Gephyrin: where do we stand, where do we go?

Gephyrin is a multifunctional protein responsible for molybdenum cofactor synthesis and the clustering of glycine and GABA(A) receptors at inhibitory synapses. Based on the structure of its two conserved domains, G and E, gephyrin is thought to form a hexagonal lattice serving as a scaffold for accessory proteins at postsynaptic sites. However, important aspects of gephyrin gene expression, protein structure and regulation, as well as the role of gephyrin in synapse formation and plasticity, remain poorly understood. Here we review the current state of knowledge about gephyrin, highlighting new research avenues based on a different structural model and a revised nomenclature for gephyrin splice variants. Unraveling the biology of gephyrin will further our understanding of glycinergic and GABAergic synapses in health and disease.     

Why do we sleep?

Slow-wave sleep consists in slowly recurring waves that are associated with a large-scale spatio-temporal synchrony across neocortex. These slow-wave complexes alternate with brief episodes of fast oscillations, similar to the sustained fast oscillations that occur during the wake state. We propose that alternating fast and slow waves consolidate information acquired previously during wakefulness. Slow-wave sleep would thus begin with spindle oscillations that open molecular gates to plasticity, then proceed by iteratively 'recalling' and 'storing' information primed in neural assemblies. This scenario provides a biophysical mechanism consistent with the growing evidence that sleep serves to consolidate memories.     

How do seizures stop?

Although often overshadowed by factors influencing seizure initiation, seizure termination is a critical step in the return to the interictal state. Understanding the mechanisms contributing to seizure termination could potentially identify novel targets for anticonvulsant drug development and may also highlight the pathophysiological processes contributing to seizure initiation. In this article, we review known physiological mechanisms contributing to seizure termination and discuss additional mechanisms that are likely to be relevant even though specific data are not yet available. This review is organized according to successively increasing "size scales"-from membranes to synapses to networks to circuits. We first discuss mechanisms of seizure termination acting at the shortest distances and affecting the excitable membranes of neurons in the seizure onset zone. Next we consider the contributions of ensembles of neurons and glia interacting at intermediate distances within the region of the seizure onset zone. Lastly, we consider the contribution of brain nuclei, such as the substantia nigra pars reticulata (SNR), that are capable of modulating seizures and exert their influence over the seizure onset zone (and neighboring areas) from a relatively great-in neuroanatomical terms-distance. It is our hope that the attention to the mechanisms contributing to seizure termination will stimulate novel avenues of epilepsy research and will contribute to improved patient care.     

Probabilistic categorization: how do normal participants and amnesic patients do it?

In probabilistic categorization tasks, various cues are probabilistically (but not perfectly) predictive of class membership. This means that a given combination of cues sometimes belongs to one class and sometimes to another. It is not yet clear how categorizers approach such tasks. Here, we review evidence in favor of two alternative conceptualizations of learning in probabilistic categorization: as rule-based learning, or as incremental learning. Each conceptualization forms the basis of a way of analyzing performance: strategy analysis assumes rule-based learning, while rolling regression analysis assumes incremental learning. Here, we contrasted the ability of each to predict performance of normal categorizers. Both turned out to predict responses about equally well. We then reviewed performance of patients with damage to regions deemed important for either rule-based or incremental learning. Evidence was again about equally compatible with either alternative conceptualization of learning, although neither predicted an involvement of the medial temporal lobe. We suggest that a new way of conceptualizing probabilistic categorization might be fruitful, in which the medial temporal lobe help set up representations that are then used by other regions to assign patterns to categories.     

Community-dwelling persons with dementia: What do they need? What do they demand? What do they do? A systematic review on the subjective experiences of persons with dementia

Objectives: Including the perspectives of persons with dementia (PwD) is essential in order to organize care structures for them. With this systematic review, we set out to screen the existing scientific evidence on self-expressions of community-dwelling individuals with dementia in order to provide a research base for developing an intervention for persons in early stages of the disease. The leading research questions for this review are: What needs do PwD living at home express? What are their subjective demands? What do they do to cope with their situation?

Methods: We performed a systematic literature review of review publications on subjective experiences of PwD. The publications were analysed using MAXQDA 10 to perform a thematic analysis.

Results: We identified 41 relevant reviews, of which 6 met our inclusion criteria. PwD experience the whole range of human emotions. Their needs and demands do not differ significantly from those of other groups of patients with chronic conditions. Coming to terms with the disease and maintaining normality appeared to be major themes. With regard to expectations from the side of professional health care, the need for accompanying, continuous support and counselling appeared to be central. Furthermore, disclosure of diagnosis represents a critical stage for PwD, but our findings indicated that they prefer to be included in this process.

Conclusions: PwD are well able to express their needs. They should be included in research since they can provide valuable findings. Furthermore, those findings should be implemented in applied dementia care.     

Progressive changes in schizophrenia: do they exist and what do they mean?

Schizophrenia is a disorder characterized by multiple symptoms, with a varied course and outcome. The etiology is yet unknown, but multiple pathological processes or, equally likely, a unique pathophysiological process, may be involved. Here, we review evidence for progressive changes in schizophrenia in order to understand further the pathophysiology of this disorder. We first present evidence for clinical and psycho-social changes over time, followed by evidence from structural brain studies that suggests that schizophrenia is a brain disorder. We then review findings from the small number of longitudinal studies that have evaluated structural brain changes in schizophrenia, followed by a review of the evidence for neurophysiological changes, both cross-sectional and longitudinal. This is followed by a discussion of possible cellular mechanisms, including NMDA receptor abnormalities, that might account for structural and functional brain changes (temporal and frontal), and we discuss how these abnormalities might be related to not only the specific signs and symptoms of schizophrenia but also to the onset and course of the illness. Finally, we discuss neurodevelopment (static and perhaps non-static alterations) and neurodegenerative theories of schizophrenia. We propose that the two are not mutually exclusive, but instead likely reflect a "two-hit" model for some subtypes of schizophrenia.     

