Neurobiological Data Research Articles

Catechol-O-methyltransferase, Cognition and Alzheimer's Disease.

Cognition is a complex trait representing a set of all mental abilities and processes related to knowledge. Although diverse brain regions are involved, most cognitive processes appear to engage cortical regions. The activity of dopaminergic neurons in prefrontal cortex represents a biological substrate underlying cognitive functions. Alzheimer's Disease (AD) is the most frequent dementia associated with cognitive impairments. Cognitive impairment in AD starts slowly with discrete deterioration in memory, language, thinking and reasoning, but it progresses into more severe and debilitating cognitive dysfunction. Cognitive function is affected by the complex interactions between various genetic, epigenetic, developmental and environmental factors. One of the most studied genes, associated with cognitive disturbances, is the gene coding for Catechol-O-methyltransferase (COMT), the enzyme with major role in dopamine metabolism and modulation of different brain functions. Therefore, COMT is studied as a target for many neuropsychiatric disorders, including dementias and AD. The COMT Val158/108Met functional polymorphism affects significantly the enzyme activity and consequently cognitive performance associated with altered dopamine function. The association of COMT Val158/108Met polymorphism with some cognitive domains and psychosis in AD was reported in some but not in all studies. Besides COMT Val158/108Met polymorphism, other risk genotypes or haplotypes should be evaluated to determine the association of COMT with cognitive decline in AD. Better understanding of the role of COMT in cognitive processes in AD, as well as integration of neurobiological, genetic, genomic and epigenetic data, might help in developing new potential therapies of cognitive impairments and psychotic symptoms, characteristic features of AD.

Not all smokers appear to seek nicotine for the same reasons: implications for preclinical research in nicotine dependence.

Tobacco use leads to 6 million deaths every year due to severe long-lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70 percent of smokers wish to do so. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Evidence supports that the population of smokers is heterogeneous, particularly as regards the breadth of motives that determine the urge to smoke. Here, we review converging psychological, genetic and neurobiological data from clinical and preclinical studies supporting that the mechanisms controlling nicotine seeking may vary from individual to individual. It appears timely that basic neuroscience integrates this heterogeneity to refine our understanding of the neurobiology of nicotine seeking, as tremendous progress has been made in modeling the various psychopharmacological mechanisms driving nicotine seeking in rodents. For a better understanding of the mechanisms that drive nicotine seeking, we emphasize the need for individual-based research strategies in which nicotine seeking, and eventually treatment efficacy, are determined while taking into account individual variations in the mechanisms of nicotine seeking.

Assimilation of Biophysical Neuronal Dynamics in Neuromorphic VLSI.

Representing the biophysics of neuronal dynamics and behavior offers a principled analysis-by-synthesis approach toward understanding mechanisms of nervous system functions. We report on a set of procedures assimilating and emulating neurobiological data on a neuromorphic very large scale integrated (VLSI) circuit. The analog VLSI chip, NeuroDyn, features 384 digitally programmable parameters specifying for 4 generalized Hodgkin-Huxley neurons coupled through 12 conductance-based chemical synapses. The parameters also describe reversal potentials, maximal conductances, and spline regressed kinetic functions for ion channel gating variables. In one set of experiments, we assimilated membrane potential recorded from one of the neurons on the chip to the model structure upon which NeuroDyn was designed using the known current input sequence. We arrived at the programmed parameters except for model errors due to analog imperfections in the chip fabrication. In a related set of experiments, we replicated songbird individual neuron dynamics on NeuroDyn by estimating and configuring parameters extracted using data assimilation from intracellular neural recordings. Faithful emulation of detailed biophysical neural dynamics will enable the use of NeuroDyn as a tool to probe electrical and molecular properties of functional neural circuits. Neuroscience applications include studying the relationship between molecular properties of neurons and the emergence of different spike patterns or different brain behaviors. Clinical applications include studying and predicting effects of neuromodulators or neurodegenerative diseases on ion channel kinetics.

