Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.

BACKGROUND: In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen. AIMS: We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum). METHOD: We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls. RESULTS: Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen. CONCLUSIONS: Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen-right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.

Trends of patient referral to a memory clinic and towards earlier diagnosis from 1985-2009.

BACKGROUND: It may be assumed that increased public awareness of dementia due to Alzheimer's disease (AD) together with the availability of efficacious treatment will result in diagnostic evaluation at earlier stages of cognitive decline and diagnosis of dementia due to AD at earlier stages. METHODS: All persons that were examined at a university based memory clinic, in Germany, between 1985 and 2009 were included. RESULTS: In the 3,951 persons identified, linear regression analysis revealed a positive association between Mini Mental State Examination (MMSE) score and year of initial examination (yearIE) (ß = 0.266; p < 0.001). In the 1,821 patients diagnosed with dementia due to AD, a positive association between MMSE score and yearIE (ß = 0.230; p < 0.001) was revealed. MMSE scores were higher (ß = 0.195; p < 0.001) after the introduction of cholinesterase inhibitors in Germany in 1997. CONCLUSIONS: Diagnostic evaluation of individuals occurred at progressively earlier stages of cognitive decline. Dementia due to AD was diagnosed at progressively earlier stages, and this trend was associated with the availability of efficacious treatment. This is the first study on changes in patient referral and diagnosis based on a continuous 25 years period.

Development of the brain's default mode network from wakefulness to slow wave sleep.

Falling asleep is paralleled by a loss of conscious awareness and reduced capacity to process external stimuli. Little is known on sleep-associated changes of spontaneously synchronized anatomical networks as detected by resting-state functional magnetic resonance imaging (rs-fMRI). We employed functional connectivity analysis of rs-fMRI series obtained from 25 healthy participants, covering all non-rapid eye movement (NREM) sleep stages. We focused on the default mode network (DMN) and its anticorrelated network (ACN) that are involved in internal and external awareness during wakefulness. Using independent component analysis, cross-correlation analysis (CCA), and intraindividual dynamic network tracking, we found significant changes in DMN/ACN integrity throughout the NREM sleep. With increasing sleep depth, contributions of the posterior cingulate cortex (PCC)/retrosplenial cortex (RspC), parahippocampal gyrus, and medial prefrontal cortex to the DMN decreased. CCA revealed a breakdown of corticocortical functional connectivity, particularly between the posterior and anterior midline node of the DMN and the DMN and the ACN. Dynamic tracking of the DMN from wakefulness into slow wave sleep in a single subject added insights into intraindividual network fluctuations. Results resonate with a role of the PCC/RspC for the regulation of consciousness. We further submit that preserved corticocortical synchronization could represent a prerequisite for maintaining internal and external awareness.

Outcome of Bleb Revision With Autologous Conjunctival Graft Alone or Combined With Donor Scleral Graft for Late-onset Bleb Leakage With Hypotony After Standard Trabeculectomy With Mitomycin C.

PRCIS: Treatment of leakage with ocular hypotony after trabeculectomy with mitomycin C (MMC) can be safely achieved through conjunctival patch alone or combined with donor scleral graft in cases of melted underlying sclera. PURPOSE: To report outcomes of 2 surgical approaches for treating ocular hypotony in eyes with blebs with late-onset leakage after standard trabeculectomy with MMC. METHODS: Thirty consecutive cases with bleb leakage and hypotony underwent bleb revision surgery between 2009 and 2014 by the same surgeon (J.W.) at the Department of Ophthalmology of the Mainz University Medical Center, Germany. In 18 patients, an autologous conjunctival patch graft was applied. In 12 patients, the underlying sclera was found melted and an additional scleral donor graft was sutured in place. The authors analyzed intraocular pressure, visual acuity, and optical coherence tomography of the macula preoperatively at 1 day, 1 week, 4 weeks, and 6 months after surgery. RESULTS: The mean IOP was 6.2±3.5 mm Hg preoperatively and 21.7±16.4 mm Hg at 1 day, 13.7±6.7 at 1 week, 13.1±5.1 mm Hg at 4 weeks, and 12.1±4.7 mm Hg at 6 months after surgery. Visual acuity (logMar) increased from 0.57±0.49 preoperatively to 0.49±0.40 at 6 months. Optical coherence tomography showed flattening of macular folds that were present before treatment. No serious adverse event was reported. CONCLUSIONS: This revision technique with conjunctival patch and/or additional donor scleral graft is an effective and safe method for treating late bleb leakage and hypotony maculopathy after trabeculectomy with MMC.

