Evidencing a place for the hippocampus within the core scene processing network

Functional neuroimaging studies have identified several “core” brain regions that are preferentially activated by scene stimuli, namely posterior parahippocampal gyrus (PHG), retrosplenial cortex (RSC), and transverse occipital sulcus (TOS). The hippocampus (HC), too, is thought to play a key role in scene processing, although no study has yet investigated scene‐sensitivity in the HC relative to these other “core” regions. Here, we characterised the frequency and consistency of individual scene‐preferential responses within these regions by analysing a large dataset (n = 51) in which participants performed a one‐back working memory task for scenes, objects, and scrambled objects. An unbiased approach was adopted by applying independently‐defined anatomical ROIs to individual‐level functional data across different voxel‐wise thresholds and spatial filters. It was found that the majority of subjects had preferential scene clusters in PHG (max = 100% of participants), RSC (max = 76%), and TOS (max = 94%). A comparable number of individuals also possessed significant scene‐related clusters within their individually defined HC ROIs (max = 88%), evidencing a HC contribution to scene processing. While probabilistic overlap maps of individual clusters showed that overlap “peaks” were close to those identified in group‐level analyses (particularly for TOS and HC), inter‐individual consistency varied across regions and statistical thresholds. The inter‐regional and inter‐individual variability revealed by these analyses has implications for how scene‐sensitive cortex is localised and interrogated in functional neuroimaging studies, particularly in medial temporal lobe regions, such as the HC. Hum Brain Mapp 37:3779–3794, 2016. © 2016 Wiley Periodicals, Inc .     

Evidence for the persistence of contextual fear memories following immediate extinction

Evidence suggests that extinction, the suppression of a learned response to a Pavlovian signal that is produced by exposure to the signal alone after conditioning, is a consequence of new inhibitory learning. However, it has been proposed that extinction given immediately after conditioning reflects memory ‘erasure’. Using contextual fear conditioning, we examine the nature of extinction further using a novel behavioral paradigm that probes for the absence or presence of a memory. Rats received a context paired with one of three different shock intensities (0.8, 1.2 or 1.6 mA) and then received extinction either immediately (15 min) or after a delay (24 h). Spontaneous recovery was roughly equivalent in the immediate and delayed extinction groups when they were tested at 24 h after extinction. To further test the status of the original memory trace, we exploited the effect that only the first, but not second, learning of contextual fear requires N‐methyl‐D‐aspartate receptors (NMDArs) in the dorsal hippocampus [ M.J. Sanders & M.S. Fanselow (2003) Neurobiology of Learning and Memory 80 ,123–129]. Here we use this property of second learning to determine if memory of an immediately extinguished fear also persists. Rats received bilateral infusions of the NMDAr antagonist DL‐2‐amino‐5‐phosphonopentanoic acid into the dorsal hippocampus prior to training in a novel second context. Memory for the second learning is not affected by NMDAr blockade in either group, suggesting that the extinguished memory is not erased but inhibited. Overall, the results provide little evidence that extinction conducted immediately after conditioning destroys or erases the original memory trace.     

The case for long-acting antipsychotic agents in the post-CATIE era

OBJECTIVE: Long-acting antipsychotic agents were developed to promote treatment compliance in patients requiring maintenance treatment for schizophrenia. METHOD: An analysis of the impact of non-compliance on treatment outcomes in schizophrenia and the advantages and disadvantages of long-acting antipsychotics. RESULTS: Partial or total non-compliance with oral antipsychotics remains widespread and is associated with significant increases in the risk of relapse, rehospitalization, progressive brain tissue loss and further functional deterioration. Long-acting agents have the potential to address issues of all-cause discontinuation and poor compliance. The development of the first long-acting atypical antipsychotic, which appears to be effective and well tolerated, should further improve the long-term management of schizophrenia. CONCLUSION: Long-acting agents represent a valuable tool for the management of schizophrenia and merit wider use, especially in light of emerging literature regarding the neuroprotective advantages of atypical antipsychotics over conventional agents in terms of regenerating brain tissue during maintenance therapy.     

