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PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV.Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017.Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses.NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4 and CD8 HLA-DR-/CD38 subsets both increased (P = 0.05, 0.02).Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

Trauma-focused cognitive behavioral therapy (CBT) is an important component of evidence-based treatment for post-traumatic stress disorder (PTSD), but the efficacy of treatment varies from individual to individual. It is hypothesized that some of this variability derives from interindividual differences in the brain’s intrinsic response to trauma-related stimuli and in activity of executive functional regions. We sought to characterize these differences using functional magnetic resonance imaging (fMRI) in patients about to undergo CBT for PTSD. Blood oxygenation level-dependent (BOLD) signal was measured in 12 individuals with PTSD related to sexual trauma while they read words with positive, neutral, and negative content. Some negative words had PTSD-relevant themes while others did not. We hypothesized that PTSD-relevant words, would evoke emotional processes likely to be engaged by the CBT process, and would be most likely to activate brain circuitry important for CBT success. A group-level analysis showed that the rostral dorsomedial prefrontal cortex (rdmPFC) activated to a greater degree in response to PTSD-relevant words than other word types. This activation was strongest among patients with the best CBT response, particularly in the latter part of the task, when differences between individuals were most pronounced. We propose that the rdmPFC activation observed in this study reflects the engagement of neural processes involved in introspection and self-reflection. CBT may be more effective for individuals with a greater ability to engage these processes.

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

ObjectiveThe goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET.MethodsFatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60–90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized.ResultsPeak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS.ConclusionSubstantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.

Background and ObjectivesThis [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti–leucine-rich, glioma–inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined.MethodsFDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non–LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses.ResultsP-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non–LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84–0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non–LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up.DiscussionSemiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE.Classification of EvidenceThis study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Context Children in treatment for cancer experience multiple, troubling, and interrelated symptoms. Analyzing the interrelatedness of symptoms and how that changes during treatment could yield clinically relevant patient profiles to guide patient care. Objectives The aims were to identify pediatric profiles with respect to Patient-Reported Outcomes Measurement Information System® (PROMIS®; U.S. Department of Health and Human Services, National Institutes of Health) symptom measures, changes in profile status throughout a chemotherapy cycle, and if a baseline single-item fatigue measure could significantly predict symptom profile status and its changes. Methods In a longitudinal, single-site, three data point (T1, T2, and T3) design, children between 8 and 18 years completed the PROMIS Pediatric short form measures for fatigue, depression, anxiety, and pain and one fatigue item from the Symptom Distress Scale. Latent profile analysis and latent transition analysis were conducted. Results About 96 children participated; 58.3% were between 13 and 18 years, and 54.2% were males. Two latent profiles (less severe symptoms and severe symptoms) were identified. The prevalence of the severe symptom profile remained relatively unchanged from T1 to T2 but significantly declined at T3. The baseline single-item fatigue score significantly predicted the child's profile membership and its changes. Conclusion Children experiencing troubling symptoms during cancer treatment are heterogeneous. With respect to the PROMIS symptom measures, two a priori unknown distinct latent profiles of patients were identified in a course of chemotherapy, and the transitions in the profile status were significantly predicted by a baseline single-item fatigue measure.

Objectives To compare Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Fatigue Short Form measures and legacy patient-reported outcome fatigue measures to capture cancer-related fatigue change in pediatric patients with cancer. . Sample & setting 96 racially diverse children and adolescents with cancer. The study occurred in a 32-bed inpatient unit and three regional outpatient clinics. . Methods & variables The Fatigue Scale-Child, Fatigue Scale-Adolescent, and the PROMIS Pediatric Fatigue Short Form measures were administered at three time points during chemotherapy. Descriptive, correlational, psychometric, and receiver operating characteristic (ROC) curve analyses were conducted. The variable was pediatric patient-reported fatigue. . Results All measures were positively correlated at each time point. ROC curves were not statistically different from each other at any data point. . Implications for nursing Nurses have psychometrically strong options for measuring cancer-related fatigue in pediatric patients with cancer, but the PROMIS Pediatric Fatigue Short Form is applicable to more age groups.

