Psychometric properties of the generalised version of the Screener for Substance and Behavioural Addictions (SSBA-G): A comprehensive screening tool for substance-related and behavioural addictions.

Assessing addictive behaviours comprehensively and efficiently is a challenge in both research and clinical practice. Consequently, we tested the psychometric properties of the Generalized Screener for Substance and Behavioural Addictions (SSBA-G), a novel, brief screening tool measuring functional impairment resulting from both substance and behavioural addictions. The SSBA-G was developed from the Screener for Substance and Behavioural Addictions (Schluter et al., 2018) and tested in four samples including university students in Canada (n = 481) and the US (n = 164) as well as community adults in Canada (n = 301), and Hungary (n = 79). Confirmatory factor analysis supported the hypothesized bifactor model of the SSBA-G. Receiver-operation characteristic analyses revealed high differentiation accuracy (AUC=0.86-.95), as well as identical ideal cut points across the Substance Addiction (SSBA-G-S) and Behavioural Addiction (SSBA-G-B) Subscales. Results indicated good-to-excellent sensitivity and moderate-to-good specificity. The SSBA-G demonstrated excellent internal consistency and test-retest reliability as well as promising concurrent validity in relation to the original SSBA and additional questions regarding addiction-related impairment. The SSBA-G also showed good convergent and divergent validity with indicators of general mental health. These results indicate that the SSBA-G is a psychometrically sound and efficient measure of addiction-related impairment across substances and excessive behaviours.

The Effectiveness of Family Constellation Therapy in Reducing Psychopathological Symptoms in a Naturalistic Setting.

BACKGROUND: The aim of this study (ClinicalTrials.gov identifier: NCT03233958) was to provide further evidence on the effectiveness and safety of family/systemic constellation therapy, a widely used but rarely investigated form of brief group psychotherapy. SUBJECTS AND METHODS: Altogether, 102 individuals from the general population were followed up 1- and 6 months after their participation in the 2-day intervention. Indicators of general and problem-area-specific psychopathology, interpersonal quality of life, meaning in life, and general wellbeing were assessed. Both statistical and clinical significance were considered, and active surveillance of potential iatrogenic effects was also conducted. RESULTS: The data showed significant improvement post-intervention in the case of the vast majority of the 17 outcome variables. At 1-month follow-up, the magnitude of improvements was typically in the moderate range. The patterns were very similar at the 6-month follow-up, suggesting that most intervention benefits were sustained in the middle term. Sensitivity analyses showed no therapist effects across the three intervention providers. Analyses into clinical significance showed that the most reliable improvements occurred in relation to interpersonal quality of life and non-diagnosis-specific psychopathology, with approximately half of the participants showing reliable improvement. Iatrogenic effects were comparable - both in terms of frequency and severity - to those reported for other forms of psychotherapy. CONCLUSIONS: Findings of the present study point toward the safety and effectiveness of family constellation therapy in reducing a variety of psychopathological symptoms (e.g., depression and anxiety) and increasing general well-being. This effectiveness is especially remarkable when considering the brevity and cost-effectiveness of the intervention.

Ripple-selective GABAergic projection cells in the hippocampus.

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.

Supramammillary regulation of locomotion and hippocampal activity.

Locomotor speed is a basic input used to calculate one's position, but where this signal comes from is unclear. We identified neurons in the supramammillary nucleus (SuM) of the rodent hypothalamus that were highly correlated with future locomotor speed and reliably drove locomotion when activated. Robust locomotion control was specifically identified in Tac1 (substance P)­expressing (SuMTac1+) neurons, the activation of which selectively controlled the activity of speed-modulated hippocampal neurons. By contrast, Tac1-deficient (SuMTac1−) cells weakly regulated locomotion but potently controlled the spike timing of hippocampal neurons and were sufficient to entrain local network oscillations. These findings emphasize that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a manner that may support spatial navigation.

Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior.

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.

Alternating sources of perisomatic inhibition during behavior.

Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the in vivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.

Detrimental impacts of mixed-ion radiation on nervous system function.

Galactic cosmic radiation (GCR), composed of highly energetic and fully ionized atomic nuclei, produces diverse deleterious effects on the body. In researching the neurological risks of GCR exposures, including during human spaceflight, various ground-based single-ion GCR irradiation paradigms induce differential disruptions of cellular activity and overall behavior. However, it remains less clear how irradiation comprising a mix of multiple ions, more accurately recapitulating the space GCR environment, impacts the central nervous system. We therefore examined how mixed-ion GCR irradiation (two similar 5-6 beam combinations of protons, helium, oxygen, silicon and iron ions) influenced neuronal connectivity, functional generation of activity within neural circuits and cognitive behavior in mice. In electrophysiological recordings we find that space-relevant doses of mixed-ion GCR preferentially alter hippocampal inhibitory neurotransmission and produce related disruptions in the local field potentials of hippocampal oscillations. Such underlying perturbation in hippocampal network activity correspond with perturbed learning, memory and anxiety behavior.