Psychosis subgroups differ in intrinsic neural activity but not task-specific processing

Individuals with psychosis often show high levels of intrinsic, or nonspecific, neural activity, but attenuated stimulus-specific activity. Clementz et al. (2016) proposed that one subgroup of psychosis cases has accentuated intrinsic activity (Biotype-2's) and a different subgroup (Biotype-1's) has diminished intrinsic activity, with both groups exhibiting varying degrees of cognitive deficits. This model was studied by assessing neural activity in psychosis probands (N=105) during baseline and a 5second period in preparation for a pro-/anti-saccade task. Steady-state stimuli allowed real-time assessment of modulation of visuocortical investment to different target locations.Psychosis probands as a whole showed poor antisaccade performance. As expected, Biotype-1 showed diminished intrinsic neural activity and the worst behavior, and Biotype-2 showed accentuated intrinsic activity and less deviant behavior. Both of these groups also exhibited less dynamic oscillatory phase synchrony. Biotype-3 showed no neurophysiological differences from healthy individuals, despite a history of psychosis. Interestingly, all psychosis subgroups showed normal (i.e., not different from healthy) preparatory modulation of visuocortical investment as a function of cognitive demands, despite varying levels of task performance. Similar analyses conducted subgrouping cases by psychotic symptomatology revealed fewer and less consistent differences, including no intrinsic activity differences between any clinical subgroup and healthy individuals. This study illustrates that (i) differences in intrinsic neural activity may be a fundamental characteristic of psychosis and need to be evaluated separately from stimulus-specific responses, and (ii) grouping patients based on multidimensional classification using neurobiological data may have advantages for resolving heterogeneity and clarifying illness mechanisms relative to traditional psychiatric diagnoses.

Interpersonal trauma: psychodynamic psychotherapy and neurobiology

ABSTRACTIn psychodynamic theory, trauma is associated with a life event, which is defined by its intensity, by the inability of the person to respond adequately and by its pathologic long-lasting effects on the psychic organization. In this paper, we describe how neurobiological changes link to psychodynamic theory.Initially, Freud believed that all types of neurosis were the result of former traumatic experiences, mainly in the form of sexual trauma. According to the first Freudian theory (1890–1897), hysteric patients suffer mainly from relevant memories. In his later theory of ‘differed action’, i.e., the retroactive attribution of sexual or traumatic meaning to earlier events, Freud links the consequences of sexual trauma in childhood with the onset of pathology in adulthood (Boschan, 2008).The transmission of trauma from parents to children may take place from one generation to the other. The trauma that is being experienced by the child has an interpersonal character and is being reinforced by the parents’ own traumatic experience. The subject’s interpersonal exposure through the relationship with the direct victims has been recognized as a risk factor for the development of a post-traumatic stress disorder.Trauma may be transmitted from the mother to the foetus during the intrauterine life (Opendak & Sullivan, 2016). Empirical studies also demonstrate that in the first year of life infants that had witnessed violence against their mothers presented symptoms of a post-traumatic disorder. Traumatic symptomatology in infants includes eating difficulties, sleep disorders, high arousal level and excessive crying, affect disorders and relational problems with adults and peers. Infants that are directly dependant to the caregiver are more vulnerable and at a greater risk to suffer interpersonal trauma and its neurobiological consequences (Opendak & Sullivan, 2016). In older children symptoms were more related to the severity of violence they had been exposed to than to the mother’s actual emotional state, which shows that the relationship between mother’s and child’s trauma is different in each age stage.The type of attachment and the quality of the mother-child interactional relationship contribute also to the transmission of the trauma. According to Fonagy (2003), the mother who is experiencing trauma is no longer a source of security and becomes a source of danger. Thus, the mentalization ability may be destroyed by an attachment figure, which caused to the child enough stress related to its own thoughts and emotions to an extent, that the child avoids thoughts about the other’s subjective experience.At a neurobiological level, many studies have shown that the effects of environmental stress on the brain are being mediated through molecular and cellular mechanisms. More specifically, trauma causes changes at a chemical and anatomical level resulting in transforming the subject’s response to future stress.The imprinting mechanisms of traumatic experiences are directly related to the activation of the neurobiological circuits associated with emotion, in which amygdala play a central role. The traumatic experiences are strongly encoded in memory and difficult to be erased. Early stress may result in impaired cognitive function related to disrupted functioning of certain areas of the hippocampus in the short or long term.Infants or young children that have suffered a traumatic experience may are unable to recollect events in a conscious way. However, they may maintain latent memory of the reactions to the experience and the intensity of the emotion. The neurobiological data support the ‘deferred action’ of the psychodynamic theory according which when the impact of early interpersonal trauma is so pervasive, the effects can transcend into later stages, even after the trauma has stopped.The two approaches, psychodynamic and neurobiological, are not opposite, but complementary. Psychodynamic psychotherapists and neurobiologists, based on extended theoretical bases, combine data and enrich the understanding of psychiatric disorders in childhood. The study of interpersonal trauma offers a good example of how different approaches, biological and psychodynamic, may come closer and possibly be unified into a single model, which could result in more effective therapeutic approaches.