Immunohistochemical localization of candidates for vesicular glutamate transporters in the rat brain

Vesicular glutamate transporter 1 (VGluT1) is one of the best markers for glutamatergic neurons, because it accumulates transmitter glutamate into synaptic vesicles. Differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI) shows 82% amino acid identity to VGluT1, and is another candidate for vesicular glutamate transporters. Here, we report the immunocytochemical localization of DNPI and compare it with that of VGluT1 in the adult rat brain. Both DNPI and VGluT1 immunoreactivities were found mostly in neuropil, presumably in axon terminals, throughout the brain. In the telencephalic regions, intense DNPI immunoreactivity was observed in the glomeruli of the olfactory bulb, layer IV of the neocortex, granular layer of the dentate gyrus, presubiculum, and postsubiculum. In contrast, VGluT1 immunoreactivity was intense in the olfactory tubercle, layers I-III of the neocortex, piriform cortex, entorhinal cortex, hippocampus, dentate gyrus, and subiculum. In the thalamic nuclei, DNPI-immunoreactive terminal-like profiles were much larger than VGluT1-immunoreactive ones, suggesting that DNPI immunoreactivity was subcortical in origin. DNPI immunoreactivity was much more intense than VGluT1 immunoreactivity in many brainstem and spinal cord regions, except the pontine nuclei, interpeduncular nucleus, cochlear nuclei, and external cuneate nucleus. In the molecular layer of the cerebellar cortex, climbing-like fibers showed intense DNPI immunoreactivity, whereas neuropil contained dense VGluT1-immnoreactive deposits. Both DNPI and VGluT1 immunoreactivities were observed as mossy fiber terminal-like profiles in the cerebellar granular layer. DNPI and VGluT1 immunoreactivities appeared associated with synaptic vesicles in the axon terminals forming asymmetric synapses in several regions examined electron microscopically. The present results indicate that DNPI and VGluT1 are used by different neural components in most, if not all, brain regions, suggesting the complementary functions of DNPI and VGluT1.     

Further evidence for the efficacy of association splitting as a self-help technique for reducing obsessive thoughts

Background: Despite improved treatment options, many people with obsessive–compulsive disorder (OCD) do not seek or even actively avoid therapy due to shame or fear of stigmatization. Self‐help treatment is increasingly acknowledged as a means to “treat the untreated” and to motivate patients for face‐to‐face psychotherapy. Our group has gathered preliminary evidence for the efficacy of a novel self‐help approach entitled association splitting (AS) aimed at the reduction of obsessions. Methods: For this study, a total of 46 participants with a likely diagnosis of OCD were randomly allocated to either AS or a waitlist control (WL). Treatment consisted of the self‐study of a manual sent via e‐mail. At baseline and four weeks later symptoms were assessed online using the self‐report version of the Yale‐Brown Obsessive‐Compulsive Scale (Y‐BOCS), the Obsessive‐Compulsive Inventory‐Revised (OCI‐R), and the Beck Depression Inventory (BDI). Results: A total of 74% of the initial sample took part in the re‐assessment. Results were in accordance with prior uncontrolled data indicating that AS is a feasible approach leading to a symptom decline of approximately 25% on the Y‐BOCS. The technique also exerted a positive effect on depression (BDI) and the OCI‐R subscale obsessive thoughts. Conclusions: The study confirms the feasibility and efficacy of AS for a subgroup of patients with OCD. Ongoing studies explore whether short‐term effects are maintained over time and whether therapist‐guided therapy may enhance the efficacy of AS. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.     