Context: Some men who use finasteride for hair loss report persistent sexual and other symptoms after discontinuing finasteride therapy. Objective: To determine whether these persistent symptoms after discontinuation of finasteride use are due to androgen deficiency, decreased peripheral androgen action, or persistent inhibition of steroid 5α-reductase (SRD5A) enzymes. Participants: Finasteride users, who reported persistent sexual symptoms after discontinuing finasteride (group 1); age-matched finasteride users who did not report sexual symptoms (group 2); and healthy men who had never used finasteride (group 3). Outcomes: Sexual function, mood, affect, cognition, hormone levels, body composition, functional magnetic resonance imaging (fMRI) response to sexually and affectively valenced stimuli, nucleotide sequences of androgen receptor (AR), SRD5A1, and SRD5A2; expression levels of androgen-dependent genes in skin. Setting: Academic medical center. Results: Symptomatic finasteride users were similar in body composition, strength, and nucleotide sequences of AR, SRD5A1, and SRD5A2 genes to asymptomatic finasteride users and nonusers. Symptomatic finasteride users had impaired sexual function, higher depression scores, a more negative affectivity balance, and more cognitive complaints than men in groups 2 and 3 but had normal objectively assessed cognitive function. Testosterone, dihydrotestosterone, 5α-androstane-3α,17β-diol-glucuronide, testosterone to dihydrotestosterone and androsterone glucuronide to etiocholanolone glucuronide ratios, and markers of peripheral androgen action and expression levels of AR-dependent genes in skin did not differ among groups. fMRI blood oxygen level-dependent responses to erotic and nonerotic stimuli revealed abnormal function in brain circuitry linked to sexual arousal and major depression. Conclusions: We found no evidence of androgen deficiency, decreased peripheral androgen action, or persistent peripheral inhibition of SRD5A in men with persistent sexual symptoms after finasteride use. Symptomatic finasteride users revealed depressed mood and fMRI findings consistent with those observed in depression.

Myths about fertility are commonplace in society. Few studies have investigated educational approaches to bridge gaps in knowledge among consumers. We evaluated the effectiveness of an animated, 15-minute whiteboard video to effect change in knowledge about infertility.We recruited medical students in their first or second year of training for participation. The students completed the study before their formal lectures on infertility issues. Participants completed questionnaires assessing infertility knowledge immediately before and one week after watching the educational video. Before and after scores (maximum = 50 points) were compared using paired t tests.The study cohort included 101 medical students; 69% (70/101) were female and 31% (31/101) were male. Overall, students increased their score by 4.0/50 (95% CI 3.2 to 4.8, P 0.001) from 36.5/50 to 40.5/50. Female students improved slightly more in their responses than did male students (mean improvement 4.7/50 vs. 2.5/50).A whiteboard video presentation on infertility resulted in short-term improvement in medical students' knowledge of basic reproductive biology, infertility risk factors, treatments, and common myths associated with infertility.

ObjectiveTo determine the value of [F-18]PBR06-PET for assessment of microglial activation in the cerebral gray matter in patients with MS.MethodsTwelve patients with MS (7 relapsing-remitting and 5 secondary progressive [SP]) and 5 healthy controls (HCs) had standardized uptake value (SUV) PET maps coregistered to 3T MRI and segmented into cortical and subcortical gray matter regions. SUV ratios (SUVRs) were global brain normalized. Voxel-by-voxel analysis was performed using statistical parametric mapping (SPM). Normalized brain parenchymal volumes (BPVs) were determined from MRI using SIENAX.ResultsCortical SUVRs were higher in the hippocampus, amygdala, midcingulate, posterior cingulate, and rolandic operculum and lower in the medial-superior frontal gyrus and cuneus in the MS vs HC group (allp< 0.05). Subcortical gray matter SUVR was higher in SPMS vs RRMS (+10.8%,p= 0.002) and HC (+11.3%,p= 0.055) groups. In the MS group, subcortical gray matter SUVR correlated with the Expanded Disability Status Scale (EDSS) score (r = 0.75,p= 0.005) and timed 25-foot walk (T25FW) (r = 0.70,p= 0.01). Thalamic SUVRs increased with increasing EDSS scores (r = 0.83,p= 0.0008) and T25FW (r = 0.65,p= 0.02) and with decreasing BPV (r = −0.63,p= 0.03). Putaminal SUVRs increased with increasing EDSS scores (0.71,p= 0.009) and with decreasing BPV (r = −0.67,p= 0.01). On SPM analysis, peak correlations of thalamic voxels with BPV were seen in the pulvinar and with the EDSS score and T25FW in the dorsomedial thalamic nuclei.ConclusionsThis study suggests that [F-18]PBR06-PET detects widespread abnormal microglial activation in the cerebral gray matter in MS. Increased translocator protein binding in subcortical gray matter regions is associated with brain atrophy and may link to progressive MS.

In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented “threat words.” The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian “semantic access network” involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes.