Sleep deprivation in depression: what do we know, where do we go?

Manipulations of the sleep-wake cycle, whether of duration (total or partial sleep deprivation [SD]) or timing (partial SD, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders. Relapse after recovery sleep is less when patients are receiving medication; it may be prevented by co-administration of lithium, pindolol, serotonergic antidepressants, bright light, or a subsequent phase advance procedure. Diurnal and day-to-day mood variability predict both short-term response to SD and long-term response to antidepressant drug treatment. These mood patterns can be understood in terms of a "two-process model of mood regulation" based on the model well established for sleep regulation: the interaction of circadian and homeostatic processes. The therapeutic effect of SD is postulated to be linked to changes in disturbed circadian- and sleep-wake-dependent phase relationships and concomitant increase of slow-wave-sleep pressure; additionally, SD-induced sleepiness may counteract the hyperarousal state in depression. This model has the advantage of providing a comprehensive theoretical framework and stringent protocols ("constant routine," "forced desynchrony") to dissect out specific disturbances. Many aspects tie in with current serotonergic receptor hypotheses of SD action. A treatment inducing euthymia in severely depressed patients within hours is an important therapeutic option that has come of age for clinical use.     

Stroke care in Spain. What do we have? What do we need?

The high level of scientific evidence which supports the recommendations for the care of acute stroke in Stroke Units (SU) with a good health care network, it does not correspond to the level of introduction in Spain. In this regard, the Cerebrovascular Diseases Study Group (GEECV) of the Spanish Society of Neurology has taken the initiative to conduct the "National Survey of Stroke Care" that will help to determine the real situation in acute stroke management in Spain just before the approval of the National Stroke Strategy (NSS) by the Ministry of Health and concludes that in the first semester of 2009 there were 39 SUs, unevenly distributed with higher concentration in Madrid and Barcelona. Although the approval of the NSS was a major achievement, much remains to be done to meet the objectives. We thank the GEECV?s initiative, which gives us an "X-ray" of the, not very satisfactory, state of stroke care in Spain in December 2008, and highlighting some achievements and the many shortcomings. Therefore, we must continue to improve, refine our data collection with records that include all available resources and all the stroke patients attended. We invite GEECV to carry out a second study to evaluate the impact of NSS and to serve as a stimulus to achieve a substantial improvement in stroke care in Spain, closer to the recommendations of the new PASI document.     

Why do people injure themselves?

The aim of this study was to evaluate a questionnaire for the assessment of immediate functions of self-injurious behavior (SIB). SIB is defined as deliberate injuries of the skin such as burning, cutting or beating. Suicidal attempts as well as self-injuries for aesthetic reasons were excluded. Immediate functions were collected from the literature as well as from statements of SIB sufferers. Finally, 154 questions with the response options 'right', 'wrong' and 'unknown' -- for phenomena people did not know -- were given to 120 persons with SIB aged 13-54 years. They were recruited from SIB-related homepages as well as from psychologists and psychiatrists in hospitals in Austria and Germany. Twelve factors were extracted via factor analysis (varimax rotation): 'self-punishment', 'coping with emotions', 'extreme rage', 'vitality', 'dissociation', 'changed perception', 'control over body', 'uniqueness', 'interaction', 'addiction', 'coping with sexuality' and 'expression of sexuality'. All items of each factor were analyzed and unsatisfactory ones excluded to devise a questionnaire as short as possible but with high expressiveness and good reliability. The remaining 107 items have a reliability of r = 0.9118 (Cronbach's alpha). Evaluation of this questionnaire is in progress.     

What do psychotherapists really do in practice? An Internet study of over 2,000 practitioners

Over 2,200 North American psychotherapists completed a Web-based survey concerning their clinical work, including theoretical orientation, client characteristics, and use of specific psychotherapy techniques. Psychotherapeutic integration was common, with the majority of respondents identifying with more than one theoretical orientation or as having an eclectic orientation. The modal patient was a White female adult suffering from a mood or anxiety disorder and interpersonal problems. Individual psychotherapy was the preferred treatment modality. The most frequently endorsed techniques were relationship-oriented such as conveying warmth, acceptance, understanding, and empathy. The least frequently endorsed techniques were biofeedback, neurofeedback, body and energy therapies, and hypnotherapy. Efforts to disseminate empirically based therapies require understanding and accommodating clinicians' tendencies to integrate techniques.     

How do you define remission?

OBJECTIVE: To underscore the need to attain remission in the treatment of depression, taking into consideration the appropriate definitions of response and remission, as well as the impact of residual symptomatology. METHOD: A review of research pertaining to successful response and remission of depression following antidepressant intervention, as identified by a comprehensive MEDLINE search. RESULTS: Complete remission is both critical and attainable with appropriate antidepressant therapy. CONCLUSION: While adequate response to antidepressant medication is desired, the ultimate goal of therapy is remission, the achievement of an asymptomatic state characterized by complete functional recovery.     

Where do perseverations come from?

RB, a patient with probable Alzheimer's disease, makes continuous perseverations of single letters when writing (e.g. fruit-->fruuit), particularly on high frequency letters. An analysis of her errors reveals that her perseverations do not reflect letter substitutions or transpositions, nor do they suggest difficulty with geminates. No continuous perseverations were found in oral production, in graphic and simple motor tasks, and in oral spelling. RB's data do not support an attention deficit as the basis of her continuous perseverations. It is proposed that a deficit at the level of abstract letter representations is the source of RB's perseverations. The implications of this conclusion for accounts of perseveration and of spelling models are discussed.