Showing papers in "Dialogues in Clinical Neuroscience in 2012"

Autism risk factors: genes, environment, and gene-environment interactions.

Abstract: The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.

Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior.

Abstract: Current diagnostic systems for mental disorders were established before the tools of neuroscience were available, and although they have improved the reliability of psychiatric classification, progress toward the discovery of disease etiologies and novel approaches to treatment and prevention may benefit from alternative conceptualizations of mental disorders. The Research Domain Criteria (RDoC) initiative is the centerpiece of NIMH's effort to achieve its strategic goal of developing new methods to classify mental disorders for research purposes. The RDoC matrix provides a research framework that encourages investigators to reorient their research perspective by taking a dimensional approach to the study of the genetic, neural, and behavioral features of mental disorders, RDoCs integrative approach includes cognition along with social processes, arousal/regulatory systems, and negative and positive valence systems as the major domains, because these neurobehavioral systems have all evolved to serve the motivational and adaptive needs of the organism. With its focus on neural circuits informed by the growing evidence of the neurodevelopmental nature of many disorders and its capacity to capture the patterns of co-occurrence of behaviors and symptoms, the RDoC approach holds promise to advance our understanding of the nature of mental disorders.

Brain rhythms and neural syntax: implications for efficient coding of cognitive content and neuropsychiatric disease.

Abstract: The perpetual activity of the cerebral cortex is largely supported by the variety of oscillations the brain generates, spanning a number of frequencies and anatomical locations, as well as behavioral correlates. First, we review findings from animal studies showing that most forms of brain rhythms are inhibition-based, producing rhythmic volleys of inhibitory inputs to principal cell populations, thereby providing alternating temporal windows of relatively reduced and enhanced excitability in neuronal networks. These inhibition-based mechanisms offer natural temporal frames to group or "chunk" neuronal activity into cell assemblies and sequences of assemblies, with more complex multi-oscillation interactions creating syntactical rules for the effective exchange of information among cortical networks. We then review recent studies in human psychiatric patients demonstrating a variety alterations in neural oscillations across all major psychiatric diseases, and suggest possible future research directions and treatment approaches based on the fundamental properties of brain rhythms.

Heuristic decision making in medicine

Abstract: Can less information be more helpful when it comes to making medical decisions? Contrary to the common intuition that more information is always better, the use of heuristics can help both physicians and patients to make sound decisions. Heuristics are simple decision strategies that ignore part of the available information, basing decisions on only a few relevant predictors. We discuss: (i) how doctors and patients use heuristics; and (ii) when heuristics outperform information-greedy methods, such as regressions in medical diagnosis. Furthermore, we outline those features of heuristics that make them useful in health care settings. These features include their surprising accuracy, transparency, and wide accessibility, as well as the low costs and little time required to employ them. We close by explaining one of the statistical reasons why heuristics are accurate, and by pointing to psychiatry as one area for future research on heuristics in health care.

Complicated grief after perinatal loss.

Abstract: The loss of an infant through stillbirth, miscarriage, or neonatal death is recognized as a traumatic life event. Predictors of development of complicated grief after prenatal loss include lack of social support, pre-existing relationship difficulties, or absence of surviving children, as well as ambivalent attitudes or heightened perception of the reality of the pregnancy. Risk of complicated grief was found to be especially high after termination of a pregnancy due to fetal abnormality. Studies have revealed that men and women show different patterns of grief, potentially exacerbating decline in a relationship. Although it is clear that prenatal loss has a large psychological impact, it is concluded that there is a substantial lack of randomized controlled studies in this field of research.

Translational animal models of autism and neurodevelopmental disorders.

Abstract: Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

Grief and mourning gone awry: Pathway and course of complicated grief

Abstract: Complicated grief is a recently recognized condition that occurs in about 7% of bereaved people. People with this condition are caught up in rumination about the circumstances of the death, worry about its consequences, or excessive avoidance of reminders of the loss. Unable to comprehend the finality and consequences of the loss, they resort to excessive avoidance of reminders of the loss as they are tossed helplessly on waves of intense emotion. People with complicated grief need help, and clinicians need to know how to recognize the symptoms and how to provide help. This paper provides a framework to help clinicans understand bereavement, grief, and mourning. Evidence-based diagnostic criteria are provided to help clinicians recognize complicated grief, and differentiate it from depression as well as anxiety disorder. We provide an overview of risk factors and basic assumptions and principles that can guide treatment.