Persecutory delusions are a clinically important symptom in schizophrenia associated with social avoidance and increased violence. Few studies have investigated the neurobiology of persecutory delusions, which is a prerequisite for developing novel treatments. The aim of this two-paradigm functional magnetic resonance imaging (fMRI) study is to characterize social “real world” and linguistic threat brain activations linked to persecutory delusions in schizophrenia (n=26) using instructed-fear/safety and emotional word paradigms. Instructed-fear/safety activations correlated to persecutory delusion severity demonstrated significant increased lateral orbitofrontal cortex and visual association cortex activations for the instructed-fear vs. safety and instructed-fear vs. baseline contrasts; decreased lateral orbitofrontal cortex and ventral occipital-temporal cortex activations were observed for the instructed-safety stimuli vs. baseline contrast. The salience network also showed divergent fear and safety cued activations correlated to persecutory delusions. Emotional word paradigm analyses showed positive correlations between persecutory delusion severity and left-lateralized linguistic and hippocampal-parahippocampal activations for the threat vs. neutral word contrast. Visual word form area activations correlated positively with persecutory delusions for both threat and neutral word vs. baseline contrasts. This study links persecutory delusions to enhanced neural processing of threatening stimuli and decreased processing of safety cues, and helps elucidate systems-level activations associated with persecutory delusions in schizophrenia.

The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine mapped the genetic signal to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection.

Dietary and physical activity habits are developed early in life and are influenced by family environments. We describe and evaluate an intervention for low-income families to encourage healthy habits. The RD Parent Empowerment Program (http://www.eatright.org/programs/kidseatright/activities/content.aspx?id=6442477891) consists of four workshops centered on the 8 Habits of Healthy Children and Families (Academy of Nutrition and Dietetics Foundation). Registered dietitian nutritionists conduct the workshops in school and community settings using a structured leader guide and tailor the communication and interactive activities to the audience. Participants are parents of young children. Our goals were to use a phenomenologic approach to elicit participant feedback, determine whether participants in the RD Parent Empowerment Program made healthier choices for their families after attending the workshops, and identify which elements of the program participants believed contributed most to its success. The evaluation design used a pragmatic, mixed-methods approach utilizing postintervention focus groups and pre-post intervention scores on the Family Nutrition and Physical Activity (FNPA) survey. All workshop attendees aged 18 years or older were eligible to participate in the evaluation. One hundred twenty-three parents participated in the intervention across seven sites. Focus group results were analyzed using thematic analysis methods to match themes to the main intervention goals. t Tests were used to compare pre- and postintervention FNPA scores and demographic characteristics pooled across sites. FNPA scores significantly improved from pre- to postintervention by a mean of 4.3 FNPA points (6.5%; P0.01). Focus group participants reported behavior changes as a result of the program and identified the site leaders as integral to the program's success, triangulating the results. The RD Parent Empowerment Program generates meaningful self-reported behavior change in parents. Long-term sustainability of the changes must be investigated.

Purpose This study assessed the responsiveness to change over time and theorized associations of Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures in children and adolescents in treatment for cancer to determine measure readiness for use in cancer clinical trials. Methods We administered eight PROMIS (three symptom, two psychological, and three performance) pediatric short-form measures and the Symptom Distress Scale (SDS) to 96 pediatric oncology patients at three time points during a course of chemotherapy. We assessed responsiveness using paired t tests and generalized estimating equation (GEE) models, calculated standardized response mean (SRM) values for PROMIS measures, and examined scores over three data points (T1-T3). Guided by the theory of unpleasant symptoms (TOUS), we examined associations among the PROMIS measures, the SDS, and other variables using GEE. Results The paired t tests showed statistically significant changes in two psychological measures and one performance measure from T1 to T2; three symptom, two psychological and two performance measures from T2 to T3; and three symptom and two psychological measures from T1 to T3. Findings from GEE models indicate PROMIS pediatric measures had statistically significant short-term and long-term changes, controlling for demographic and clinical variables. One performance measure did not achieve significant change at any time point. We found positive support for theorized relationships in the TOUS. Conclusions Most of the PROMIS pediatric measures demonstrated changes over time and had significant relationships as theorized, thus supporting concurrent and construct validity of these measures when administered to pediatric oncology patients during a course of chemotherapy. This evidence supports the measures' readiness for use in clinical trials.

Background: Qualitative aspects of diet influence eating behavior, but the physiologic mechanisms for these calorie-independent effects remain speculative. Objective: We examined effects of the glycemic index (GI) on brain activity in the late postprandial period after a typical intermeal interval. Design: With the use of a randomized, blinded, crossover design, 12 overweight or obese men aged 18‐35 y consumed high- and low-GI meals controlled for calories, macronutrients, and palatability on 2 occasions. The primary outcome was cerebral blood flow as a measure of resting brain activity, which was assessed by using arterial spin-labeling functional magnetic resonance imaging 4 h after test meals. We hypothesized that brain activity would be greater after the high-GI meal in prespecified regions involved in eating behavior, reward, and craving. Results: Incremental venous plasma glucose (2-h area under the curve) was 2.4-fold greater after the high- than the low-GI meal (P = 0.0001). Plasma glucose was lower (mean 6 SE: 4.7 6 0.14 compared with 5.3 6 0.16 mmol/L; P = 0.005) and reported hunger was greater (P = 0.04) 4 h after the high- than the low-GI meal. At this time, the high-GI meal elicited greater brain activity centered in the right nucleus accumbens (a prespecified area; P = 0.0006 with adjustment for multiple comparisons) that spread to other areas of the right striatum and to the olfactory area. Conclusions: Compared with an isocaloric low-GI meal, a high-GI meal decreased plasma glucose, increased hunger, and selectively stimulated brain regions associated with reward and craving in the late postprandial period, which is a time with special significance to eating behavior at the next meal. This trial was registered at clinicaltrials.gov as NCT01064778. Am J Clin Nutr 2013;98:641‐7.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.

Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, Posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects.

The authors sought to test the hypothesis that in patients with borderline personality disorder, the ventromedial prefrontal cortex and associated regions would not be activated during a task requiring motor inhibition in the setting of negative emotion. Such a finding would provide a plausible neural basis for the difficulty borderline patients have in modulating their behavior during negative emotional states and a potential marker for treatment interventions.A specifically designed functional magnetic resonance imaging (fMRI) activation probe was used, with statistical parametric mapping analyses, to test hypotheses concerning decreased prefrontal inhibitory function in the context of negative emotion in patients with borderline personality disorder (N=16) and healthy comparison subjects (N=14). 3-T fMRI scanning was used to study brain activity while participants performed an emotional linguistic go/no-go task.Analyses confirmed that under conditions associated with the interaction of behavioral inhibition and negative emotion, borderline patients showed relatively decreased ventromedial prefrontal activity (including medial orbitofrontal and subgenual anterior cingulate) compared with healthy subjects. In borderline patients, under conditions of behavioral inhibition in the context of negative emotion, decreasing ventromedial prefrontal and increasing extended amygdalar-ventral striatal activity correlated highly with measures of decreased constraint and increased negative emotion, respectively.These findings suggest specific frontolimbic neural substrates associated with core clinical features of emotional and behavioral dyscontrol in borderline personality disorder.

The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.

Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.

Background Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects. Methods Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μg ml −1 , or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models. Results Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia. Conclusions Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder. Clinical trial registration NCT00504894.

Most of the functional neuroimaging studies of depression have focused primarily on the resting state or responses to negatively valenced stimuli. However, depression consists not only of an accentuation of negative affective processing but of an inability to experience pleasure or positive motivation. The authors tested the hypothesis that depressed subjects would show less activation than healthy comparison subjects, in response to positive stimuli, in ventral striatal regions associated with processing of reward and positive stimuli.Positive, negative, and neutral words were presented to 10 unmedicated depressed patients and 12 healthy comparison subjects in the context of a 3T functional magnetic resonance imaging (MRI) paradigm. Image processing and analysis were performed using statistical parametric mapping with a mixed-effects model. Significant differences in neural responses were assessed, examining group, condition, and interaction effects of interest within the context of a general linear model.Relative to comparison subjects, depressed patients demonstrated significantly less bilateral ventral striatal activation to positive stimuli, correlating with decreased interest/pleasure in and performance of activities. They also displayed decreased activation to positive stimuli in a dorsomedial frontal region associated with processing of self-related stimuli. Responses of depressed subjects to negative stimuli were consistent with the growing literature on frontolimbic dysfunction in depression.This finding 1) supports a pathophysiological model of depression that includes reward/motivational pathway dysfunction, 2) suggests a contributing neural substrate of the inability to experience pleasure or engage in rewarding activities, 3) provides greater specification of abnormalities of basal ganglia function in depression, and 4) may help guide treatment approaches.

The present study aimed at validating a computerized mental rotation task developed for use in functional Magnetic Resonance Imaging (fMRI) studies. Eighty-three females and 74 males completed the computerized task, two pencil-and-paper tests of mental rotation, and reported their high school grades in mathematics, English, and history. The computerized task involved the presentation of pairs of three-dimensional stimuli that differed in orientation by 0, 40, 80, 120, or 160 degrees. Results showed significant gender differences in favor of males in the three main tasks, although gender interacted with angle of rotation in the computerized task. Evidence for concurrent validity was obtained in the form of significant correlations between performance on tasks relevant to mental rotation (paper and pencil tests and mathematics grades), whereas discriminant validity was demonstrated by a lack of correlation with tasks deemed irrelevant to mental rotation (English and history grades). These findings support the use of our computerized mental rotation task as a valid measure of mental rotation abilities in fMRI studies.