A new statistical model for the Day Reconstruction Method

The Day Reconstruction Method (DRM) is a method to measure one's subjective affective status by soliciting information in a questionnaire about the previous day's activities. We developed a new model to examine the association of daily activities, the friendliness of interacting partners, and time‐of‐day on net affect scores among 10,377 adults participating in the World Health Organization's Study on global ageing and adult health (SAGE). A multilevel regression was fitted and the time‐of‐day effect was modeled by restricted cubic spline. The net affect score was a serpentine curve; stable from 4 a.m. to 6 a.m., increased from 7 a.m. to 12 noon, and became stable onwards. Participants had the highest net affect scores during religious activities (0.48, 95% confidence interval [CI]: 0.44, 0.53), and they enjoyed leisure activities, exercising, and household responsibilities more than work. Compared with events that lacked interacting partners, activities with very friendly interacting partners were associated with higher net affect scores (0.21, 95% CI: 0.19, 0.22), but events with slightly friendly interacting partners, slightly irritating or very irritating partners had lower net affect scores. To conclude, researchers using DRM for assessing well‐being status across time should include the type of activities and the friendliness of the interacting partners.     

Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis

The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.     

Enhancing the representation of functional connectivity networks by fusing multi‐view information for autism spectrum disorder diagnosis

Functional connectivity network provides novel insights on how distributed brain regions are functionally integrated, and its deviations from healthy brain have recently been employed to identify biomarkers for neuropsychiatric disorders. However, most of brain network analysis methods utilized features extracted only from one functional connectivity network for brain disease detection and cannot provide a comprehensive representation on the subtle disruptions of brain functional organization induced by neuropsychiatric disorders. Inspired by the principles of multi‐view learning which utilizes information from multiple views to enhance object representation, we propose a novel multiple network based framework to enhance the representation of functional connectivity networks by fusing the common and complementary information conveyed in multiple networks. Specifically, four functional connectivity networks corresponding to the four adjacent values of regularization parameter are generated via a sparse regression model with group constraint ( l_2,1 ‐norm), to enhance the common intrinsic topological structure and limit the error rate caused by different views. To obtain a set of more meaningful and discriminative features, we propose using a modified version of weighted clustering coefficients to quantify the subtle differences of each group‐sparse network at local level. We then linearly fuse the selected features from each individual network via a multi‐kernel support vector machine for autism spectrum disorder (ASD) diagnosis. The proposed framework achieves an accuracy of 79.35%, outperforming all the compared single network methods for at least 7% improvement. Moreover, compared with other multiple network methods, our method also achieves the best performance, that is, with at least 11% improvement in accuracy.     

A model for the differentiation between grid and conjunctive units in medial entorhinal cortex

The multiple layers of medial entorhinal cortex (mEC) contain cells that differ in selectivity, connectivity, and cellular properties. Grid cells in layer II and in the deeper layers express triangular grid patterns in the environment. The firing rate of the conjunctive cells found in layer III and below, on the other hand, show grid‐by‐head direction tuning. In this study, we model the differentiation between grid and conjunctive cells in a network with self‐organized connections. Arranged into distinct “layers”, the model grid units and conjunctive units develop, with a similar time course, grid fields resulting from firing rate adaptation and competitive learning. Grid alignment in both layers is delayed with respect to the formation of triangular grids. A common grid orientation among conjunctive units is produced, in the model, by head‐direction modulated collateral interactions, while the grids of grid units inherit the same orientation through connections from conjunctive units. Grid units as well as conjunctive units share a similar spacing but show a random distribution of spatial phases. Grid units however carry more spatial information than conjunctive units, thus providing better inputs for the hippocampus to form spatial memories. © 2013 Wiley Periodicals, Inc.     

Immunocytochemical localization of candidates for vesicular glutamate transporters in the rat cerebral cortex.

