The Efficacy of Neurofeedback in Patients with Major Depressive Disorder: An Open Labeled Prospective Study

The purpose of this study was to evaluate the effect of neurofeedback on depressive symptoms and electrophysiological disturbances in patients with major depressive disorder. We recruited participants suffering from depression to evaluate efficacy of left prefrontal beta with alpha/theta training. An 8-week, prospective, open-label study was undertaken. Twenty participants were recruited. The treatment protocol was twice or three times a week training of beta at F3 with alpha/theta at Pz for 8 weeks. When every visit, patients were received beta training for 30 min, and then alpha/theta training for 30 min. Baseline, 4 and 8 week scores of; the Hamilton rating scale for Depression (HAM-D), the Hamilton rating scale for Anxiety (HAM-A), the Beck Depression Inventory (BDI)-II, the Beck Anxiety Inventory (BAI), Clinical global impression-severity (CGI-S), and pre- and post-treatment resting state EEGs were compared. Interhemispheric alpha power asymmetry (A score) was computed for homologous sites F3–F4. Pre- and post-training clinical assessments revealed significant improvements in HAM–D, HAM-A, BDI, and CGI-S scores. Cumulative response rates by HAM-D were 35.0 and 75.0 % at 4 and 8 weeks, respectively, corresponding cumulative remission rates by HAM-D were 15.0 and 55.0 %, respectively. No significant differences were found between pre- and post-treatment A score. Neurofeedback treatment could improve depressive symptoms significantly. In addition, anxiety symptoms and clinical illness severity decreased significantly after neurofeedback treatment. Despite its several limitations, such as, small sample size and lack of a control group, this study suggested neurofeedback has significant effects in patients with major depressive disorder.     

Can Neurofeedback Training Enhance Performance? An Evaluation of the Evidence with Implications for Future Research

There have been many claims regarding the possibilities of performance enhancement training. The aim of such training is for an individual to complete a specific function or task with fewer errors and greater efficiency, resulting in a more positive outcome. The present review examined evidence from neurofeedback training studies to enhance performance in a particular area. Previous research has documented associations between specific cortical states and optimum levels of performance in a range of tasks. This information provides a plausible rationale for the use of neurofeedback to train individuals to enhance their performance. An examination of the literature revealed that neurofeedback training has been utilised to enhance performance from three main areas; sport, cognitive and artistic performance. The review examined evidence from neurofeedback training studies within each of these three areas. Some suggestive findings have been reported with regard to the use of neurofeedback training to enhance performance. However, due to a range of methodological limitations and a general failure to elicit unambiguous changes in baseline EEG activity, a clear association between neurofeedback training and enhanced performance has yet to be established. Throughout, the review highlights a number of recommendations to aid and stimulate future research.     

Evaluation of the effectiveness of EEG neurofeedback training for ADHD in a clinical setting as measured by changes in T.O.V.A. scores,behavioral ratings,and WISC-R performance

A study with three component parts was performed to assess the effectiveness of neurofeedback treatment for Attention Deficit/Hyperactivity Disorder (ADHD). The subject pool consisted of 23 children and adolescents ranging in age from 8 to 19 years with a mean of 11.4 years who participated in a 2-to 3-month summer program of intensive neurofeedback training. Feedback was contingent on the production of 16–20 hertz (beta) activity in the absence of 4–8 hertz (theta) activity. Posttraining changes in EEG activity, T.O.V.A. performance, (ADDES) behavior ratings, and WISC-R performance were assessed. Part I indicated that subjects who successfully decreased theta activity showed significant improvement in T.O.V.A. performance; Part II revealed significant improvement in parent ratings following neurofeedback training; and Part III indicated significant increases in WISC-R scores following neurofeedback training. This study is significant in that it examines the effects of neurofeedback training on both objective and subjective measures under relatively controlled conditions. Our findings corroborate and extend previous research, indicating that neurofeedback training can be an appropriate and efficacious treatment for children with ADHD.The first author (Joel F. Lubar) has provided consultative services for both Lexicor and Stoelting-Autogenics Corporations in order to help them develop appropriate protocols for neurofeedback. He is not an owner, stockholder, or employee for either organization.     