Clinical applications of neuropsychological assessment.

Abstract: Neuropsychological assessment is a performance-based method to assess cognitive functioning. This method is used to examine the cognitive consequences of brain damage, brain disease, and severe mental illness. There are several specific uses of neuropsychological assessment, including collection of diagnostic information, differential diagnostic information, assessment of treatment response, and prediction of functional potential and functional recovery. We anticipate that clinical neuropsychological assessment will continue to be used, even in the face of advances in imaging technology, because it is already well known that the presence of significant brain changes can be associated with nearly normal cognitive functioning, while individuals with no lesions detectable on imaging can have substantial cognitive and functional limitations.

Functional magnetic resonance imaging of autism spectrum disorders

Abstract: This review presents an overview of functional magnetic resonance imaging findings in autism spectrum disorders (ASDS), although there is considerable heterogeneity with respect to results across studies, common themes have emerged, including: (i) hypoactivation in nodes of the "social brain" during social processing tasks, including regions within the prefrontal cortex, the posterior superior temporal sulcus, the amygdala, and the fusiform gyrus; (ii) aberrant frontostriatal activation during cognitive control tasks relevant to restricted and repetitive behaviors and interests, including regions within the dorsal prefrontal cortex and the basal ganglia; (iii) differential lateralization and activation of language processing and production regions during communication tasks; (iv) anomalous mesolimbic responses to social and nonsocial rewards; (v) task-based long-range functional hypoconnectivity and short-range hyper-connectivity; and (vi) decreased anterior-posterior functional connectivity during resting states. These findings provide mechanistic accounts of ASD pathophysiology and suggest directions for future research aimed at elucidating etiologic models and developing rationally derived and targeted treatments.

Suicide bereavement and complicated grief.

Abstract: Losing a loved to suicide is one is one of life's most painful experiences. The feelings of loss, sadness, and loneliness experienced after any death of a loved one are often magnified in suicide survivors by feelings of quilt, confusion, rejection, shame, anger, and the effects of stigma and trauma. Furthermore, survivors of suicide loss are at higher risk of developing major depression, post-traumatic stress disorder, and suicidal behaviors, as well as a prolonged form of grief called complicated grief. Added to the burden is the substantial stigma, which can keep survivors away from much needed support and healing resources. Thus, survivors may require unique supportive measures and targeted treatment to cope with their loss. After a brief description of the epidemiology and circumstances of suicide, we review the current state of research on suicide bereavement, complicated grief in suicide survivors, and grief treatment for survivors of suicide.

Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan.

Abstract: This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed.

Physiological correlates of bereavement and the impact of bereavement interventions

Abstract: The death of a loved one is recognized as one of life's greatest stresses, with reports of increased mortality and morbidity for the surviving spouse or parent, especially in the early months of bereavement. The aim of this paper is to review the evidence to date to identify physiological changes in the early bereaved period, and evaluate the impact of bereavement interventions on such physiological responses, where they exist. Research to date suggests that bereavement is associated with neuroendocrine activation (cortisol response), altered sleep (electroencephalography changes), immune imbalance (reduced T-lymphocyte proliferation), inflammatory cell mobilization (neutrophils), and prothrombotic response (platelet activation and increased vWF-ag) as well as hemodynamic changes (heart rate and blood pressure), especially in the early months following loss. Additional evidence suggests that bereavement interventions have the potential to be of value in instances where sleep disturbance becomes a prolonged feature of complicated grief, but have limited efficacy in maintaining immune function in the normal course of bereavement.

The relationship of Rett syndrome and MECP2 disorders to autism.

Abstract: Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.

Constructive memory: past and future.