A method is presented for mapping intravoxel fiber structures using spectral decomposition onto a circular distribution of measured apparent diffusion coefficients (ADCs). The zeroth-, second-, and fourth-order harmonic components of the ADC distribution on the circle spanned by the major and median eigenvectors of the diffusion tensor can be used to provide quantitative indices for isotropic, linear, and fiber-crossing diffusion, respectively. A diffusion-weighted MRI technique with 90 encoding orientations was implemented to estimate the circular ADC distribution and calculate the circular spectrum. A digital phantom was used to simulate various diffusion patterns. Comparisons were made between the circular spectrum and regular DTI-based index maps. The results indicated that the zeroth- and second-order circular spectrum maps exhibited a strong consistency with the DTI-based mean diffusivity and linear indices, respectively, and the fourth-order circular spectrum map was able to identify the fiber crossings. MRI experiments were performed on seven healthy human brains using a 3T scanner. The in vivo fourth-order maps showed significantly higher densities in several brain regions, including the corpus callosum, cingulum bundle, superior longitudinal fasciculus, corticospinal tract, and middle cerebellar peduncle, which indicated the existence of fiber crossings in these regions.

Cortical field boundaries of sensory areas can be physiologically defined. The delineation of the human auditory cortical architecture remains incomplete. Here we used systematic variation of pitch and duration of sinusoidal tones to define auditory cortical fields along Heschl's gyrus with a silent, event-related fMRI scanning technique that allowed us to determine spatially small shifts of neuronal responses. Thus, we were able to establish higher-resolution tonotopic maps. Acoustic intervals of two octaves correspond to an average 2-mm anatomical distance along Heschl's gyrus. We also demonstrate that one tonotopic map with a medio-lateral low- to high-frequency gradient is located on the lateral half of Heschl's gyrus, which might correspond to field R in primates. Furthermore, we studied cortical responses to brief (50-ms) transients with fMRI and demonstrate that silent, event-related fMRI is capable of measuring significant blood oxygen level-dependent effect to such brief events in the acoustic domain. Our results add to current knowledge on the number and precise localization of multiple tonotopic maps in human auditory cortex. More specifically, they support the hypothesis that there may be two primary auditory cortical fields with mirror tonotopic organization on Heschl's gyrus in man.

The feasibility of mapping transient, randomly occurring neuropsychological events using independent component analysis (ICA) was evaluated in an auditory sentence-monitoring fMRI experiment, in which prerecorded short sentences of random content were presented in varying temporal patterns. The efficacy of ICA on fMRI data with such temporal characteristics was assessed by a series of simulation studies, as well as by human activation studies. The effects of contrast-to-noise ratio level, spatially varied hemodynamic response within a brain region, time lags of the responses among brain regions, and different simulated activation locations on the ICA were investigated in the simulations. Component maps obtained from the auditory sentence-monitoring experiments in each subject using ICA showed distinct activation in bilateral auditory and language cortices, as well as in superior sensorimotor cortices, consistent with previous PET studies. The associated time courses in the activated brain regions matched well to the timing of the sentence presentation, as evidenced by the recorded button-press response signals. Methods for ICA component ordering that may rank highly the components of primary interest in such experiments were developed. The simulation results characterized the performance of ICA under various conditions and may provide useful information for experimental design and data interpretation.

Attentional modulation of normal sensory processing has a two-fold impact on human brain activity: activation of a network of localized brain regions is associated with paying attention, and activation of specific sensory regions is enhanced relative to passive stimulation. The mechanisms underlying attentional modulation of perception in patients with lesions of sensory cortices are less well understood. Here we report a unique patient suffering from extensive bilateral destruction of the auditory cortices (including the primary auditory fields) who demonstrated conscious perception of the onset and offset of sounds only when selectively attending to the auditory modality. This is the first description of such an attentively modulated 'deaf-hearing' phenomenon and its neural correlates, using H(2)(15)O-PET. Increases in cerebral blood flow associated with conscious awareness of sound that was achieved by listening attentively (compared with identical auditory stimulation presented when the patient was inattentive) were found bilaterally in the lateral (pre)frontal cortices, the spared middle temporal cortices and the cerebellar hemispheres. We conclude that conscious awareness of sounds may be achieved in the absence of the primary auditory cortex, and that selective, 'top-down' attention, associated with prefrontal systems, exerts a crucial modulatory effect on auditory perception within the remaining auditory system.

Neurocircuitry models of panic disorder have hypothesized that the panic attack itself stems from loci in the brainstem including the ascending reticular system and respiratory and cardiovascular control centers. Voxel-based morphometry with acobian modulation was used to examine gray matter volume changes in 10 panic disorder patients and 23 healthy controls. The panic disorder patients had a relatively increased gray matter volume in the midbrain and rostral pons of the brainstem. Increased ventral hippocampal and decreased regional prefrontal cortex volumes were also noted at a lower significance threshold. This finding has implications for pathophysiologic models of panic disorder, and provides structural evidence for the role of the brainstem in neurocircuitry models of panic disorder.