Brain-specific Na(+)-dependent inorganic phosphate cotransporter (BNPI) was recently reported to serve as a vesicular glutamate transporter (VGluT), and was renamed VGluT1 (Bellocchio et al. [ 2000] Science 289:957-960; Takamori et al. [2000] Nature 407:189-194). Ahead of these reports, cDNA encoding another brain-specific inorganic phosphate transporter, which showed 82% amino acid identity to VGluT1, was cloned and designated differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI; Aihara et al. [2000] J Neurochem 74:2622-2625). In the present study, we produced a specific antibody against a C-terminal portion of DNPI, and studied the immunohistochemical localization of DNPI in the rat cerebral cortex in comparison with that of VGluT1. DNPI immunoreactivity was enriched in neuropil of layers I and IV and to a lesser extent in the upper portion of layer VI of the cerebral neocortex, whereas VGluT1 immunoreactivity was distributed more evenly in neuropil of the neocortex. Electron microscopic observation revealed that both DNPI and VGluT1 immunoreactivities were mainly located on synaptic vesicles in nerve terminals which made asymmetrical contacts in the neocortex. Furthermore, neither DNPI nor VGluT1 immunoreactivity in the neocortex was colocalized with gamma aminobutyric acid (GABA)ergic axon terminal markers, immunoreactivity for glutamic acid decarboxylase or vesicular GABA transporter. Neuronal depletion in the ventrobasal thalamic nuclei produced by the kainic acid injection resulted in a clear reduction of DNPI immunoreactivity in layers I, IV, and VI of the somatosensory cortex. These results indicate that DNPI is located on the membrane of synaptic vesicles in thalamocortical axon terminals, and that it may be a candidate for VGluT of thalamocortical glutamatergic neurons.     

Pre‐hospital notification reduced the door‐to‐needle time for iv t‐PA in acute ischaemic stroke

Background and purpose: Intrahospital delay is the most serious obstacle in thrombolysis in acute ischaemic stroke (AIS). We implemented the pre‐hospital notification system from the emergency medical information system in our metropolitan area to reduce intrahospital delay. Methods: From October 2007, we implemented a 24‐h hotline system between our stroke center and the Korean Emergency Medical Information System in Busan. We compared processing times and clinical outcomes amongst patients after using intravenous tissue type plasminogen activator (iv t‐PA) with and without the hotline system. Results: After the pre‐hospital notification system was implemented, the rate of iv t‐PA use increased from 6.5% to 14.3%. Time of onset in patients with pre‐hospital notification was much longer than in patients without (121.5 ± 34.8 min vs. 74.7 ± 38.5 min, P < 0.01) notification but door‐to‐needle time was significantly reduced (28.9 ± 11.4 min vs. 47.7 ± 22.8 min, P < 0.01). However, there were no significant differences in 90‐day clinical outcomes between the two groups. Conclusions: The pre‐hospital notification system reduced intrahospital processing times which led to increased iv t‐PA use after AIS. However, the improvement of clinical outcomes in thrombolysis might require organization of not only intrahospital processes but of outside processes such as the early recognition and rapid dispatch of patients with suspected AIS.     

The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse

Background The role of intestinal microbiota in the development and function of host physiology is of high interest, especially with respect to the nervous system. While strong evidence has accrued that intestinal bacteria alter host nervous system function, mechanisms by which this occurs have remained elusive. For this reason, we have carried out experiments examining the electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system (ENS) in germ‐free (GF) mice compared with specific pathogen‐free (SPF) control mice and adult germ‐free mice that have been conventionalized (CONV‐GF) with intestinal bacteria. Methods Segments of jejunum from 8 to 12 week old GF, SPF, and CONV‐GF mice were dissected to expose the myenteric plexus. Intracellular recordings in current‐clamp mode were made by impaling cells with sharp microelectrodes. Action potential (AP) shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured. Key Results In GF mice, excitability was decreased in myenteric afterhyperpolarization (AH) neurons as measured by a lower resting membrane potential and by the number of APs generated at 2× threshold. The post AP slow afterhyperpolarization (sAHP) was prolonged for GF compared with SPF and CONV‐GF animals. Passive membrane characteristics were also altered in GF mice by a decrease in input resistance. Conclusions & Inferences Here, we report the novel finding that commensal intestinal microbiota are necessary for normal excitability of gut sensory neurons and thus provide a potential mechanism for the transfer of information between the microbiota and nervous system.     