Abstract: Human memory is not a literal reproduction of the past, but instead relies on constructive processes that are sometimes prone to error and distortion. Understanding of constructive memory has accelerated during recent years as a result of research that has linked together its cognitive and neural bases. This article focuses on three aspects of constructive memory that have been the target of recent research: (i) the idea that certain kinds of memory distortions reflect the operation of adaptive cognitive processes that contribute to the efficient functioning of memory; (ii) the role of a constructive memory system in imagining or simulating possible future events; and (iii) differences between true and false memories that have been revealed by functional neuroimaging techniques. The article delineates the theoretical implications of relevant research, and also considers some clinical and applied implications.

Mechanisms of change in psychosocial interventions for autism spectrum disorders.

Abstract: Research into psychosocial interventions (particularly cognitive-behavior therapies and social skills training) for social-communication deficits among individuals with autism spectrum disorder (ASD) has proliferated over the past decade. While this research has provided some empirical support for the efficacy of these interventions, little work has begun to elucidate therapeutic mechanisms-the when, why, how, for whom, and under what conditions an intervention may produce change, identification of mechanisms underlying these effects should help advance ASD intervention research. This article describes methods for assessing such mechanisms (ie, mediators and moderators) and presents promising candidates for common mechanisms impacting treatment response: behavior modification, therapeutic relationship, social knowledge, social motivation, social information processing, executive functioning, and internalizing comorbidities. Finally, future directions are discussed as a program of psychosocial intervention research designed to identify predictors of individual differences in treatment response (including biomarkers), isolate active therapeutic ingredients, and promote dissemination of optimized interventions.

Complicated grief in those bereaved by violent death: The effects of post-traumatic stress disorder on complicated grief

Abstract: Violent death, such as homicide, accident, and suicide, is sudden, unexpected, and caused by intentional power, The prevalence of complicated grief among those bereaved by violent death is 12,5% to 78,0%. The factors affecting this prevalence rate are considered to be comorbid mental disorders, lack of readiness for the death, difficulty in making sense of the death, high level of negative appraisal about the self and others, and various social stressors. Post-traumatic stress disorder is, in particular, considered to contribute to the development of complicated grief by suppressing function of the medial prefrontal cortex and the anterior cingulate cortex, which works at facilitating the normal mourning process. An understanding of the mechanism and biological basis of complicated grief by violent death will be helpful in developing effective preventive intervention and treatment.

The effects of extremely low-frequency magnetic fields on melatonin and cortisol, two marker rhythms of the circadian system.

Abstract: In the past 30 years the concern that daily exposure to extremely low-frequency magnetic fields (ELF-EMF) (1 to 300 Hz) might be harmful to human health (cancer, neurobehavioral disturbances, etc) has been the object of debate, and has become a public health concern. This has resulted in the classification of ELF-EMF into category 2B, ie, agents that are “possibly carcinogenic to humans” by the International Agency for Research on Cancer. Since melatonin, a neurohormone secreted by the pineal gland, has been shown to possess oncostatic properties, a “melatonin hypothesis” has been raised, stating that exposure to EMF might decrease melatonin production and therefore might promote the development of breast cancer in humans. Data from the literature reviewed here are contradictory. In addition, we have demonstrated a lack of effect of ELF-EMF on melatonin secretion in humans exposed to EMF (up to 20 years' exposure) which rebuts the melatonin hypothesis. Currently, the debate concerns the effects of ELF-EMF on the risk of childhood leukemia in children chronically exposed to more than 0.4 μT. Further research is thus needed to obtain more definite answers regarding the potential deleterious effects of ELF-EMF.

Creativity in art and science: are there two cultures?

Abstract: The study of creativity is characterized by a variety of key questions, such as the nature of the creative process, whether there are multiple types of creativity, the relationship between high levels of creativity (“Big C”) and everyday creativity (“little c”), and the neural basis of creativity. Herein we examine the question of the relationship between creativity in the arts and the sciences, and use functional magnetic resonance imaging to explore the neural basis of creativity in a group of “Big C” individuals from both domains using a word association protocol. The findings give no support for the notion that the artists and scientists represent “two cultures. ” Rather, they suggest that very gifted artists and scientists have association cortices that respond in similar ways. Both groups display a preponderance of activation in brain circuits involved in higher-order socioaffective processing and Random Episodic Silent Thought /the default mode.

