Disentangling negative and positive symptoms in schizophrenia and autism spectrum disorder.

Autism spectrum disorder (ASD) and schizophrenia (SZ) share traits, especially in social skills and negative symptoms, and to a lesser degree positive symptoms. Differential diagnosis can be challenging and discerning expressive and experiential negative symptoms may provide knowledge with potential diagnostic and functional relevance that can guide treatment. Two exploratory factor analyses (EFA) were conducted to reveal the underlying dimensions of negative and positive symptoms using the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms & Negative Symptoms (SAPS/SANS) and the Autism Diagnostic Observation Schedule-Generic (ADOS-G). Three factors emerged from the negative symptom EFA (70.5 % variance): NF1) Expressive Negative; NF2) Experiential Negative; and NF3) Preoccupation, Absorption & Expressive Affective Flattening. Three positive factors emerged (68.6 % variance): PF1) Hallucinations-Delusions; PF2) Grandiosity; and PF3) Thought Disorder-ADOS positive Symptoms. SZ showed higher PF1 scores, and ASD had higher PF3 scores. No differences between groups were observed in the negative factors. Across groups, all negative factors were inversely associated with quality of life. Only NF1 and NF2 and PF1 were detrimentally related to social functioning. A discriminant function analysis using all factors classified correctly 84.4 % of participants, with PF1, NF1 followed by NF2 being the best predictors of diagnosis. Expressive negative followed by Experiential negative symptoms are of diagnostic value independent of and beyond SZ-related positive symptoms and are related with detrimental functioning. Findings confirm the need to distinctively target negative symptoms, and specific SZ-related and ASD-related positive symptoms, and especially the use of several assessment tools for diagnostic classification.

Using micro-cognition biomarkers of neurosystem dysfunction to redefine ADHD subtypes: A scalable digital path to diagnosis based on brain function.

Symptom-based diagnosis does not align with underlying neruropathology, confounding new treatment development and treatment selection for individual patients. Using high precision micro-cognition biomarkers of neurosystem dysfunction acquired during digital neurotherapy (DNT), we characterized subgroups of ADHD children with different neuropathology. K-means clustering applied to 69 children 6-9 years old with ADHD using performance variables from a Go/NoGo test normalized against 58 typically developing (TD) children identified four subgroups that were validated and further characterized by micro-cognition biomarkers extracted from thousands of responses during the DNT. The clusters differed on emblematic features of ADHD. Cluster 4 showed poor response inhibition and inconsistent attention. Cluster 3 showed only poor response inhibition and the other two showed neither. Cluster 2 showed faster and more consistent responses, higher detection of simple targets and better working memory than TD children but marked performance decrements when required to track multiple targets or ignore distractors. Cluster 1 showed much greater ability recognizing members of abstract categories rather than natural categories that children learn through physical interaction with the environment while Cluster 4 was the opposite. Fine-grained, low-cost, noninvasive, and scalable digital micro-cognition biomarkers can identify patients with the same symptom-based diagnosis but differing neuropathology.

Aberrant hippocampus and amygdala morphology associated with cognitive deficits in schizophrenia.

Background: Working memory deficits are thought to be a primary disturbance in schizophrenia. We aimed to identify differences in morphology of the hippocampus and amygdala in patients with schizophrenia compared with healthy controls (HCs), and in patients who were either neuropsychologically near normal (NPNN) or neuropsychologically impaired (NPI). Morphological disturbances in the same subfields of the hippocampus and amygdala, but of greater magnitude in those with NPI, would strengthen evidence for the centrality of these limbic regions and working memory deficits in the pathogenesis of schizophrenia. Methods: We acquired anatomical MRIs in 69 patients with schizophrenia (18 NPNN, 46 NPI) and 63 age-matched HC participants. We compared groups in hippocampus and amygdala surface morphologies and correlated morphological measures with clinical symptoms and working memory scores. Results: Schizophrenia was associated with inward deformations of the head and tail of the hippocampus, protrusion of the hippocampal body, and widespread inward deformations of the amygdala. In the same regions where we detected the effects of schizophrenia, morphological measures correlated positively with the severity of symptoms and inversely with working memory performance. Patients with NPI displayed a similar pattern of anatomical abnormality compared to patients with NPNN. Conclusion: Our findings indicate that anatomical abnormalities of the hippocampus relate to working memory performance and clinical symptoms in persons with schizophrenia. Moreover, NPNN and NPI patients may lie on a continuum of severity, both in terms of working memory abilities and altered brain structure, with NPI patients being more severe than NPNN patients in both domains.

