ObjectiveThis article reviews the conceptual basis, definitions, and evolution of cognitive training approaches for the treatment of mental disorders.MethodThe authors review the current state of the ...knowledge on cognitive training in psychiatric illnesses, and its neural and behavioral targets, and summarize the factors that appear to relate to a successful response, including learner characteristics that influence clinical outcome. They also discuss methodological issues relevant to the development and testing of cognitive training approaches, with the goal of creating maximally efficient and effective approaches to training. Finally, they identify gaps in existing knowledge and outline key research directions for the future.ResultsWhile much of the early research has been conducted in schizophrenia, cognitive training has more recently been applied to a widening range of neuropsychiatric illnesses, including attention deficit hyperactivity disorder, mood disorders, and substance use disorders. Cognitive training harnesses the inherent neuroplastic capacities of the brain, targeting neural system function across psychiatric disorders, thus improving the cognitive processes that play a role in emotion regulation, clinical symptoms, and adaptive community functioning.ConclusionsCognitive training offers considerable promise, especially given the limited efficacy of pharmacological interventions in ameliorating cognitive deficits. However, more research is needed to understand the mechanisms underlying cognitive training, predictors of response, generalization and real-world applicability, and approaches to dissemination in practice settings.
Objective:The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine ...whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms.Methods:In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline.Results:A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change.Conclusions:These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.
Abstract Although dementia praecox or schizophrenia has been considered a unique disease entity for the past century, its definitions and boundaries have continued to vary over this period. At any ...given time, the changing concept of schizophrenia has been influenced by available diagnostic tools and treatments, related conditions from which it most needs to be distinguished, extant knowledge and scientific paradigms. There is significant heterogeneity in the etiopathology, symptomatology, and course of schizophrenia. It is characterized by an admixture of positive, negative, cognitive, mood, and motor symptoms whose severity varies across patients and through the course of the illness. Positive symptoms usually first begin in adolescence or early adulthood, but are often preceded by varying degrees of negative and cognitive symptomatology. Schizophrenia tends to be a chronic and relapsing disorder with generally incomplete remissions, variable degrees of functional impairment and social disability, frequent comorbid substance abuse, and decreased longevity. Although schizophrenia may not represent a single disease with a unitary etiology or pathogenetic process, alternative approaches have thus far been unsuccessful in better defining this syndrome or its component entities. The symptomatologic, course, and etio-pathological heterogeneity can usefully be addressed by a dimensional approach to psychopathology, a clinical staging approach to illness course, and by elucidating endophenotypes and markers of illness progression, respectively. This will allow an approach to the deconstruction of schizophrenia into its multiple component parts and strategies to reconfigure these components in a more meaningful manner. Possible implications for DSM-V and ICD-11 definitions of schizophrenia are discussed.
Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. ...Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.
Objective:Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. ...Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations.Method:A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected.Results:Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders.Conclusions:These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.
Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have ...been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches.
Abstract The introduction of second-generation antipsychotics and cognitive therapies for schizophrenia over the past two decades generated considerable optimism about possibilities for recovery. To ...what extent have these developments resulted in better outcomes for affected individuals? What is the current state of our science and how might we address the many unmet needs in the prevention and treatment of schizophrenia? We trace the evolution of various treatments for schizophrenia and summarize current knowledge about available pharmacological and psychosocial treatments. We consider the widely prevalent efficacy–effectiveness gap in the application of available treatments and note the significant variability in individual treatment response and outcome. We outline an individualized treatment approach which emphasizes careful monitoring and collaborative decision-making in the context of ongoing benefit–risk assessment. We note that the evolution of both pharmacological and psychosocial treatments thus far has been based principally on serendipity and intuition. In view of our improved understanding of the etiology and pathophysiology of schizophrenia, there is an opportunity to develop prevention strategies and treatments based on this enhanced knowledge. In this context, we discuss potential psychopathological treatment targets and enumerate current pharmacological and psychosocial development efforts directed at them. Considering the stages of schizophrenic illness, we review approaches to prevent progression from the pre-symptomatic high-risk to the prodrome to the initial psychotic phase to chronicity. In view of the heterogeneity of risk factors, we summarize approaches towards targeted prevention. We evaluate the potential contribution of pharmacogenomics and other biological markers in optimizing individual treatment and outcome in the future.
Background Current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs—Biotypes—previously ...developed from cognitive and neurophysiologic measures (1), we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes. Methods Whole brain GMD measures were examined in probands, their relatives, and healthy subjects organized by Biotype, and then by DSM diagnosis (n=1,409), using Voxel-Based Morphometry with subsequent subject-level regional characterization and distribution analyses. Results Probands grouped by Biotype vs. healthy showed a step-wise pattern of GMD reductions: Biotype1, extensive and diffusely distributed GMD loss, with the largest effects in frontal, anterior/middle cingulate, temporal regions; Biotype2, intermediate and more localized reductions, with the largest effects in insula, fronto-temporal regions; Biotype3, small reductions localized to anterior limbic regions. Relatives showed regionally distinct GMD reductions vs. healthy, with primarily anterior (fronto-temporal) effects in Biotype1; posterior (temporo-parieto-cerebellar) in Biotype2; and normal GMD in Biotype3. Schizophrenia and schizoaffective probands vs. healthy showed overlapping GMD reductions, with the largest effects in fronto-temporal and parietal regions; psychotic bipolar probands had small reductions, primarily in frontal regions. GMD changes in relatives followed regional patterns observed in probands, albeit less extensive. Biotypes showed stronger between-group separation based on GMD than the conventional diagnoses, and were the strongest predictor of GMD change. Conclusions The GMD biomarkers depicted unique brain structure characteristics within Biotypes consistent with their cognitive and sensorimotor profiles, and provided stronger discrimination for biologically-driven Biotypes than symptom-based diagnoses.
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