Neurobiology of comorbid post‐traumatic stress disorder and alcohol‐use disorder

Post‐traumatic stress disorder (PTSD) and alcohol‐use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state‐of‐the‐science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co‐occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross‐talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact.     

Role of social cognition in post‐traumatic stress disorder: A review and meta‐analysis

Social functioning is a key component of recovery after a potentially traumatic experience, and the buffering role of the social support in trauma resilience and recovery has been very well documented. Factors contributing to resilience and recovery are notable because although most people will experience a traumatic event during their lifetimes, only 6% to 10% are diagnosed with post‐traumatic stress disorder (PTSD). The relationship between an individual and their social environment is determined both by the quality of the social environment itself, and by the individual's perception and understanding of information conveyed by the other people around them. However, little research has considered the contribution of these internal social cognitive processes to PTSD risk or resilience. The current review draws on the existing literature on social cognitive functioning in trauma exposure and PTSD, identifying key questions and themes for future research. We utilized a meta‐analytic approach to assess the evidence for alterations in social cognition in PTSD, finding a consistent large deficit in social cognitive performance in PTSD groups relative to trauma‐exposed and healthy controls. We then reviewed the literature on the interaction of genes and the social environment, supporting the hypothesis that social cognitive deficits are a preexisting risk factor for PTSD. Finally, we reviewed relevant neuroimaging findings, which suggest that alterations in social cognition affect the perception of threat cues in PTSD. Overall, research on social cognition and PTSD is still emerging, but existing findings suggest this is an important and understudied area for the understanding of PTSD.     

Sleeping Patterns of Afghan Unaccompanied Asylum-Seeking Adolescents: A Large Observational Study

Unaccompanied asylum-seeking children (UASC) have experienced multiple traumas and are a high-risk group for posttraumatic stress disorder (PTSD). The effects of trauma are known to be associated with sleep problems; indeed sleeping problems are core features of PTSD. However, there has been no systematic research examining the sleep of this high risk group of children. This study presents the first evidence on the sleeping patterns of Afghan UASC living in the UK. A total of 222 male Afghan children, aged 13–18, were interviewed using validated self-report questionnaires measuring sleeping patterns and PTSD. Overall, UASC patterns for bed time and rise time appear acculturated to the country of asylum. Mean UASC sleep onset latency scores were approximately 20 minutes greater compared with normative scores, which may be a reflection of UASC pre-migration and post-migration experiences. As expected, UASC who screened above the clinical cut-off for PTSD reported significantly greater sleep onset latency, increased nightmares, and less total sleep time compared to the non-PTSD group. The results may be of particular interest to clinicians given that, compared to screening for PTSD, screening for sleep problems may be a less culturally disputed form of initial assessment indicating distress in UASC. Similarly, the field of UASC and refugee child interventions is largely focused on trauma, yet sleep may provide a novel avenue for equally or more effective treatment.     

Dysregulation in microRNA Expression Is Associated with Alterations in Immune Functions in Combat Veterans with Post-Traumatic Stress Disorder

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.     

Identifying Indices of Learning for Alpha Neurofeedback Training

Neurofeedback has been around for decades and has applications for both clinical and healthy populations yet there is no standard method for measuring learning or a way of defining successful learning. Thus the aim of this study was to focus on alpha neurofeedback and examine changes in three different measures: amplitude, percent time, and integrated alpha, across four methods: within sessions, across sessions, within sessions compared to baseline, and across sessions compared to baseline. Participants completed 10 weekly sessions of eyes open alpha (8–12 Hz) neurofeedback training (NFT) at Pz. Whilst all three measures showed changes within sessions, the inclusion of baselines revealed that such changes represented a return to baseline levels rather than an increase in alpha. Changes across sessions were only evident in amplitude and inclusion of baseline showed that NFT did not elicit any changes beyond baseline levels. Given this a case is made for incorporating baseline measures when attempting to identify evidence of learning. It is also suggested that both amplitude and percent time measures are used independently rather than incorporate them into a more conservative and less sensitive integrated measure. Finally, focusing on within sessions changes may be a more useful approach in identifying changes resulting from NFT.     