Transcranial direct current stimulation (tDCS) combined with cognitive training in adolescent boys with ADHD: a double-blind, randomised, sham-controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) could be a side-effect-free alternative to psychostimulants in attention-deficit/hyperactivity disorder (ADHD). Although there is limited evidence for clinical and cognitive effects, most studies were small, single-session and stimulated left dorsolateral prefrontal cortex (dlPFC). No sham-controlled study has stimulated the right inferior frontal cortex (rIFC), which is the most consistently under-functioning region in ADHD, with multiple anodal-tDCS sessions combined with cognitive training (CT) to enhance effects. Thus, we investigated the clinical and cognitive effects of multi-session anodal-tDCS over rIFC combined with CT in double-blind, randomised, sham-controlled trial (RCT, ISRCTN48265228). METHODS: Fifty boys with ADHD (10-18 years) received 15 weekday sessions of anodal- or sham-tDCS over rIFC combined with CT (20 min, 1 mA). ANCOVA, adjusting for baseline measures, age and medication status, tested group differences in clinical and ADHD-relevant executive functions at posttreatment and after 6 months. RESULTS: ADHD-Rating Scale, Conners ADHD Index and adverse effects were significantly lower at post-treatment after sham relative to anodal tDCS. No other effects were significant. CONCLUSIONS: This rigorous and largest RCT of tDCS in adolescent boys with ADHD found no evidence of improved ADHD symptoms or cognitive performance following multi-session anodal tDCS over rIFC combined with CT. These findings extend limited meta-analytic evidence of cognitive and clinical effects in ADHD after 1-5 tDCS sessions over mainly left dlPFC. Given that tDCS is commercially and clinically available, the findings are important as they suggest that rIFC stimulation may not be indicated as a neurotherapy for cognitive or clinical remediation for ADHD.

The effect of transcranial direct current stimulation (tDCS) combined with cognitive training on EEG spectral power in adolescent boys with ADHD: A double-blind, randomized, sham-controlled trial.

Transcranial direct current stimulation (tDCS) is a possible alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD), but its mechanisms of action in children and adolescents with ADHD are poorly understood. We conducted the first 15-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC) combined with cognitive training (CT) in 50 children/adolescents with ADHD. We investigated the mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD (n, sham = 10; anodal tDCS = 13). We failed to find a significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, a correlation between QEEG and Go/No-Go Task performance, and changes in clinical and cognitive measures. These findings extend the non-significant clinical and cognitive effects in our sample of 50 children/adolescents with ADHD. Given that the subgroup of 23 participants would have been underpowered, the interpretation of our findings is limited and should be used as a foundation for future investigations. Larger, adequately powered randomized controlled trials should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD.

Returning to basic principles to develop more effective treatments for central nervous system disorders.

Development of new treatments for diseases of the central nervous system (CNS) is stalled. Of candidate drugs developed through costly preclinical research, 93% fail clinical trials. Hoped-for improvements in diagnosis or treatment from decades of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) imaging have yet to materialize. To understand what we are doing wrong, I begin with recognition that all aspects of life, including the brain and mind, are physical phenomena consistent with processes described by physicists. Two processes, emergence and entropy, are of particular relevance in complex arrangements of matter that constitute life in general and the brain in particular. The human brain functions through dynamically reconfiguring and hierarchically organized neural functional systems with emergent properties of cognition, emotion, and conscious experience. These systems are shaped and maintained by negentropic environmental input transformed by sensory receptors into neural signals that trigger epigenetic neuroplastic processes. CNS diseases produce clinical disorders by disrupting these systems. As researchers seek appropriate levels of system organization at which to characterize and treat illness, focus has been on medications that impact processes at lower levels or transcranial electric or magnetic stimulation that impact broad contiguous swaths of tissue. Neither align with the brain's neurosystem organization and therefore lack specificity necessary to be effective and to limit side effects. Digital neurotherapies (DNTs), in contrast, align with neurosystem organization and achieve the needed specificity using the same input pathways and neuroplastic processes that created the neural systems organization to repair it. The omission of DNTs from major systems-based initiatives represents powerful residua of dualist thinking. Interventions based on perceptual and cognitive processes are not thought of as being as physical as drugs or electric or magnetic stimulation through the skull. In fact, they are examples of the most basic processes that create and support life itself.