Subtle visuomotor deficits and reduced benefit from practice in early treated phenylketonuria

ABSTRACTIntroduction: Phenylketonuria (PKU) is a rare metabolic disease that causes slight-to-severe neurological symptoms. Slow performance has been observed in PKU but the influence of high-order (i.e., not purely motor) deficits and of temporary variations of the phenylalanine (Phe) level on this slowness has not been fully corroborated as yet. Response speed and the effect of motor practice during the performance of a visuomotor coordination task were measured, in a group of patients with early-treated phenylketonuria (ET PKU). Method: We compared the performance of a group of early-treated PKU patients with ages ranging from 11 to 25 years and a control group of healthy volunteers on a computerized visuomotor task. Participants performed rapid movements towards one of five response buttons, as indicated by a visual stimulus that could appear in five different positions on a computer screen. The results of our visuomotor task were correlated with neurobiological data (Phe levels) and with neuropsychological measures of motor (finger tapping) and executive functions (Stroop task). Results: The ET PKU group showed slower responses than the control group. Furthermore, an absence of a practice effect (i.e., faster response times at the end of the study) was found in the PKU group but not in the control group. Our results also revealed that this absence of practice effect correlated with higher Phe levels on the testing day with respect to the average Phe level of the previous 12 months and, although weakly, with performance on the Stroop task. Conclusions: This pattern of results indicates slower visuomotor performance and a less beneficial effect of practice in ET PKU. The correlations found among our visuomotor measures, the same-day Phe level, and the Stroop test may reflect the negative effects of dopamine reduction in brain areas involved in motor control, selective attention, and learning.

Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder that is characterized by several motor and phonic tics. Tics usually develop before 10 years of age, exhibit a waxing and waning course and typically improve with increasing age. A prevalence of approximately 1% is estimated in children and adolescents. The condition can result in considerable social stigma and poor quality of life, especially when tics are severe (for example, with coprolalia (swearing tics) and self-injurious behaviours) or when GTS is accompanied by attention-deficit/hyperactivity disorder, obsessive-compulsive disorder or another neuropsychiatric disorder. The aetiology is complex and multifactorial. GTS is considered to be polygenic, involving multiple common risk variants combined with rare, inherited or de novo mutations. These as well as non-genetic factors (such as perinatal events and immunological factors) are likely to contribute to the heterogeneity of the clinical phenotype, the structural and functional brain anomalies and the neural circuitry involvement. Management usually includes psychoeducation and reassurance, behavioural methods, pharmacotherapy and, rarely, functional neurosurgery. Future research that integrates clinical and neurobiological data, including neuroimaging and genetics, is expected to reveal the pathogenesis of GTS at the neural circuit level, which may lead to targeted interventions.

Differential predictors of DSM-5 PTSD and ICD-11 complex PTSD among African American women

ABSTRACTBackground: Complex posttraumatic stress disorder (CPTSD) is proposed for inclusion in the ICD-11 as a diagnosis distinct from posttraumatic stress disorder (PTSD), reflecting deficits in affective, self-concept, and relational domains. There remains significant controversy over whether CPTSD provides useful diagnostic information beyond PTSD and other comorbid conditions, such as depression or substance use disorders.Objective: The present study examined differences in psychiatric presentation for three groups: traumatized controls, DSM-5 PTSD subjects, and ICD-11 CPTSD subjects.Method: The sample included 190 African American women recruited from an urban public hospital where rates of trauma exposure are high. PTSD was measured using Clinician Administered PTSD Scale for DSM-5 and CPTSD was measured using clinician administered ICD-Trauma Interview. Psychiatric diagnoses and emotion dysregulation were also assessed. In a subset of women (n = 60), emotion recognition was measured using the Penn Emotion Recognition Task.Results: There were significant differences across groups on current and lifetime major depression (p < .001) and current and lifetime alcohol and substance dependence (p < .05), with CPTSD showing the highest rates of comorbidities. CPTSD women also showed significantly higher levels of childhood abuse and lower rates of adult secure attachment. Multivariate analysis of variance showed significantly more severe PTSD and depression symptoms and, as expected, more severe emotion dysregulation and dissociation, compared to DSM-5 PTSD and traumatized control groups. Individuals with CPTSD also had higher levels of emotion recognition to faces on a computer-based behavioural assessment, which may be related to heightened vigilance toward emotional cues from others. CPTSD women had better facial emotion recognition on a computer-based assessment, which may suggest heightened vigilance toward emotional cues.Conclusions: Our results suggest clear, clinically-relevant differences between PTSD and CPTSD, and highlight the need for further research on this topic with other traumatized populations, particularly studies that combine clinical and neurobiological data.