Testing the Benefits of Neurofeedback on Selective Attention Measured Through Dichotic Listening

The electrophysiological changes after a single session of neurofeedback training (↑SMR/↓Theta) and its effects on executive attention during a dichotic listening test with forced attentional procedures were measured in a sample of 20 healthy women. A pre–post moment test double blind design, with the inclusion of a group receiving sham neurofeedback, allowed for minimization of alien influences. The interaction of Moment × Group was significant, indicating an enhancement of SMR band after the real neurofeedback. The dichotic listening scores were correlated with the amplitude of Beta band in baseline conditions. The performance on the forced left attentional condition in dichotic listening was significantly improved and correlated positively with the post-training enhancement of the SMR band. The sham neurofeedback group also improved DL scores, so a clear affirmation about the benefits of neurofeedback training over cognitive performance could not be unambiguously established. It is concluded that the protocol showed a good independence and acceptable trainability in modifying the EEG results, but there was limited interpretability regarding cognitive outcomes.     

Open-Loop Audio-Visual Stimulation (AVS): A Useful Tool for Management of Insomnia?

Audio Visual Stimulation (AVS), a form of neurofeedback, is a non-pharmacological intervention that has been used for both performance enhancement and symptom management. We review the history of AVS, its two sub-types (close- and open-loop), and discuss its clinical implications. We also describe a promising new application of AVS to improve sleep, and potentially decrease pain. AVS research can be traced back to the late 1800s. AVS’s efficacy has been demonstrated for both performance enhancement and symptom management. Although AVS is commonly used in clinical settings, there is limited literature evaluating clinical outcomes and mechanisms of action. One of the challenges to AVS research is the lack of standardized terms, which makes systematic review and literature consolidation difficult. Future studies using AVS as an intervention should; (1) use operational definitions that are consistent with the existing literature, such as AVS, Audio-visual Entrainment, or Light and Sound Stimulation, (2) provide a clear rationale for the chosen training frequency modality, (3) use a randomized controlled design, and (4) follow the Consolidated Standards of Reporting Trials and/or related guidelines when disseminating results.     

The Mouse Grimace Scale: A Clinically Useful Tool?

Medical research has a heavy and continuing demand for rodent models across a range of disciplines. Behavioural assessment of pain in such models is highly time consuming, thus limiting the number of models and analgesics that can be studied. Facial expressions are widely used to assess pain in human infants. Recently the mouse grimace scale (MGS) has been developed and shown to be accurate and reliable, requiring only a short amount of training for the observer. This system therefore has the potential to become a highly useful tool both in pain research and clinical assessment of mouse pain. To date, the MGS has only been used as a research tool, however there is increasing interest in its use in cage-side clinical assessment. It is often wrongly assumed that MGS scores of animals not in pain (i.e. at baseline) are zero. Here, we aimed to assess the variability in baseline MGS scores between cohorts, sexes and strains of mice. Establishing the presence of a consistent baseline MGS score could lead to a valuable clinical pain assessment tool for mice when baseline information from the individual mouse may not be available as a comparator. Results demonstrated a significant difference in baseline MGS scores between both sexes (males > females) and strains of mice. The method used to score the facial action units (Live vs. retrospectively from still images) demonstrated significant differences in scores with live scores being significantly lower than retrospective scoring from images. The level of variation shown demonstrates the need for further research to be undertaken with regard to establishing baseline MGS scores for specific strains and sexes of mice, taking into account the method of scoring, prior to considering clinical implementation of this method in pain assessment.     