Predictive Value of Osteoprotegerin and Neutrophil Gelatinase-associated Lipocalin on Multiple Organ Failure in Multiple Trauma.

BACKGROUND/AIM: Multiple organ dysfunction syndrome (MODS) is the leading cause of late posttraumatic mortality. This study analyzed the prognostic values of osteoprotegerin (OPG) and neutrophil gelatinase-associated lipocalin (NGAL/lipocalin 2) compared to interleukin-6 (IL-6) in multiply injured patients. PATIENTS AND METHODS: A retrospective observational cohort study on multiply injured patients with an injury severity score (ISS) of ≥16 was performed. OPG, NGAL and IL-6 blood concentrations were measured. Statistical analysis comprised receiver-operating-characteristic (ROC) analysis with the corresponding area under the curve (AUC). RESULTS: Thirty-nine patients with a mean ISS of 34±11 were included. Fourteen patients (36%) developed MODS and 8 patients (21%) died. Plasma levels of NGAL, OPG, and IL-6 were significantly elevated in the MODS+ group. Each biomarker positively correlated with MODS score and diagnosis of MODS. CONCLUSION: NGAL and OPG might be indicative of MODS and could have the potential to be biomarkers in the early detection of patients at risk of posttraumatic MODS.

Prospective acceptance of distinct mobile mental health features in psychiatric patients and mental health professionals.

BACKGROUND: Despite numerous mobile health (mHealth) applications available, current impact on mental healthcare is low. Users face overwhelming variety of applications and sensors. Evidence for distinct features' effectiveness is largely lacking. Along with technical feasibility and data security issues, readiness and preferences of patients predetermine engagement and impact of mHealth in psychiatry. OBJECTIVE: We aimed to assess the prospective attitudes of psychiatric patients and mental health professionals (MHP) towards mHealth applications in general and with regard to distinct features. METHODS: We conducted a survey entailing 486 subjects (297 MHP and 189 patients). RESULTS: Professionals and patients indicate both, considerable acceptance and rejection for most features. Marked concerns across groups relate to data security in general. Actimetry and geotracking were considered particularly skeptical. Importantly, most patients prefer to be prompted timely about health status changes. CONCLUSION: Altogether, evidence indicates substantial support for mHealth features in mental healthcare despite considerable rejection of distinct features. We conclude that tighter collaboration between researchers, developers and clinicians must address matching mHealth-apps to patients' needs. Improved information on potential risks and possibilities associated with mHealth features is strongly indicated in MHP and psychiatric patients in order to reach an appropriately informed decision on individual involvement.

Exploring the Time Trend of Stress Levels While Using the Crowdsensing Mobile Health Platform, TrackYourStress, and the Influence of Perceived Stress Reactivity: Ecological Momentary Assessment Pilot Study.

BACKGROUND: The mobile phone app, TrackYourStress (TYS), is a new crowdsensing mobile health platform for ecological momentary assessments of perceived stress levels. OBJECTIVE: In this pilot study, we aimed to investigate the time trend of stress levels while using TYS for the entire population being studied and whether the individuals' perceived stress reactivity moderates stress level changes while using TYS. METHODS: Using TYS, stress levels were measured repeatedly with the 4-item version of the Perceived Stress Scale (PSS-4), and perceived stress reactivity was measured once with the Perceived Stress Reactivity Scale (PSRS). A total of 78 nonclinical participants, who provided 1 PSRS assessment and at least 4 repeated PSS-4 measurements, were included in this pilot study. Linear multilevel models were used to analyze the time trend of stress levels and interactions with perceived stress reactivity. RESULTS: Across the whole sample, stress levels did not change while using TYS (P=.83). Except for one subscale of the PSRS, interindividual differences in perceived stress reactivity did not influence the trajectories of stress levels. However, participants with higher scores on the PSRS subscale reactivity to failure showed a stronger increase of stress levels while using TYS than participants with lower scores (P=.04). CONCLUSIONS: TYS tracks the stress levels in daily life, and most of the results showed that stress levels do not change while using TYS. Controlled trials are necessary to evaluate whether it is specifically TYS or any other influence that worsens the stress levels of participants with higher reactivity to failure.

Neurocognitive and neuroanatomical maturation in the clinical high-risk states for psychosis: A pattern recognition study.

BACKGROUND: Findings from neurodevelopmental studies indicate that adolescents with psychosis spectrum disorders have delayed neurocognitive performance relative to the maturational state of their healthy peers. Using machine learning, we generated a model of neurocognitive age in healthy adults and investigated whether individuals in clinical high risk (CHR) for psychosis showed systematic neurocognitive age deviations that were accompanied by specific structural brain alterations. METHODS: First, a Support Vector Regression-based age prediction model was trained and cross-validated on the neurocognitive data of 36 healthy controls (HC). This produced Cognitive Age Gap Estimates (CogAGE) that measured each participant's deviation from the normal cognitive maturation as the difference between estimated neurocognitive and chronological age. Second, we employed voxel-based morphometry to explore the neuroanatomical gray and white matter correlates of CogAGE in HC, in CHR individuals with early (CHR-E) and late (CHR-L) high risk states. RESULTS: The age prediction model estimated age in HC subjects with a mean absolute error of ±2.2 years (SD = 3.3; R2 = 0.33, P < .001). Mean (SD) CogAGE measured +4.3 (8.1) years in CHR individuals compared to HC (-0.1 (5.5) years, P = .006). CHR-L individuals differed significantly from HC subjects while this was not the case for the CHR-E group. CogAGE was associated with a distributed bilateral pattern of increased GM volume in the temporal and frontal areas and diffuse pattern of WM reductions. CONCLUSION: Although the generalizability of our findings might be limited due to the relatively small number of participants, CHR individuals exhibit a disturbed neurocognitive development as compared to healthy peers, which may be independent of conversion to psychosis and paralleled by an altered structural maturation process.

Progressively Disrupted Intrinsic Functional Connectivity of Basolateral Amygdala in Very Early Alzheimer's Disease.

Very early Alzheimer's disease (AD) - i.e., AD at stages of mild cognitive impairment (MCI) and mild dementia - is characterized by progressive structural and neuropathologic changes, such as atrophy or tangle deposition in medial temporal lobes, including hippocampus and entorhinal cortex and also adjacent amygdala. While progressively disrupted intrinsic connectivity of hippocampus with other brain areas has been demonstrated by many studies, amygdala connectivity was rarely investigated in AD, notwithstanding its known relevance for emotion processing and mood disturbances, which are both important in early AD. Intrinsic functional connectivity (iFC) patterns of hippocampus and amygdala overlap in healthy persons. Thus, we hypothesized that increased alteration of iFC patterns along AD is not limited to the hippocampus but also concerns the amygdala, independent from atrophy. To address this hypothesis, we applied structural and functional resting-state MRI in healthy controls (CON, n = 33) and patients with AD in the stages of MCI (AD-MCI, n = 38) and mild dementia (AD-D, n = 36). Outcome measures were voxel-based morphometry (VBM) values and region-of-interest-based iFC maps of basolateral amygdala, which has extended cortical connectivity. Amygdala VBM values were progressively reduced in patients (CON > AD-MCI and AD-D). Amygdala iFC was progressively reduced along impairment severity (CON > AD-MCI > AD-D), particularly for hippocampus, temporal lobes, and fronto-parietal areas. Notably, decreased iFC was independent of amygdala atrophy. Results demonstrate progressively impaired amygdala intrinsic connectivity in temporal and fronto-parietal lobes independent from increasing amygdala atrophy in very early AD. Data suggest that early AD disrupts intrinsic connectivity of medial temporal lobe key regions, including that of amygdala.