Atypical Dynamic Functional Network Connectivity State Engagement during Social-Emotional Processing in Schizophrenia and Autism.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are separate clinical entities but share deficits in social-emotional processing and static neural functional connectivity patterns. We compared patients' dynamic functional network connectivity (dFNC) state engagement with typically developed (TD) individuals during social-emotional processing after initially characterizing such dynamics in TD. Young adults diagnosed with ASD (n = 42), SZ (n = 41), or TD (n = 55) completed three functional MRI runs, viewing social-emotional videos with happy, sad, or neutral content. We examined dFNC of 53 spatially independent networks extracted using independent component analysis and applied k-means clustering to windowed dFNC matrices, identifying four unique whole-brain dFNC states. TD showed differential engagement (fractional time, mean dwell time) in three states as a function of emotion. During Happy videos, patients spent less time than TD in a happy-associated state and instead spent more time in the most weakly connected state. During Sad videos, only ASD spent more time than TD in a sad-associated state. Additionally, only ASD showed a significant relationship between dFNC measures and alexithymia and social-emotional recognition task scores, potentially indicating different neural processing of emotions in ASD and SZ. Our results highlight the importance of examining temporal whole-brain reconfiguration of FNC, indicating engagement in unique emotion-specific dFNC states.

Predictors of social functioning and quality of life in schizophrenia and autism spectrum disorder.

Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) show overlap in social cognitive and functioning impairments. Proposed predictors of social functioning (SF) and quality of life (QL) have been symptom severity, IQ and social cognition. Empathy has rarely been compared between ASD and SZ and its predictive power on functional outcomes is unclear. We investigated general, affective, and cognitive empathy in 46 SZ, 30 ASD and 51 healthy controls (HC) and examined their relationship to SF and QL in addition to IQ and symptoms. SZ and ASD shared deficits in general and cognitive empathy, and personal distress, but only SZ showed deficits in affective empathy. Both groups showed lower performance-based empathy scores and only ASD showed slower responses compared to HC. Negative symptoms predicted QL in both groups, the more negative symptoms the worse QL (ASD t=-3.22; SZ t= -3.43; p<0.01), and only in ASD, IQ predicted QL, the higher the IQ the higher QL (t = 2.1; p<0.05). In ASD only, negative symptoms predicted SF, the greater negative symptoms the worse SF (t=-3.45; p<0.01), and communication deficits predicted SF, the higher deficits, the higher SF (t = 2.9; p<0.01). Negative symptoms but not empathy were the shared predictors of functioning across ASD and SZ.

An integrated program of computer-presented and physical cognitive training exercises for children with attention-deficit/hyperactivity disorder.