Post-Traumatic Growth in Children and Adolescents

Introduction: Children and adolescents often suffer from adverse or even traumatic events. While clinicians and researchers so far have focused predominantly on their negative consequences more recently it has been postulated that traumatic events may exert positive effects in some individuals. In this context the concept of post-traumatic growth (PTG) has been investigated increasingly in adults. However, so far data in children and adolescents is rare. Method: We performed a narrative review of the current literature regarding PTG especially in children and adolescents as well as the pertinent literature on the PTG framework in general. Results: Data indicates that PTG in youth is quite similar to that observed among adults and can be assessed reliably in childhood and adolescents. However, mechanisms underlying the origination of PTG are still not sufficiently understood and further factors influencing its development have to be identified. Furthermore, there seems to be an overlap between PTG and concepts of resilience. Conclusion: PTG should be considered in the aftermath of trauma and may be useful in therapeutic contexts. There is a considerable dearth of objective measures of PTG causing an intensive debate whether PTG is a real positive identity change or rather a kind of safety mechanism that may be interpreted as a subconscious strategy. Neurobiological data may help to further investigate the “real” character of PTG in the future.

No calorie comfort: Viewing and drawing "comfort foods" similarly augment positive mood for those with depression.

Based on behavioral and neurobiological data, we tested the hypothesis that viewing/drawing visual images of comfort foods in the absence of eating will increase positive mood and that this effect is augmented for those with clinical symptoms of depression. A counterbalanced design was used for 60 participants with and without clinical symptoms in two variations: food image and food art. In each variation, participants viewed/drew foods high or low in fat/sugar; pre-post mood was recorded. Results show a consistent pattern: viewing/drawing comfort foods [food image (95% confidence interval): 2.72-4.85; food art (95% confidence interval): 2.65-4.62] and fruits [food image (95% confidence interval): 1.20-2.23; food art (95% confidence interval): 1.51-2.56] enhanced mood. For comfort foods, mood was augmented for those with clinical symptoms of depression [food image (95% confidence interval): 0.95-3.59; food art (95% confidence interval): 0.97-3.46]. Findings corroborate previous data and reveal a novel finding of augmented mood increases for those with clinical symptoms.

Quantum Biology: Unit Membrane Reduces Entropy Due To Wave Particle Duality

For decades the conflict between the 2nd thermodynamic law and the evolution of life has been discussed in science. Entropy should increase continuously and this fact contradicts evolution of higher ordered biological states. The current paper presents a quantum biological approach which is based on ion currents of sodium or alike channels that is supposed to produce negative entropy. The concept of matter waves when passing through ion channels leads to highly structured interference signals which can be interpreted as an increase of order or negative entropy following the Boltzmann´s statistics. The concept is supported both by neurobiological data and recent observations of entanglement and coherence in unit membranes.

The possible role of the insula in the epilepsy and the gambling disorder of Fyodor Dostoyevsky.

BackgroundThe retrospective diagnosis of Fyodor Mikhailovich Dostoyevsky’s (1821–1881) neurological and psychiatric disease proves to be particularly interesting. Recent neurobiological data suggest a solution to the questions regarding the writer’s retrospective diagnosis, claiming the insular cortex to be the origin of the rare ecstatic seizures. Regarding Dostoyevsky’s pathological gambling, this hypothesis is consistent with another finding from recent neuroscience, namely that the malfunction of the insula could be an important underlying pathology in gambling disorder.Case studyLiterary and scientific overview (1928–2015) on the subjects of Dostoyevsky’s epilepsy and gambling disorder.Discussion and conclusionTaking Dostoyevsky’s neurological (ecstatic seizures) and psychiatric (pathological gambling) disease and the crossroads into consideration, these two disciplines make regarding the underlying pathology, we would like to suggest a speculative theory that these two disorders have a common insular pathomechanism, namely, the malfunctioning of the risk prediction–risk prediction error coding system. Furthermore, based on Dostoyevsky’s case, regarding gambling disorder in general, we would like to hypothesize that the three common gambling-related cognitive distortions (near-miss effect, gambler’s fallacy, and the illusion of control) can be all attributed to the impairment of the anterior insular risk prediction–risk prediction error coding system.