H2(15)O-PET was used to investigate the functional anatomy of recovery in a patient (J.B.) with bilateral perisylvian strokes and auditory agnosia, who partially regained the ability to recognize environmental sounds, but remained clinically word-deaf. The patient and a group of six normal volunteers were scanned in the following three conditions: (i) passive listening to environmental sounds; (ii) categorization of environmental sounds; (iii) at rest. In normal subjects, passive listening as compared with rest was associated with significant activations in the auditory cortices and posterior thalami, and in the inferior parietal lobe and anterior insula/frontal opercular region on the right. In J.B., activations were observed in the spared auditory cortex and inferior parietal lobe of the right hemisphere and in regions adjacent to the perisylvian lesion in the left hemisphere (anterior insula/frontal opercular region, middle temporal gyrus and inferior parietal lobe). The recovered function, as measured by categorization of sounds compared with passive listening, in J.B. was associated with bilateral activation of a distributed network comprising (pre)frontal, middle temporal and inferior parietal cortices, as well as the right cerebellum and the right caudate nucleus. In addition, there was a left-sided activation of the anterior cingulate gyrus. In normal subjects, the same categorization task led to activation of a network comprising (pre)frontal, middle temporal and inferior parietal cortices in the left hemisphere only. These results suggest that bilateral activation (with recruitment of areas homologous to those known to be responsible for normal function), the engagement of peri-infarct regions, and the involvement of a more widespread neocortical network, are mechanisms of functional reorganization after injury that may enable recovery from, or compensation for, cognitive deficits.

Many neuropsychiatric symptom states are idiosyncratic, involuntary, randomly occurring, subjective, and transient. The brain states associated with these clinically important mental states cannot be imaged directly with existing positron emission tomography (PET) techniques. A new PET method that brings such mental/brain states under experimental control for analysis in single subjects is described. It utilizes a slow bolus H215O three-dimensional (3D) regional CBF imaging technique. The analysis focuses upon natural or experimentally induced variance in the temporal distribution of specific neuropsychological events over the course of a study session. For each scan, the amount of radioactivity entering the brain during these events is calculated to derive a score reflecting the contribution of the events to the image. A statistical analysis is then performed to identify those pixels in which the intensity covaries with the scan scores over the subject's scans. This permits the identification of the brain areas associated with the mental state of interest. The method is validated using an auditory sentence-monitoring task. The detection in single subjects of cerebral activations associated with recurrent events as brief as 2 s in duration is demonstrated. This method may be used as a means of imaging ephemeral neurologic or neuropsychiatric symptom states or as an alternative to a subtraction design for activation studies.

Positron emission tomography regional CBF (rCBF) studies of cognitive processes have traditionally required 30–60 mCi of H215O per scan and intersubject averaging to achieve statistical significance. However, intersubject anatomical, functional, and disease variability can make such an approach problematic. A new method that produces significant results in single subjects is presented. It is based upon high-sensitivity three-dimensional imaging and a “slow” bolus administration of >15 mCi of H215O per scan. The method is validated in four normal volunteers using control and auditory-language activation tasks with four scans per condition and statistical parametric mapping analysis. It is demonstrated that the rCBF distribution associated with the cognitive state is detected during the arrival of radiotracer in the brain. This occurs over 30 s and constitutes a critical temporal window during which stimulation should be performed. A 90-s acquisition time is found to produce results of greater significance than a 60-s acquisition time. The implications of the results and the functional neuroanatomical findings are discussed. This method is suitable for the study of individual functional neuroanatomy in many neuropsychological, pharmacologic, and symptom states in normal subjects and in patients with psychiatric and neurologic disorders.

Most functional neuroimaging studies of major depressive disorder (MDD) employ univariate methods of statistical analysis to localize abnormalities of neural activity. Less has been done to investigate functional relations between these regions, or with regions not usually implicated in depression. Examination of intraneuronal and interneural network relations is important for the advancement of emerging network models for MDD. Principal component analysis (PCA), a multivariate statistical method, was used to examine differences in functional connectivity between 10 unmedicated patients with MDD and 12 healthy subjects engaged in a positive word viewing task. In healthy subjects, principal component (PC) 1 (33% variance) revealed functional connectivity of task-specific sensory, linguistic, and motor regions, along with functional anticorrelations in the default mode network; PC2 (10% variance) displayed functional connectivity of areas involved in emotional processing. This segregation of functions did not occur in the depressed group, where regions involved in emotional functions appeared in PC1 (34% variance) co-varying with those involved in linguistic, motor, and default mode network processing. The lack of segregation of emotional processing from cognitive and sensorimotor functions may represent a systems level neural substrate for a core phenomenon of depression: the interconnection of affective disturbance with experience, cognition, and behavior.