Alterations?in?White?Matter?Microstructure?as?Vulnerability?Factors?and?Acquired?Signs?of?Traffic?Accident-Induced?PTSD

It remains unclear whether white matter (WM) changes found in post-traumatic stress disorder (PTSD) patients are stress-induced or precursors for vulnerability. The current study aimed to identify susceptibility factors relating to the development of PTSD and to examine the ability of these factors to predict the course of longitudinal PTSD. Sixty two victims who had experienced traffic accidents underwent diffusion tensor imaging using a 3.0T MRI system within 2 days after their accidents. Of these, 21 were diagnosed with PTSD at 1 or 6 months using the Clinician-Administered Ptsd Scale (CAPS). Then, 11 trauma-exposed victims with PTSD underwent the second MRI scan. Compared with the victims without PTSD, the victims with PTSD showed decreased fractional anisotropy (FA) in WM of the anterior cingulate cortex, ventromedial prefrontal cortex (vmPFC), temporal lobes and midbrain, and increased mean diffusivity (MD) in the vmPFC within 2 days after the traumatic event. Importantly, decreased FA of the vmPFC in the acute phase predicted greater future CAPS scores. In addition, we found decreased FA in the insula in the follow-up scan in the victims with PTSD, which correlated with the decreased FA of the vmPFC in their baseline scan. These results suggested that the WM might have changed within 2 days after the traumatic event in the individuals who would later develop PTSD. Furthermore, decreased FA of the vmPFC could be a possible vulnerability marker predicting future development of PTSD and may provide an outcome prediction of the acquired signs.     

Cardiovascular Correlates of Motor Vehicle Accident Related Posttraumatic Stress Disorder and its Successful Treatment

Persons with posttraumatic stress disorder (PTSD) have been shown to display elevated baseline cardiovascular activity and a heightened physiological reactivity to trauma-related stimuli. Study 1 examined differences in baseline heart rate (HR) and HR reactivity in 68 survivors of motor vehicle accidents (MVAs) and healthy controls without MVA. MVA survivors with PTSD (n=26), subsyndromal PTSD (n=22), traumatized controls without PTSD (non-PTSD with MVA, n=20) and healthy controls without MVA (HC, n=27) underwent measurement of HR during baseline and exposure to a neutral, positive, negative, and trauma-related picture. PTSD patients showed elevated baseline HR and increased HR reactivity only during exposure to the trauma-related picture. Study 2 investigated whether the elevated physiological responses observed in Study 1 normalized after cognitive behavioral therapy (CBT). We conducted a randomized, controlled treatment trial comparing CBT (n=17) to a Wait-list condition (WLC, n=18). Results showed a greater decrease in HR reactivity for CBT than for WLC. The change in HR reactivity was associated with clinical improvement.     

Real-Time fMRI Pattern Decoding and Neurofeedback Using FRIEND: An FSL-Integrated BCI Toolbox

The demonstration that humans can learn to modulate their own brain activity based on feedback of neurophysiological signals opened up exciting opportunities for fundamental and applied neuroscience. Although EEG-based neurofeedback has been long employed both in experimental and clinical investigation, functional MRI (fMRI)-based neurofeedback emerged as a promising method, given its superior spatial resolution and ability to gauge deep cortical and subcortical brain regions. In combination with improved computational approaches, such as pattern recognition analysis (e.g., Support Vector Machines, SVM), fMRI neurofeedback and brain decoding represent key innovations in the field of neuromodulation and functional plasticity. Expansion in this field and its applications critically depend on the existence of freely available, integrated and user-friendly tools for the neuroimaging research community. Here, we introduce FRIEND, a graphic-oriented user-friendly interface package for fMRI neurofeedback and real-time multivoxel pattern decoding. The package integrates routines for image preprocessing in real-time, ROI-based feedback (single-ROI BOLD level and functional connectivity) and brain decoding-based feedback using SVM. FRIEND delivers an intuitive graphic interface with flexible processing pipelines involving optimized procedures embedding widely validated packages, such as FSL and libSVM. In addition, a user-defined visual neurofeedback module allows users to easily design and run fMRI neurofeedback experiments using ROI-based or multivariate classification approaches. FRIEND is open-source and free for non-commercial use. Processing tutorials and extensive documentation are available.     

Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges

Post‐traumatic stress disorder (PTSD) is arguably the most common psychiatric disorder to arise after exposure to a traumatic event. Since its formal introduction in the DSM‐III in 1980, knowledge has grown significantly regarding its causes, maintaining mechanisms and treatments. Despite this increased understanding, however, the actual definition of the disorder remains controversial. The DSM‐5 and ICD‐11 define the disorder differently, reflecting disagreements in the field about whether the construct of PTSD should encompass a broad array of psychological manifestations that arise after trauma or should be focused more specifically on trauma memory phenomena. This controversy over clarifying the phenotype of PTSD has limited the capacity to identify biomarkers and specific mechanisms of traumatic stress. This review provides an up‐to‐date outline of the current definitions of PTSD, its known prevalence and risk factors, the main models to explain the disorder, and evidence‐supported treatments. A major conclusion is that, although trauma‐focused cognitive behavior therapy is the best‐validated treatment for PTSD, it has stagnated over recent decades, and only two‐thirds of PTSD patients respond adequately to this intervention. Moreover, most people with PTSD do not access evidence‐based treatment, and this situation is much worse in low‐ and middle‐income countries. Identifying processes that can overcome these major barriers to better management of people with PTSD remains an outstanding challenge.     

Post-traumatic stress disorder after childbirth: the phenomenon of traumatic birth

CHILDBIRTH CAN BE A VERY PAINFUL EXPERIENCE, often associated with feelings of being out of control. It should not, therefore, be surprising that childbirth may be traumatic for some women. Most women recover quickly post partum; others appear to have a more difficult time. The author asserts that post-traumatic stress disorder (PTSD) may occur after childbirth. He calls this variant of PTSD a "traumatic birth experience." There is very little literature on this topic. The evidence available is from case series, qualitative research and studies of women seeking elective cesarean section for psychologic reasons. Elective cesarean section exemplifies the avoidance behaviour typical of PTSD. There are many ways that health care professionals, including physicians, obstetric nurses, midwives, psychologists, psychiatrists and social workers, can address this phenomenon. These include taking a careful history to determine whether a woman has experienced trauma that could place her at risk for a traumatic birth experience; providing excellent pain control during childbirth and careful postpartum care that includes understanding the woman''s birth experience; and ruling out postpartum depression. Much more research is needed in this area.     

Response variation following trauma: a translational neuroscience approach to understanding PTSD

Exposure to traumatic stress is a requirement for the development of posttraumatic stress disorder (PTSD). However, because the majority of trauma-exposed persons do not develop PTSD, examination of the typical effects of a stressor will not identify the critical components of PTSD risk or pathogenesis. Rather, PTSD represents a specific phenotype associated with a failure to recover from the normal effects of trauma. Thus, research must focus on identifying pre- and posttraumatic risk factors that explain the development of the disorder and the failure to reinstate physiological homeostasis. In this review, we summarize what is known about the clinical and biological characteristics of PTSD and articulate some of the gaps in knowledge that can be addressed by basic neuroscience research. We emphasize how knowledge about individual differences related to genetic and epigenetic factors in behavioral and brain responses to stress offers the hope of a deeper understanding of PTSD.     