The prognostic value of immediate post-TAVI hemodynamic evaluation is superior to aortography and transoesophageal echocardiography in predicting patient survival.

BACKGROUND: Although post-TAVI PAR is commonly seen, its exact evaluation, grading and the true impact on patients' survival are still debated. This single center study aimed to evaluate the effect of post transcatheter aortic valve implantation (TAVI) paravalvular aortic regurgitation (PAR) on patients' survival. The outcome was evaluated by the three most commonly used techniques just after TAVI in the interventional arena. METHODS: 201 high risk patients with severe symptomatic aortic stenosis underwent TAVI with the self-expandable system. The severity of post-TAVI PAR was prospectively evaluated by aortography and transesophageal echocardiography (TEE) using a four-class scheme and hemodynamic evaluation by calculation of the regurgitation index (RI). Median follow up time was 763 days. RESULTS: Post-TAVI PAR results of the three different modalities were concordant with each other (all p < 0.001). Patients with grade 0-I PAR by aortography had better long term outcomes compared to those who had grade II-III PAR (unadjusted HR 1.77 [95% CI, 1.04-3.01], p = 0.03). Although in multivariate analysis neither aortography nor TEE were shown to be significant predictors of survival, hemodynamic assessment using the exact RI result was a significant predictor of survival and its effect was found to be linear (adjusted HR 0.72 [95% CI, 0.52-0.98] for 10% point increase in RI, p = 0.03595). CONCLUSIONS: Among the three modalities that are frequently used to evaluate the outcome, post-TAVI RI showed the highest added predictive value for survival.

Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy.

Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.

Detailed assessment of spatial and temporal variations in river channel changes and meander evolution as a preliminary work for effective floodplain management. The example of Sajó River, Hungary.

The quasi-natural meandering type of alluvial rivers is quite unusual in Central European watersheds. The lack of extensive regulation allows such rivers to shift along their floodplain and cause erosion of natural and agricultural lands. Description of channel morphometric parameters over decadal timescales allows a better understanding of such river systems like Sajó River (Slovakia-Hungary) where no preliminary work is available regarding channel dynamics. In addition, to just describing the geomorphic processes, the environmental management implications of these meandering rivers need to be investigated as well. Thus, this study represents a bend-scale morphological analysis on the 124 km long section of the Sajó River in the Hungarian territory in eight different periods between 1952 and 2011. Archive aerial imagery, orthophotographs and topographical maps were organized into a database, then GIS-based analyses were performed to quantify the rate and extent of channel shifts, bend development and the area of erosion/accretion. On the bend scale, we have calculated several morphometric parameters (bend length, chord, amplitude, the radius of curvature) to quantify the evolutionary trajectory of reaches. Hydrological time series data were evaluated to reveal its possible role in the processes. Based on the available GIS-data of natural elements and anthropogenic intervention, we delineated 12 different reaches showing similar characteristics, from which six reaches were defined as natural. According to the morphometric parameters of the natural reaches, channel widths became narrower and the planform became more concentrated spatially in most of the reaches while the overall sinuosity of almost all natural reaches increased. Although artificial cutoffs mainly reduced the reach complexity, in some cases, they have accelerated the bend development downstream in the following few years. Erosion and accretion activity were higher in the periods when the discharge was higher than the effective discharge but its effect became less apparent in the second half of the investigated time period. By 1980, major artificial cutoffs and bank protection works were carried out that could have an impact in reducing the potential channel shifting. Based on our results, we propose a possible preservation and some modifications along the Hungarian part of the Sajó River reaches to be carried out by the local river management authorities. We conclude that this study provides a detailed demonstration of the Sajó River morphodymanics which can be used for further land planning to avoid harmful consequences of recent bank erosion processes not only along the Sajó River, but other similar rivers in Europe.

Improved Efficacy of Synthesizing *MIII-Labeled DOTA Complexes in Binary Mixtures of Water and Organic Solvents. A Combined Radio- and Physicochemical Study.