Frontolimbic structures involved in fear conditioning have also been associated with hypothalamic-pituitary-adrenal (HPA)-axis modulation, including amygdaloid, hippocampal, and ventromedial prefrontal cortex regions. Although HPA-axis function and endocrine changes have been investigated in the context of stress provocation, much research has not been conducted using functional neuroimaging in the study of the HPA axis and frontolimbic function in response to emotional stimuli. Using functional magnetic resonance imaging, the association of blood-oxygen-level dependent signal with salivary cortisol in response to an emotional visual scene paradigm was investigated, with prescan and postscan salivary cortisol analyzed as a covariate of interest during specific conditions. Cortisol reactivity to the paradigm was positively associated with amygdalar and hippocampal activity and negatively associated with ventromedial prefrontal cortex activity in conditions involving emotional imagery.

Ventral anterior cingulate cortex (vACC) is a highly interconnected brain region considered to reflect the sometimes competing demands of cognition and emotion. A reciprocal relationship between vACC and dorsal ACC (dACC) may play a role in maintaining this balance between cognitive and emotional processing. Using functional MRI in association with a cognitively-demanding visuospa- tial task (mental rotation), we found that only women demonstrated vACC suppression and inverse functional connectivity with dACC. Sex differences in vACC functioning—previously described under conditions of negative emotion—are extended here to cognition. Consideration of participant sex is essential to understanding the role of vACC in cognitive and emotional processing. Hum Brain Mapp 28:1206-1212, 2007. V C 2007 Wiley-Liss, Inc.

Neural substrates of behavioral inhibitory control have been probed in a variety of animal model, physiologic, behavioral, and imaging studies, many emphasizing the role of prefrontal circuits. Likewise, the neurocircuitry of emotion has been investigated from a variety of perspectives. Recently, neural mechanisms mediating the interaction of emotion and behavioral regulation have become the focus of intense study. To further define neurocircuitry specifically underlying the interaction between emotional processing and response inhibition, we developed an emotional linguistic go/no-go fMRI paradigm with a factorial block design which joins explicit inhibitory task demand (i.e., go or no-go) with task-unrelated incidental emotional stimulus valence manipulation, to probe the modulation of the former by the latter. In this study of normal subjects focusing on negative emotional processing, we hypothesized activity changes in specific frontal neocortical and limbic regions reflecting modulation of response inhibition by negative stimulus processing. We observed common fronto-limbic activations (including orbitofrontal cortical and amygdalar components) associated with the interaction of emotional stimulus processing and response suppression. Further, we found a distributed cortico-limbic network to be a candidate neural substrate for the interaction of negative valence-specific processing and inhibitory task demand. These findings have implications for elucidating neural mechanisms of emotional modulation of behavioral control, with relevance to a variety of neuropsychiatric disease states marked by behavioral dysregulation within the context of negative emotional processing.

Functional MRI during performance of a validated mental rotation task was used to assess a neurobiological basis for sex differences in visuospatial processing. Between-sex group analysis demonstrated greater activity in women than in men in dorsalmedial prefrontal and other high-order heteromodal association cortices, suggesting women performed mental rotation in an effortful, "top-down" fashion. In contrast, men activated primary sensory cortices as well as regions involved in implicit learning (basal ganglia) and mental imagery (precuneus), consistent with a more automatic, "bottom-up" strategy. Functional connectivity analysis in association with a measure of behavioral performance showed that, in men (but not women), accurate performance was associated with deactivation of parieto-insular vestibular cortex (PIVC) as part of a visual-vestibular network. Automatic evocation by men to a greater extent than women of this network during mental rotation may represent an effective, unconscious, bottom-up neural strategy which could reasonably account for men's traditional visuospatial performance advantage.

Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies.

Environmental sounds convey specific meanings and the neural circuitry for their recognition may have preceded language. To dissociate semantic mnemonic from sensory perceptual processing of non-verbal sound stimuli we systematically altered the inherent semantic properties of non-verbal sounds from natural and man-made sources while keeping their acoustic characteristics closely matched. We hypothesized that acoustic analysis of complex non-verbal sounds would be right lateralized in auditory cortex regardless of meaning content and that left hemisphere regions would be engaged when meaningful concept could be extracted. Using H(2) (15)O-PET imaging and SPM data analysis, we demonstrated that activation of the left superior temporal and left parahippocampal gyrus along with left inferior frontal regions was specifically associated with listening to meaningful sounds. In contrast, for both types of sounds, acoustic analysis was associated with activation of right auditory cortices. We conclude that left hemisphere brain regions are engaged when sounds are meaningful or intelligible.