From the Influence of Traumas to Therapeutic Letting Go: The Contribution of Hypnosis and EMDR

The development of new psychotherapies such as Eye Movement Desensitization and Reprocessing (EDMR) has led to numerous fresh approaches to both the treatment of trauma and to the understanding of underlying psychopathology. A unified view appears to be slowly emerging in an attempt to corroborate clinical practice with neurobiological data. This article attempts to demonstrate links between alternate psychotherapies by highlighting what appears to be an invariant among these approaches, namely “letting go.” This concept refers to a psycho-physical dynamic that combines psychological dissociation and reassociation, as well as the body’s vagotonic mechanisms. Following an explanation of this process, it is demonstrated how letting go can manifest itself physiologically and why this may be significant in the study of trauma.

Counting numbers of synaptic proteins: absolute quantification and single molecule imaging techniques.

The ability to count molecules is essential to elucidating cellular mechanisms, as these often depend on the absolute numbers and concentrations of molecules within specific compartments. Such is the case at chemical synapses, where the transmission of information from presynaptic to postsynaptic terminals requires complex interactions between small sets of molecules. Be it the subunit stoichiometry specifying neurotransmitter receptor properties, the copy numbers of scaffold proteins setting the limit of receptor accumulation at synapses, or protein packing densities shaping the molecular organization and plasticity of the postsynaptic density, all of these depend on exact quantities of components. A variety of proteomic, electrophysiological, and quantitative imaging techniques have yielded insights into the molecular composition of synaptic complexes. In this review, we compare the different quantitative approaches and consider the potential of single molecule imaging techniques for the quantification of synaptic components. We also discuss specific neurobiological data to contextualize the obtained numbers and to explain how they aid our understanding of synaptic structure and function.

Environmental enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and GABAergic interneurons

The use of more ethological animal models to study the neurobiology of anxiety has increased in recent years. We assessed the effect of an environmental enrichment (EE) protocol (24h/day over a period of two months) on anxiety-related behaviors when aged Wistar rats (21months old) were confronted with cat odor stimuli. Owing to the relationship between GABAergic interneurons and the anxiety-related neuronal network, we examined changes in the expression of Parvalbumin (PV) and 67kDa form of glutamic acid decarboxylase (GAD-67) immunoreactive cells in different brain regions involved in stress response. Behavioral results revealed that enriched rats traveled further and made more grooming behaviors during the habituation session. In the cat odor session, they traveled longer distances and they showed more active interaction with the odor stimuli and less time in freezing behavior. Zone analysis revealed that the enriched group spent more time in the intermediate zone according to the proximity of the predator odor. Regarding the neurobiological data, the EE increased the expression of PV-positive cells in some medial prefrontal regions (cingulate (Cg) and prelimbic (PL) cortices), whereas the GAD-67 expression in the basolateral amygdala was reduced in the enriched group. Our results suggest that EE is able to reduce anxiety-like behaviors in aged animals even when ethologically relevant stimuli are used. Moreover, GABAergic interneurons could be involved in mediating this resilient behavior.

How to Link Brain and Experience? Spatiotemporal Psychopathology of the Lived Body.

The focus of the present article is on sketching a psychopathology of the body in schizophrenia and linking it to brain activity. This is done providing converging data from psychopathological evidence (phenomenal), phenomenological contructs (trans-phenomenal) and neuroscientific measures (pre-phenomenal). The phenomenal level is the detailed documentation of the patients’ subjective anomalous experiences. These phenomena are explicit contents in the patients’ field of consciousness. The trans-phenomenal level targets the implicit yet operative matrix that underlies these anomalous subjective experiences. Abnormal phenomena are viewed as expressions of a modification of trans-phenomenal matrix, that is, in terms of an abnormal synthesis or integration through time of intero-, proprio- and extero-ceptive stimuli. Finally, we link the abnormalities of the trans-phenomenal matrix to pre-phenomenal alterations of the brain resting state and of its spatio-temporal organization, as documented by neurobiological methods providing spatial and temporal resolution of intrinsic brain activity (with many features of the resting state remaining yet unclear though). Based on phenomenological research, the body in schizophrenia is typically experienced in an itemized way as an object external to one’s self and unrelated to events in the external world. Based on neurobiological data, we tentatively hypothesize that such anomalies of the lived body are related to decreased integration between intero-, extero- and proprioceptive experiences by the brain’s spontaneous activity and its temporal structure. Taken all together, this suggests that we view abnormalities of bodily experience in terms of their underlying abnormal spatiotemporal features which, as we suppose, can be traced back to the spatiotemporal features of the brain’s spontaneous activity.