BACKGROUND: This study integrated an experimental medicine approach and a randomized cross-over clinical trial design following CONSORT recommendations to evaluate a cognitive training (CT) intervention for attention deficit hyperactivity disorder (ADHD). The experimental medicine approach was adopted because of documented pathophysiological heterogeneity within the diagnosis of ADHD. The cross-over design was adopted to provide the intervention for all participants and make maximum use of data. METHODS: Children (n = 93, mean age 7.3 +/- 1.1 years) with or sub-threshold for ADHD were randomly assigned to CT exercises over 15 weeks, before or after 15 weeks of treatment-as-usual (TAU). Fifteen dropped out of the CT/TAU group and 12 out of the TAU/CT group, leaving 66 for cross-over analysis. Seven in the CT/TAU group completed CT before dropping out making 73 available for experimental medicine analyses. Attention, response inhibition, and working memory were assessed before and after CT and TAU. RESULTS: Children were more likely to improve with CT than TAU (27/66 v. 13/66, McNemar p = 0.02). Consistent with the experimental medicine hypotheses, responders improved on all tests of executive function (p = 0.009-0.01) while non-responders improved on none (p = 0.27-0.81). The degree of clinical improvement was predicted by baseline and change scores in focused attention and working memory (p = 0.008). The response rate was higher in inattentive and combined subtypes than hyperactive-impulsive subtype (p = 0.003). CONCLUSIONS: Targeting cognitive dysfunction decreases clinical symptoms in proportion to improvement in cognition. Inattentive and combined subtypes were more likely to respond, consistent with targeted pathology and clinically relevant heterogeneity within ADHD.

Risk-Taking Patterns of Children, Associated Cognitive Weaknesses, and Prevention of Negative Outcomes.

Objective: Accidents, drug use, and unsafe sex associated with greater propensity for risk-taking are leading causes of illness and death among adolescents. This study aimed to help identify and further characterize children with maladaptive risk-taking to improve primary prevention interventions. Methods: Two scores from the Bubblegum Analog Risk-Taking Task for Children (BART-C), total points and average inflations of unpopped bubbles, were used in a cluster analysis to identify distinct patterns of risk-taking among 6,267 kindergarten through eighth-grade children. Clusters were compared with the Flanker Test of Focused Attention, the Go/No-Go test of inhibition, and the List Sorting Working Memory Test. Results: Both BART-C scores made significant (p<0.001) contributions in defining three clusters of children: reckless, risk avoidant, and adaptive risk-taking. Clusters differed significantly on Flanker Test measures of incongruent accuracy (p=0.004) and reaction time (p<0.001), Go/No-Go inhibition (p=0.001), and List Sorting Working Memory Test scores (p<0.001). The reckless cluster had lower Flanker accuracy and Go/No-Go inhibition than did the other groups and lower working memory than the adaptive risk-taking group. Compared with adaptive risk-takers, the risk-avoidant group was slower (p<0.001), showed a nonsignificant trend toward greater accuracy on the Flanker test, and had lower working memory scores (p<0.001). Conclusions: The BART-C defined two maladaptive risk-taking clusters: reckless and risk avoidant. Significant differences in cognitive function between these groups and the adaptive risk-taking group provides external validation of and further characterizes the clusters. Early intervention may prevent future health-compromising behaviors among reckless children and may promote fuller learning and development among risk-avoidant children.

Measurement of executive functioning with the National Institute of Health Toolbox and the association to anxiety/depressive symptomatology in childhood/adolescence.

INTRODUCTION: Despite preliminary research, there remain inconsistent findings with regard to the role of executive functioning (EF) deficits in childhood anxiety and depression. This report examined the association of The National Institute of Health (NIH) Toolbox to clinical neuropsychological measures and to childhood, anxiety/depressive symptomatology. Methods: One-hundred eight children and adolescents completed the three EF measures from the NIH Toolbox (List Sorting Working Memory Test [LSWMT], Dimensional Change Card Sorting Test [DCCST], and Flanker Test of Attention and Inhibition [Flanker]) in an outpatient neuropsychology program. These tests were compared to established measures of EF in terms of linear correlations and detection of impairment. Heaton's Global Deficit Score (GDS) was utilized to calculate impairment. The Toolbox-EF measures were paired with parent-reported EF symptoms (Behavior Rating Inventory of Executive Function [BRIEF2]) to identify the role of EF in childhood anxiety/depressive symptomatology. RESULTS: Toolbox-EF measures displayed medium sized correlations with their clinically comparable counterparts, and generally did not differ in their detection of impairment. Toolbox-GDS was associated with depression diagnosis and clinically significant child-reported anxiety and depressive symptoms. Together, Toolbox/BRIEF2 accounted for 26.8-30.9% of elevated depressive symptom variance, but only 13.2-14% of elevated anxiety symptom variance. Further, EF impairment was associated with depression across self report, parent report, and clinical diagnosis. DISCUSSION: The NIH Toolbox-EF measures display comparable psychometric properties to clinically available EF measures in a pediatric (primarily psychiatric) neuropsychology setting. The Toolbox appears to display an appropriate ability to detect EF deficits secondary to self-reported depression in childhood.