Review of the operational definition for first-episode psychosis

Aim: Given the growing interest in the study of first‐episode psychosis, clinical and research programmes would benefit from a conceptual clarification of how to operationalize ‘first‐episode psychosis’. We review the variety of definitions in use and discuss their relative merits with respect to both clinical (e.g. early treatment) and research (e.g. obtaining meaningfully homogeneous populations) agendas. Methods: We completed a selective review of the literature to investigate how first‐episode psychosis was operationally defined. Results: Operational definitions for ‘first‐episode psychosis’ fall largely into three categories: (i) first treatment contact; (ii) duration of antipsychotic medication use; and (iii) duration of psychosis. Each definitional category contains a number of underlying assumptions that contribute to the strengths and weaknesses of the definition. Conclusions: The term ‘first‐episode psychosis’ as used within clinical and research settings is misleading regardless of which operational definition is used. This term is typically used to refer to individuals early in the course of a psychotic illness or treatment rather than individuals who are truly in the midst of a first ‘episode’ of illness. The alternative of ‘recent‐onset psychosis’ with related definitions based on ‘duration of psychosis’ is proposed. Based on this review, we provide suggestions with regard to the overarching pragmatic consideration of setting up a clinical service that can attract and assemble a population of early psychosis patients for the related purposes of treatment and research.     

Reliability of the Burke-Fahn-Marsden scale in a multicenter trial for dystonia.

BACKGROUND: The multicenter SPIDY trial (pallidal stimulation for generalized, idiopathic dystonia) recently reported a marked improvement in dystonia which was assessed by the Burke-Fahn-Marsden (BFM) scale. However, the reliability of this tool has rarely been evaluated and its use in a multicenter study has never been assessed prospectively. PURPOSE: To evaluate the concordance between three unblinded clinical raters and one single-blinded rater for 10 prospective series of ratings on the BFM scale in 22 dystonic patients of the SPIDY study. METHODS: Ten assessments on the BFM scale were performed under various stimulation conditions at different time points (before surgery and 1, 3, 6, and 12 months afterwards). Patients were first evaluated by three unblinded clinical raters (one per center). All assessments were videotaped and sent to a blinded rater. Intra- and inter-rater reliability was assessed using intraclass correlation coefficients. RESULTS: The intra-rater reliability at inclusion was better for the blinded rater than for the clinical raters. The inter-rater reliability (comparing the blinded rater with each clinical rater) was "very good" at inclusion, "fair" at month 1 and was "good" at month 3, month 6, and month 12. CONCLUSION: Blinding (rather than video) is probably the key factor in better intra-rater reliability and can produce more accurate rating than clinical rating. Consequently, a blind procedure should be performed systematically in multicenter studies. As inter-rater reliability is good in trained unblinded raters, the BFM scale may also be used in the follow up of dystonic patients in movement disorders centers, in clinical practice.     

Concentric-needle single-fiber electromyography for the diagnosis of myasthenia gravis

The goal of this study was to estimate the accuracy of concentric-needle single-fiber electromyography (CN-SFEMG) for the diagnosis of myasthenia gravis (MG). A consecutive series of patients referred for CN-SFEMG was evaluated by an investigator blinded to the results of CN-SFEMG in order to determine the presence or absence of MG using an independent reference standard. Sensitivity, specificity, predictive values, and likelihood ratios were calculated. The study population included 51 patients (21 with MG). CN-SFEMG was normal in 34 patients (67%) and abnormal in 17 (33%). The sensitivity of CN-SFEMG for the diagnosis of MG was 0.67 and the specificity was 0.96. The positive likelihood ratio was 16.8 and the negative likelihood ratio was 0.34. The positive and negative predictive values were 0.93 and 0.76, respectively. These results indicate that CN-SFEMG showing abnormal jiggle is extremely useful for confirming the diagnosis of MG, but that CN-SFEMG showing normal jiggle has limited utility in excluding the diagnosis.