Background Previous neuroimaging studies have demonstrated exaggerated amygdala responses to negative stimuli in posttraumatic stress disorder (PTSD). The time course of this amygdala response is largely unstudied and is relevant to questions of habituation and sensitization in PTSD exposure therapy. Methods We applied blood oxygen level dependent functional magnetic resonance imaging and statistical parametric mapping to study amygdala responses to trauma-related and nontrauma-related emotional words in sexual/physical abuse PTSD and normal control subjects. We examined the time course of this response by separate analysis of early and late epochs. Results PTSD versus normal control subjects have a relatively increased initial amygdala response to trauma-related negative, but not nontrauma-related negative, versus neutral stimuli. Patients also fail to show the normal patterns of sensitization and habituation to different categories of negative stimuli. These findings correlate with measured PTSD symptom severity. Conclusions Our results demonstrate differential time courses and specificity of amygdala response to emotional and control stimuli in PTSD and normal control subjects. This has implications for pathophysiologic models of PTSD and treatment response. The results also extend previous neuroimaging studies demonstrating relatively increased amygdala response in PTSD and expand these results to a largely female patient population probed with emotionally valenced words.

The recognition of environmental sounds is an important feature of higher auditory processing and essential for everyday life. The present study aimed to investigate the potential impairment of this mental function in schizophrenia. This work on immediate sound recognition is complementary to recent studies on auditory linguistic processing. Fifteen schizophrenic patients and 30 control subjects were asked to identify 43 complex environmental sounds from different categories and rate their familiarity when naive to the sounds. In consecutive experiments, patients and control subjects rated the sounds according to emotional valence and arousal, as well as imageability. In both groups, correct identification of non-verbal sounds was highly associated with familiarity. Statistical analysis by group demonstrated a significantly higher error rate in identifying sounds in patients suffering from schizophrenia compared to healthy control subjects. In contrast, the affective recognition of the complex sounds was preserved in the schizophrenic patients. These results suggest a disturbance of higher-order, auditory mnemonic processing in schizophrenic patients in the non-linguistic domain. We discuss their abnormal responses in the context of recent theories of auditory physiological and semantic processing deficits in schizophrenia.

A new single-shot echo-planar imaging (EPI) sequence with interleaved z-shim and optimized compensation for susceptibility-induced signal loss is proposed in this paper. Experiments on human brain demonstrated that the new method is able to regain signal dropout in brain areas with severe susceptibility-induced local gradients, while its image acquisition speed is comparable to that of conventional single-shot EPI techniques. Significant signal-to-noise ratio improvements were demonstrated in the ventral prefrontal and lateral temporal lobes with the new technique compared to a conventional EPI. Brain activation experiments with a bilateral finger-tapping task were performed with intentionally introduced local gradients near the left sensorimotor cortex, by a small gadolinium (Gd)-doped bottle placed on the left side of the head. The results of the functional experiments showed that the interleaved z-shim EPI sequence effectively recovered the signal loss caused by the Gd-doped bottle and reliably detected activation signals in bilateral sensorimotor regions, while the activation signals on the left side diminished considerably in a conventional EPI technique. The new technique, with the capability of reducing susceptibility artifacts and rapid scanning speed, may be particularly useful for event-related functional MRI experiments in the base of the brain, which are of great importance in neuropsychiatric studies.

It is well known that natural languages share certain aspects of their design. For example, across languages, syllables like blif are preferred to lbif. But whether language universals are myths or mentally active constraints-linguistic or otherwise-remains controversial. To address this question, we used fMRI to investigate brain response to four syllable types, arrayed on their linguistic well-formedness (e.g., blif≻bnif≻bdif≻lbif, where ≻ indicates preference). Results showed that syllable structure monotonically modulated hemodynamic response in Broca's area, and its pattern mirrored participants' behavioral preferences. In contrast, ill-formed syllables did not systematically tax sensorimotor regions-while such syllables engaged primary auditory cortex, they tended to deactivate (rather than engage) articulatory motor regions. The convergence between the cross-linguistic preferences and English participants' hemodynamic and behavioral responses is remarkable given that most of these syllables are unattested in their language. We conclude that human brains encode broad restrictions on syllable structure.

OBJECTIVE: The authors assessed frontotemporal function in patients with geriatric depression, a debilitating and increasingly prevalent disorder that has not been examined with brain activation paradigms. METHOD: Six depressed elderly patients and five healthy comparison subjects underwent high-sensitivity [15O]H2O positron emission tomography scans during a paced word generation task and a resting condition. RESULTS: Bilateral activation deficits were noted in the dorsal anterior cingulate gyrus and hippocampus of the depressed geriatric patients relative to the comparison subjects. Patients had memory deficits that correlated with lower hippocampal activity during both rest and activation. CONCLUSIONS: These initial findings suggest that hippocampal and dorsal anterior cingulate hypoactivation may constitute contributing neural substrates of geriatric depression. They also suggest that hippocampal dysfunction is related to the memory dysfunction characteristic of this disorder.

Background: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. Methods: We utilized a high-sensitivity H 2 15 0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. Results: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. Conclusions: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical–subcortical neural system that includes the anterior cingulate and caudate.