The development of adaptive risk taking and the role of executive functions in a large sample of school-age boys and girls.

BACKGROUND: The Balloon Analogue Risk Task for Children (BART-C) demands self-regulation of emotion that requires risk-tolerance and adaptive risk-taking to make good decisions under stress (hot cognition). METHODS: BART-C measures of adaptive risk-taking in 5,409 children K-8th grade were analyzed for improvements by grade, for relationships to executive functioning (EF) and for associations with school characteristics and academic achievement. FINDINGS: BART-C improved across grades. Boys showed significantly greater Recklessness, particularly in middle school. EF was a partial mediator between grade and Variability and Recklessness. Better BART-C Total score and less Recklessness were related to lower free-or-reduced-school-lunch percentage and better math and reading proficiency of children's schools. CONCLUSIONS: BART-C is a potential "hot-cognition" measure of self-regulation and adaptive risk-taking for children.

Dynamic functional connectivity in schizophrenia and autism spectrum disorder: Convergence, divergence and classification.

BACKGROUND: Over the recent years there has been a growing debate regarding the extent and nature of the overlap in neuropathology between schizophrenia (SZ) and autism spectrum disorder (ASD). Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of functional connectivity (FC). We compared resting-state dFNC in SZ, ASD and healthy controls (HC), characterized the associations between temporal patterns and symptoms, and performed a three-way classification analysis based on dFNC indices. METHODS: Resting-state fMRI was collected from 100 young adults: 33 SZ, 33 ASD, 34 HC. Independent component analysis (ICA) was performed, followed by dFNC analysis (window = 33 s, step = 1TR, k-means clustering). Temporal patterns were compared between groups, correlated with symptoms, and classified via cross-validated three-way discriminant analysis. RESULTS: Both clinical groups displayed an increased fraction of time (FT) spent in a state of weak, intra-network connectivity [p < .001] and decreased FT in a highly-connected state [p < .001]. SZ further showed decreased number of transitions between states [p < .001], decreased FT in a widely-connected state [p < .001], increased dwell time (DT) in the weakly-connected state [p < .001], and decreased DT in the highly-connected state [p = .001]. Social behavior scores correlated with DT in the widely-connected state in SZ [r = 0.416, p = .043], but not ASD. Classification correctly identified SZ at high rates (81.8%), while ASD and HC at lower rates. CONCLUSIONS: Results indicate a severe and pervasive pattern of temporal aberrations in SZ (specifically, being "stuck" in a state of weak connectivity), that distinguishes SZ participants from both ASD and HC, and is associated with clinical symptoms.

Effects of Integrated Brain, Body, and Social (IBBS) intervention on ERP measures of attentional control in children with ADHD.

A primary goal of this study was to examine the impact of an Integrated Brain, Body, and Social (IBBS) intervention (multi-faceted treatment consisting of computerized cognitive training, physical exercise, and behavior management) on ERPs of attentional control (P3 & N2) in children with ADHD. The secondary goal was to test the differences between children with and without ADHD on ERP and Go/No-Go behavioral measures. A total of twenty-nine participants (M age = 7.14 years; 52% male; 41.4% white) recruited from the IBBS efficacy study comparing IBBS to Treatment-As-Usual (TAU) completed a Go/No-Go task before and after treatment as brain activity was recorded using EEG. Thirty-four matched healthy controls (HC) completed the same EEG procedures at a single time point. Following treatment, the Go P3 latency was significantly earlier for the IBBS group relative to the TAU group. No treatment effects were found on any behavioral measures. Prior to treatment, there was a significant difference between the ADHD group and HC group for the N2 difference wave. Children with ADHD also showed slower reaction times on behavioral measures. Although this pilot study did not reveal robust treatment effects, it suggests that IBBS may prevent the worsening of attentional systems in the brain and larger studies are needed for replication purposes.