More Consistently Altered Connectivity Patterns for Cerebellum and Medial Temporal Lobes than for Amygdala and Striatum in Schizophrenia.

BACKGROUND: Brain architecture can be divided into a cortico-thalamic system and modulatory "subcortical-cerebellar" systems containing key structures such as striatum, medial temporal lobes (MTLs), amygdala, and cerebellum. Subcortical-cerebellar systems are known to be altered in schizophrenia. In particular, intrinsic functional brain connectivity (iFC) between these systems has been consistently demonstrated in patients. While altered connectivity is known for each subcortical-cerebellar system separately, it is unknown whether subcortical-cerebellar systems' connectivity patterns with the cortico-thalamic system are comparably altered across systems, i.e., if separate subcortical-cerebellar systems' connectivity patterns are consistent across patients. METHODS: To investigate this question, 18 patients with schizophrenia (3 unmedicated, 15 medicated with atypical antipsychotics) and 18 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI). Independent component analysis of fMRI data revealed cortical intrinsic brain networks (NWs) with time courses representing proxies for cortico-thalamic system activity. Subcortical-cerebellar systems' activity was represented by fMRI-based time courses of selected regions-of-interest (ROIs; i.e., striatum, MTL, amygdala, cerebellum). Correlation analysis among ROI- and NWs-time courses yielded individual connectivity matrices [i.e., connectivity between NW and ROIs (allROIs-NW, separateROI-NW), only NWs (NWs-NWs), and only ROIs (allROIs-allROIs)] as main outcome measures, which were classified by support-vector-machine-based (SVM) leave-one-out cross-validation. Differences in classification accuracy were statistically evaluated for consistency across subjects and systems. RESULTS: Correlation matrices based on allROIs-NWs yielded 91% classification accuracy, which was significantly superior to allROIs-allROIs and NWs-NWs (56 and 74%, respectively). Considering separate subcortical-cerebellar systems, cerebellum-NWs and MTL-NWs reached highest accuracy values with 91 and 85%, respectively, while those of striatum-NW and amygdala-NW were significantly lower with about 65% classification accuracy. CONCLUSION: RESULTS provide initial evidence for differential consistency of altered intrinsic connectivity patterns between subcortical-cerebellar systems and the cortico-thalamic system. Data suggest that differential dysconnectivity patterns between subcortical-cerebellar and cortical systems might reflect different disease states or patient subgroups.

Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia.

In schizophrenia, consistent structural and functional changes have been demonstrated for the insula including aberrant salience processing, which is critical for psychosis. Interactions within and across default mode and central executive network (DMN, CEN) are impaired in schizophrenia. The question arises whether these 2 types of changes are related. Recently, the anterior insula has been demonstrated to control DMN/CEN interactions. We hypothesized that aberrant insula and DMN/CEN activity in schizophrenia is associated with an impaired dependence of DMN/CEN interactions on anterior insular salience network (SN) activity. Eighteen patients with schizophrenia during psychosis and 20 healthy controls were studied by resting-state-fMRI and psychometric examination. High-model-order independent component analysis of fMRI data revealed spatiotemporal patterns of synchronized ongoing blood-oxygenation-level-dependent (BOLD) activity including SN, DMN, and CEN. Scores of functional and time-lagged connectivity across networks' time courses were calculated. Connectivity scores and spatial network maps were compared between groups and related with patients' hallucination and delusion severity. Spatial BOLD-synchronicity was altered in patients' SN, DMN, and CEN, including decreased activity in the right anterior insula (rAI). Patients' functional connectivity between DMN and CEN was increased and related with hallucinations severity. Importantly, patients' time-lagged connectivity between SN and DMN/CEN was reduced, and decreased rAI activity of the SN was associated with both hallucinations and increased functional connectivity between DMN and CEN. Data provide evidence for an aberrant dependence of DMN/CEN interactions on anterior insular SN activity, linking impaired insula, DMN, CEN activity, and psychosis in schizophrenia.