Typically, the synthesis of radiometal-based radiopharmaceuticals is performed in buffered aqueous solutions. We found that the presence of organic solvents like ethanol increased the radiolabeling yields of [68Ga]Ga-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacatic acid). In the present study, the effect of organic cosolvents [ethanol (EtOH), isopropyl alcohol, and acetonitrile] on the radiolabeling yields of the macrocyclic chelator DOTA with several trivalent radiometals (gallium-68, scandium-44, and lutetium-177) was systematically investigated. Various binary water (H2O)/organic solvent mixtures allowed the radiolabeling of DOTA at a significantly lower temperature than 95 °C, which is relevant for the labeling of sensitive biological molecules. Simultaneously, much lower amounts of the chelators were required. This strategy may have a fundamental impact on the formulation of trivalent radiometal-based radiopharmaceuticals. The equilibrium properties and formation kinetics of [M(DOTA)]- (MIII= GaIII, CeIII, EuIII, YIII, and LuIII) complexes were investigated in H2O/EtOH mixtures (up to 70 vol % EtOH). The protonation constants of DOTA were determined by pH potentiometry in H2O/EtOH mixtures (0-70 vol % EtOH, 0.15 M NaCl, 25 °C). The log K1H and log K2H values associated with protonation of the ring N atoms decreased with an increase of the EtOH content. The formation rates of [M(DOTA)]- complexes increase with an increase of the pH and [EtOH]. Complexation occurs through rapid formation of the diprotonated [M(H2DOTA)]+ intermediates, which are in equilibrium with the kinetically active monoprotonated [M(HDOTA)] intermediates. The rate-controlling step is deprotonation (and rearrangement) of the monoprotonated intermediate, which occurs through H2O (*M(HL) kH2O) and OH- (*M(HL) kOH) assisted reaction pathways. The rate constants are essentially independent of the EtOH concentration, but the M(HL) kH2O values increase from CeIII to LuIII. However, the log KM(HL)H protonation constants, analogous to the log KH2 value, decrease with increasing [EtOH], which increases the concentration of the monoprotonated M(HDOTA) intermediate and accelerates formation of the final complexes. The overall rates of complex formation calculated by the obtained rate constants at different EtOH concentrations show a trend similar to that of the complexation rates determined with the use of radioactive isotopes.

Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory.

Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

Extended Interneuronal Network of the Dentate Gyrus.

Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

Different output properties of perisomatic region-targeting interneurons in the basal amygdala.

The perisomatic region of principal neurons in cortical regions is innervated by three types of GABAergic interneuron, including parvalbumin-containing basket cells (PVBCs) and axo-axonic cells (AACs), as well as cholecystokinin and type 1 cannabinoid receptor-expressing basket cells (CCK/CB1BCs). These perisomatic inhibitory cell types can also be found in the basal nucleus of the amygdala, however, their output properties are largely unknown. Here, we performed whole-cell recordings in morphologically identified interneurons in slices prepared from transgenic mice, in which the GABAergic cells could be selectively targeted. Investigating the passive and active membrane properties of interneurons located within the basal amygdala revealed that the three interneuron types have distinct single-cell properties. For instance, the input resistance, spike rate, accommodation in discharge rate, or after-hyperpolarization width at the half maximal amplitude separated the three interneuron types. Furthermore, we performed paired recordings from interneurons and principal neurons to uncover the basic features of unitary inhibitory postsynaptic currents (uIPSCs). Although we found no difference in the magnitude of responses measured in the principal neurons, the uIPSCs originating from the distinct interneuron types differed in rise time, failure rate, latency, and short-term dynamics. Moreover, the asynchronous transmitter release induced by a train of action potentials was typical for the output synapses of CCK/CB1BCs. Our results suggest that, despite the similar uIPSC magnitudes originating from the three perisomatic inhibitory cell types, their distinct release properties together with the marked differences in their spiking characteristics may contribute to accomplish specific functions in amygdala network operation.

Cannabinoid Control of Learning and Memory through HCN Channels.

The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Pass-Through Code of Synaptic Integration.

How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al. (2015) uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins.

[Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous]. / A nem szteroid gyulladásgátló készítmények cardiovascularis mellékhatásai a legújabb ajánlások fényében. Nem veszélyesebb a diclofenac.

Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti-inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non-steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid.

Resolution revolution: epilepsy dynamics at the microscale.

Our understanding of the neuronal mechanisms behind epilepsy dynamics has recently advanced due to the application of novel technologies, monitoring hundreds of neurons with single cell resolution. These developments have provided new theories on the relationship between physiological and pathological states, as well as common motifs for the propagation of paroxysmal activity. Although traditional electroencephalogram (EEG) recordings continue to describe normal network oscillations and abnormal epileptic events within and outside of the seizure focus, analysis of epilepsy dynamics at the microscale has found variability in the composition of macroscopically repetitive epileptiform events. These novel results point to heterogeneity in the underlying dynamics of the disorder, highlighting both the need and potential for more specific and targeted therapies.

Functional fission of parvalbumin interneuron classes during fast network events.

Fast spiking, parvalbumin (PV) expressing hippocampal interneurons are classified into basket, axo-axonic (chandelier), and bistratified cells. These cell classes play key roles in regulating local circuit operations and rhythmogenesis by releasing GABA in precise temporal patterns onto distinct domains of principal cells. In this study, we show that each of the three major PV cell classes further splits into functionally distinct sub-classes during fast network events in vivo. During the slower (<10 Hz) theta oscillations, each cell class exhibited its own characteristic, relatively uniform firing behavior. However, during faster (>90 Hz) oscillations, within-class differences in PV interneuron discharges emerged, which segregated along specific features of dendritic structure or somatic location. Functional divergence of PV sub-classes during fast but not slow network oscillations effectively doubles the repertoire of spatio-temporal patterns of GABA release available for rapid circuit operations.

Anatomically heterogeneous populations of CB1 cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics.

A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells.