful relative to neutral facial expressions in the amygdala and multiple cortical regions, and decreased activation to happy relative to neutral facial expressions in the anterior cingulate cortex and supramarginal gyrus. At-risk children also exhibited reduced amygdala volume. The extensive hyperactivation to negative facial expressions and hypoactivation to positive facial expressions in at-risk children are consistent with behavioral evidence that risk for major depression involves a bias to attend to negative information. These functional and structural brain differences between at-risk children and controls suggest that there are trait neurobiological underpinnings of risk for major depression.