Increased intrinsic brain activity in the striatum reflects symptom dimensions in schizophrenia.

Striatal dysfunction is thought to be a fundamental element in schizophrenia. Striatal dopamine dysfunction impacts on reward processing and learning and is present even at rest. Here, we addressed the question whether and how spontaneous neuronal activity in the striatum is altered in schizophrenia. We therefore assessed intrinsic striatal activity and its relation with disorder states and symptom dimensions in patients with schizophrenia. We performed resting-state functional (rs-fMRI) and structural magnetic resonance imaging as well as psychometric assessment in 21 schizophrenic patients during psychosis. On average 9 months later, we acquired follow-up data during psychotic remission and with comparable levels of antipsychotic medication. Twenty-one age- and sex-matched healthy controls were included in the study. Independent component analysis of fMRI data yielded spatial maps and time-courses of coherent ongoing blood-oxygen-level-dependent signal fluctuations, which were used for group comparisons and correlation analyses with scores of the positive and negative syndrome scale. During psychosis, coherent intrinsic activity of the striatum was increased in the dorsal part and correlated with positive symptoms such as delusion and hallucination. In psychotic remission of the same patients, activity of the ventral striatum was increased and correlated with negative symptoms such as emotional withdrawal and blunted affect. Results were controlled for volumetric and medication effects. These data provide first evidence that in schizophrenia intrinsic activity is changed in the striatum and corresponds to disorder states and symptom dimensions.

Aberrant intrinsic connectivity of hippocampus and amygdala overlap in the fronto-insular and dorsomedial-prefrontal cortex in major depressive disorder.

Neuroimaging studies of major depressive disorder (MDD) have consistently observed functional and structural changes of the hippocampus (HP) and amygdale (AY). Thus, these brain regions appear to be critical elements of the pathophysiology of MDD. The HP and AY directly interact and show broad and overlapping intrinsic functional connectivity (iFC) to other brain regions. Therefore, we hypothesized the HP and AY would show a corresponding pattern of aberrant intrinsic connectivity in MDD. Resting-state functional MRI was acquired from 21 patients with MDD and 20 healthy controls. ß-Maps of region-of-interest-based FC for bilateral body of the HP and basolateral AY were used as surrogates for iFC of the HP and AY. Analysis of variance was used to compare ß-maps between MDD and healthy control groups, and included covariates for age and gender as well as gray matter volume of the HP and AY. The HP and AY of MDD patient's showed an overlapping pattern of reduced FC to the dorsomedial-prefrontal cortex and fronto-insular operculum. Both of these regions are known to regulate the interactions among intrinsic networks (i.e., default mode, central executive, and salience networks) that are disrupted in MDD. These results provide the first evidence of overlapping aberrant HP and AY intrinsic connectivity in MDD. Our findings suggest that aberrant HP and AY connectivity may interact with dysfunctional intrinsic network activity in MDD.

Acoustic oddball during NREM sleep: a combined EEG/fMRI study.

BACKGROUND: A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. METHODOLOGY/PRINCIPAL FINDINGS: Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. CONCLUSIONS/SIGNIFICANCE: We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state with relatively increased stimulus processing, revealing an activity pattern resembling novelty processing as previously reported during wakefulness. The KC itself is not reflected by increased metabolic demand in BOLD based imaging, arguing that evoked KCs result from increased neural synchronicity without altered metabolic demand.