Complicated grief therapy as a new treatment approach

Abstract: Complicated grief therapy (CGT) is a relatively new psychotherapy model designed to address symptoms of complicated grief. Drawn from attachment theory and with roots in both interpersonal therapy (IPT) and cognitive-behavioral therapy, CGT includes techniques similar to prolonged exposure (repeatedly telling the story of the death and in vivo exposure activities). The treatment also involves focusing on personal goals and relationships. CGT has been demonstrated to be effective in a trial in which participants with complicated grief were randomly assigned to CGT or IPT; individuals receiving CGT responded more quickly and were more likely to respond overall (51% vs 28%). This article briefly summarizes the conceptual underpinnings of CGT, discusses the empirical evidence for its efficacy, describes its techniques, and presents a case example of a client treated in a 16-session manualized CGT protocol. The article concludes with a description of future research directions for CGT.

Light and chronobiology: implications for health and disease.

Abstract: Environmental light synchronizes the primary mammalian biological clock in the suprachiasmatic nuclei, as well as many peripheral clocks in tissues and cells, to the solar 24-hour day. Light is the strongest synchronizing agent (zeitgeber) for the circadian system, and therefore keeps most biological and psychological rhythms internally synchronized, which is important for optimum function. Circadian sleep-wake disruptions and chronic circadian misalignment, as often observed in psychiatric and neurodegenerative illness, can be treated with light therapy. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends on timing, intensity, and spectral composition of light exposure. Tailoring and optimizing indoor lighting conditions may be an approach to improve wellbeing, alertness, and cognitive performance and, in the long term, producing health benefits.

Classification of autism and related conditions: progress, challenges, and opportunities.

Abstract: Since Kanner's classic description of the syndrome of early infantile autism in 1943, conceptions of the disorder have evolved while retaining important continuity with what Kanner viewed as the hallmarks of the condition—social impairment (autism) and difficulties in dealing with change in the nonsocial world (insistence on sameness). This paper reviews the history of this evolution and the important potential advantages and disadvantages of changes being contemplated for DSM-5. The convergence of diagnostic approach in DSM-IV and ICD-10 provided a shared system that fostered a tremendous body of research. The changes proposed in DSM-5 may impact both research comparability and service eligibility.

Antidepressant chronotherapeutics for bipolar depression.

Abstract: Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in difficult-to-treat conditions such as bipolar depression, which has been associated with extremely low success rates of antidepressant drugs in naturalistic settings and with stable antidepressant response to chronotherapeutics in more than half of the patients. Recent advances in the study of the effects of chronotherapeutics on neurotransmitter systems, and on the biological clock machinery, allow us to pinpoint its mechanism of action and to transform it from a neglected or “orphan” treatment to a powerful clinical instrument in everyday psychiatric practice.

Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature.

Abstract: Complicated grief (CG) is a common and often under-acknowledged cause of profound impairment experienced after the loss of a loved one. Although both clinical and basic research suggests that pharmacological agents might be of use in the treatment of CG, research on pharmacological approaches to this condition is still scarce. Three open-label trials and one randomized trial on bereavement-related depression suggest that tricyclic antidepressants may be effective, although they may be more efficacious for depressive symptoms than for grief-specific symptoms. Four open-label trials (total number of participants, 50) of selective serotonin reuptake inhibitors (SSRIs) have yielded results, providing very preliminary support that they might be effective in the treatment of CG, both as a standalone treatment and in conjunction with psychotherapeutic interventions. These more recent studies have shown an effect on both depression and grief-specific scales. Furthermore, therapeutic interventions for CG may be more effective in conjunction with SSRI administration. Given the small number of pharmacological studies to date, there is a need for randomized trials to test the potential efficacy of pharmacological agents in the treatment of CG.

Diagnostic and clinical considerations in prolonged grief disorder.