Neocortical Dynamics: Implications for Understanding the Role of Neurofeedback and Related Techniques for the Enhancement of Attention

For nearly 25 years, EEG biofeedback (neurofeedback) has been utilized in research and clinical settings for the treatment and investigation of a number of disorders ranging from attention deficit hyperactivity disorder to seizure disorders as well as many other established and investigational applications. Until recently, mechanisms underlying the generation and origins of EEG have been poorly understood but now are beginning to become much more clarified. Now it is important to combine the information gathered on the genesis of EEG and neocortical dynamics with the findings from neurofeedback investigations. This will help us to develop models of how neurofeedback might operate in producing the changes in EEG and in clinical symptomatology. We know that the cortex operates in terms of resonant loops between neocortical columns of cells known as local, regional, and global resonances. These resonances determine the specific EEG frequencies and are often activated by groups of cells in the thalamus known as pacemakers. There are complex excitatory and inhibitory interactions within the cortex and between the cortex and the thalamus that allow these loops to operate and provide the basis for learning. Neurofeedback is a technique for modifying these resonant loops, and hence, modifying the neurophysiological and neurological basis for learning and for the management of a number of neurologically based disorders. This paper provides an introduction to understanding EEG and neocortical dynamics and how these concepts can be used to explain the results of neurofeedback training and other interventions particularly in the context of understanding attentive mechanisms and for the management of attention deficit/hyperactivity disorders.     

Estimating the risk of PTSD in recent trauma survivors: results of the International Consortium to Predict PTSD (ICPP)

A timely determination of the risk of post‐traumatic stress disorder (PTSD) is a prerequisite for efficient service delivery and prevention. We provide a risk estimate tool allowing a calculation of individuals’ PTSD likelihood from early predictors. Members of the International Consortium to Predict PTSD (ICPP) shared individual participants’ item‐level data from ten longitudinal studies of civilian trauma survivors admitted to acute care centers in six countries. Eligible participants (N=2,473) completed an initial clinical assessment within 60 days of trauma exposure, and at least one follow‐up assessment 4‐15 months later. The Clinician‐Administered PTSD Scale for DSM‐IV (CAPS) evaluated PTSD symptom severity and diagnostic status at each assessment. Participants’ education, prior lifetime trauma exposure, marital status and socio‐economic status were assessed and harmonized across studies. The study's main outcome was the likelihood of a follow‐up PTSD given early predictors. The prevalence of follow‐up PTSD was 11.8% (9.2% for male participants and 16.4% for females). A logistic model using early PTSD symptom severity (initial CAPS total score) as a predictor produced remarkably accurate estimates of follow‐up PTSD (predicted vs. raw probabilities: r=0.976). Adding respondents’ female gender, lower education, and exposure to prior interpersonal trauma to the model yielded higher PTSD likelihood estimates, with similar model accuracy (predicted vs. raw probabilities: r=0.941). The current model could be adjusted for other traumatic circumstances and accommodate risk factors not captured by the ICPP (e.g., biological, social). In line with their use in general medicine, risk estimate models can inform clinical choices in psychiatry. It is hoped that quantifying individuals’ PTSD risk will be a first step towards systematic prevention of the disorder.     

Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset

Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological alterations. This disorder is typically characterized by cyclical and recurrent episodes of mania and depression but is heterogeneous in its clinical presentation and outcome. Although the DSM-IV-TR criteria identify several features that are of phenomenological relevance, these are of less utility for defining homogeneous subgroups, for analyses of correlations with biomarkers or for directing focused medication strategies. We provide a comprehensive review of existing evidence regarding to age at onset in bipolar disorder. Eight admixture studies demonstrate three homogeneous subgroups of patients with bipolar disorder identified according to age at onset (early, intermediate and late age at onset), with two cutoff points, at 21 and 34 years. It is suggested that the early-onset subgroup has specific clinical features and outcomes different from those of the other subgroups. Early-onset subgroup may be considered a more suitable clinical phenotype for the identification of susceptibility genes with recent data demonstrating associations with genetic variants specifically in this subgroup. The use of age at onset as a specifier may also facilitate the identification of other biological markers for use in brain imaging, circadian, inflammatory and cognitive research. A key challenge is posed by the use of age at onset in treatment decision algorithms, although further research is required to increase the evidence-base. We discuss three potential benefits of specifying age at onset, namely: focused medication strategies, the targeted prevention of specific comorbid conditions and decreasing the duration of untreated illness. We argue that age at onset should be included as a specifier for bipolar disorders.