Exercise during early, but not late abstinence, attenuates subsequent relapse vulnerability in a rat model.

Exercise has shown promise as a nonpharmacological intervention for addiction, with evidence suggesting a potential utility for relapse prevention. In humans, exercise as an intervention is typically introduced well after the initiation of abstinence, yet neurobiological data from preclinical studies suggest that it may be more effective if initiated during early abstinence. Here, using rat models, we determined whether the beneficial effects of exercise on relapse vulnerability depends on when exercise is first initiated, during early versus late abstinence. Once rats (n=47) acquired cocaine self-administration, they were given 24-h access to cocaine (1.5 mg/kg per infusion) under a discrete trial procedure (four infusions per hour) for 10 days. The rats then began a 14-day abstinence period in which they had access (2 h per day) to a locked wheel throughout abstinence (sedentary) or an unlocked wheel during early (days 1–7), late (days 8–14) or throughout (days 1–14) abstinence (n=10–14 per group). Cocaine seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 15 of abstinence. Exercise beginning during early abstinence robustly attenuated subsequent cocaine seeking, and this effect persisted even when exercise ended on the seventh day of abstinence. In contrast, exercise during late abstinence was not effective and these animals displayed high levels of cocaine seeking similar to those observed in sedentary animals. These results indicate that the timing of exercise availability differentially impacts cocaine seeking with results suggesting that exercise during early, but not late, abstinence may provide long-term protection against cocaine relapse.

Investigating biological traces of traumatic stress in changing societies: challenges and directions from the ESTSS Task Force on Neurobiology

Traumatic stress can have severe consequences for both mental and physical health. Furthermore, both psychological and biological traces of trauma increase as a function of accumulating traumatic experiences. Neurobiological research may aid in limiting the impact of traumatic stress, by leading to advances in preventive and treatment interventions. To promote the possibility for clinical implementation of novel research findings, this brief review describes timely conceptual and methodological challenges and directions in neurobiological trauma research on behalf of the Task Force “Neurobiology of Traumatic Stress” of the European Society for Traumatic Stress Studies (ESTSS). The most important conceptual challenges are the heterogeneity of disorders and existence of subtypes across diagnostic categories: differential latent profiles and trajectories regarding symptom expression and neural correlates are being unraveled; however, similar latent classes’ approaches for treatment response and neurobiological data remain scarce thus far. The key to improving the efficacy of currently available preventive interventions and treatments for trauma-related disorders lies in a better understanding and characterization of individual differences in response to trauma and interventions. This could lead to personalized treatment strategies for trauma-related disorders, based on objective information indicating whether individuals are expected to benefit from them. The most important methodological challenge identified here is the need for large consortia and meta-analyses or, rather, mega-analyses on existent data as a first step. In addition, large multicenter studies, combining novel methods for repeated sampling with more advanced statistical modeling techniques, such as machine learning, should aim to translate identified disease mechanisms into molecular blood-based biomarker combinations to predict disorder vulnerability and treatment responses.

Do bipolar II and bipolar I disorder have different genotypes and why do we observe unipolar depression converting to bipolar II and then bipolar I?

We review the recent literature in order to establish the importance of a spectrum for bipolar affective disorder, and that unipolar depression, bipolar II and bipolar I are discrete entities that may however evolve in sequence. We discuss clinical, genetic and neurobiological data which illustrate the differences between bipolar I and bipolar II. To fit the data we suggest a series of multiple mood disorder genotypes, some of which evolve into other conditions on the bipolar spectrum. Thence, we discuss the nature of the bipolar spectrum and demonstrate how this concept can be used as the basis of a staging model for bipolar disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

On possible consequences of National Institute of Mental Health funding for psychotherapy research and training.

The National Institute of Mental Health (NIMH) has changed its funding priorities for psychotherapyrelated research. With the introduction of Research Domain Criteria (RDoC), the focus has moved away from supporting randomized controlled trials (RCTs) to an emphasis on gathering primarily neurobiological data that are associated with observable and dimensionalized psychological problems, even as they occur across diagnostic categories. Among the general domains that are to be funded are negative and positive valence systems, cognitive systems, social processes, and arousal and regulatory systems. Moreover, each domain will be studied at different levels of analysis, such as genetic, molecular, neural circuitry, physiological, and behavioral. Offering an overview of the history of psychotherapy research and its funding as an historical context, this article discusses some of the implications of this shifting model, and considers the potential impact the current NIMH funding priorities may have on therapyrelated research, the development of psychoactive medications, and the training of clinical psychologists as therapists.