Abstract: This review focuses on the similarities and differences between prolonged grief disorder (PGD) and post-traumatic stress disorder (PTSD). It highlights how a PTSD-related understanding aids the investigation and clinical management of PGD. Grief has long been understood as a natural response to bereavement, as serious psychological and physiological stress has been regarded as a potential outcome of extreme or traumatic stress. PTSD was first included in DSM-III in 1980. In the mid-1980s, the first systematic investigation began into whether there is an extreme or pathological form of mourning. Meanwhile, there is much research literature on complicated, traumatic, or prolonged grief This literature is reviewed in this article, with the following questions: Is it possible to distinguish normal from non-normal grief? Which clinical presentation does PGD have-and how does this compare with PTSD? Finally, diagnostic, preventive, and therapeutic approaches and existing tools are presented.

Immunological and neuroimaging biomarkers of complicated grief.

Abstract: Complicated grief (CG) is a disorder marked by intense and persistent yearning for the deceased, in addition to other criteria. The present article reviews what is known about the immunologic and neuroimaging biomarkers of both acute grief and CG, Attachment theory and cognitive stress theory are reviewed as they pertain to bereavement, as is the biopsychosocial model of CG. Reduced immune cell function has been replicated in a variety of bereaved populations. The regional brain activation to grief cues frequently includes the dorsal anterior cingulate cortex and insula, and also the posterior cingulate cortex. Using theory to point to future research directions, we may eventually learn which biomarkers are helpful in predicting CG, and its treatment.

Quantifying creativity: can measures span the spectrum?

Abstract: Because the cognitive neuroscientists have become increasingly interested in the phenomenon of creativity, the issue arises of how creativity is to be optimally measured. Unlike intelligence, which can be assessed across the full range of intellectual ability creativity measures tend to concentrate on different sections of the overall spectrum. After first defining creativity in terms of the three criteria of novelty, usefulness, and surprise, this article provides an overview of the available measures. Not only do these instruments vary according to whether they focus on the creative process, person, or product, but they differ regarding whether they tap into “little-c” versus “Big-C” creativity; only productivity and eminence measures reach into genius-level manifestations of the phenomenon. The article closes by discussing whether various alternative assessment techniques can be integrated into a single measure that quantifies creativity across the full spectrum.

Diogenes syndrome in patients suffering from dementia.

Abstract: Diogenes syndrome (DS) is a behavioral disorder of the elderly. Symptoms include living in extreme squalor, a neglected physical state, and unhygienic conditions. This is accompanied by a self-imposed isolation, the refusal of external help, and a tendency to accumulate unusual objects. To explore the phenomenon of DS in dementia we searched for the terms: “Diogenes syndrome, self-neglect, dementia. ” It has long been understood that individuals with dementia often become shut-ins, living in squalor, in the Eastern Baltimore study, dementia was present in 15% of the elderly cases with moderate and severe social breakdown syndrome; twice as many as in the general population of the same age group. Researchers have underlined the frequent presence of DS (36%) in frontotemporal dementia (FTD): different neuropsychological modifications in FTD may contribute to symptoms of DS. The initial treatment should be a behavioral program, but there is not sufficient information regarding pharmacological treatment of the syndrome.

Biological rhythms and mood disorders

Abstract: Integration of several approaches concerning time and temporality can enhance the pathophysiological study of major mood disorders of unknown etiology. We propose that these conditions might be interpreted as disturbances of temporal profile of biological rhythms, as well as alterations of time-consciousness. Useful approaches to study time and temporality include philological suggestions, phenomenological and psychopathological conceptualizations, clinical descriptions, and research on circadian and ultradian rhythms, as well as nonlinear dynamics approaches to their analysis.

Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

Abstract: In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

Complicated grief in late life.

Abstract: Complicated grief (CG) is a syndrome that affects 10% to 20% of grievers regardless of age, although proportionally more will face the death of loved ones in late life, CG is characterized by preoccupying and disabling symptoms that can persist for decades such as an inability to accept the death, intense yearning or avoidance, frequent reveries, deep sadness, crying, somatic distress, social withdrawal, and suicidal ideation. This syndrome is distinct from major depression and post-traumatic stress disorder, but CG maybe comorbid with each. This communication will focus on the impact of CG in late life (over age 60) and will include a case vignette for illustrating complicated grief therapy.