Measuring theory of mind in schizophrenia research: Cross-cultural validation.

Theory of mind (ToM) is the ability to understand mental states of others and it is crucial for building sensitivity to other persons or events. Measuring ToM is important for understanding and rehabilitating social cognitive impairments in persons with schizophrenia. The Social Attribution Task-Multiple Choice (SAT-MC) has been successfully employed to measure ToM between individuals with schizophrenia (SZ) and healthy controls (HC) in North America. Given that the SAT-MC uses geometric shapes, is nonverbal and less culturally loaded than other social cognition measures, it may serve for measuring ToM in schizophrenia across cultures. A total of 120 participants (30 per group; Korean SZ; Korean HC; North American SZ; North American HC) were selected from existing databases to examine the reliability and validity of the SAT-MC. Internal consistency, factor structure, measurement invariance, discriminant validity, and convergent/divergent validity were examined. The SAT-MC had good internal consistency regardless of the clinical and cultural group as evidence by Cronbach's α ≥ 0.78 in all groups. Confirmatory factor analysis confirmed the one-factor model with a good model fit (χ2 = 188.122, TLI = 0.958, CFI = 0.963, RMSEA = 0.045). The SAT-MC was sensitive to detect individual differences in ToM of SZ and HC, regardless of culture (p < 0.001), and significantly correlated with other social cognition tasks (Hinting and Reading the Mind in the Eyes Test) among Korean and North American patients. The SAT-MC is a reliable measure for evaluating ToM in both Koreans and North Americans with or without schizophrenia, supporting its potential utility in diverse language and cultures for schizophrenia research.

Cognitive remediation for adults with schizophrenia: Does age matter?

Cognitive remediation (CR), a novel behavioral intervention designed to improve cognitive deficits through repeated task practice and/or strategy acquisition has gained increasing empirical support in people with schizophrenia, but substantial individual differences in treatment response remain (Wykes et al., 2011). The role of age on response to CR in schizophrenia remains understudied. We evaluated the role of three age ranges in treatment response to CR relative to a closely-matched computer skills control intervention in a blinded, randomized control trial (RCT) with 112 adults with schizophrenia divided into three groups: an early-stage group (ES; 25 years or younger, mean=3.4 years of illness; n=45), an early-chronic group (EC; 26-39, mean=7.6 years of illness; n=31) and a late-chronic group (LC; 40 and over, mean=18.2 years of illness; n=36). With respect to cognitive outcomes, early-stage and early-chronic individuals with schizophrenia showed greater improvement in response to CR on a working memory measure at a trend level, relative to late-chronic clients. These findings were confirmed in analyses of a subsample of clients who received an adequate dose of treatment. These findings emphasize the need for adaptations of currently-existing CR programs to more effectively address the needs of older client populations.

Brain mechanisms of Change in Addictions Treatment: Models, Methods, and Emerging Findings.

Increased understanding of "how" and "for whom" treatment works at the level of the brain has potential to transform addictions treatment through the development of innovative neuroscience-informed interventions. The 2015 Science of Change meeting bridged the fields of neuroscience and psychotherapy research to identify brain mechanisms of behavior change that are "common" across therapies, and "specific" to distinct behavioral interventions. Conceptual models of brain mechanisms underlying effects of Cognitive Behavioral Therapy, mindfulness interventions, and Motivational Interviewing were discussed. Presentations covered methods for integrating neuroimaging into psychotherapy research, and novel analytic approaches. Effects of heavy substance use on the brain, and recovery of brain functioning with sustained abstinence, which may be facilitated by cognitive training, were reviewed. Neuroimaging provides powerful tools for determining brain mechanisms underlying psychotherapy and medication effects, predicting and monitoring outcomes, developing novel interventions that target specific brain circuits, and identifying for whom an intervention will be effective.