A Focused Review of Gamma Neuromodulation as a Therapeutic Target in Alzheimer's Spectrum Disorders.

The aging population of the world is increasing at an unprecedented rate which is expected to lead to a corresponding unparalleled increase in age related diseases. Of particular concern are the large number of older adults expected to develop Alzheimer's disease (AD), which will require extraordinary local, national and worldwide healthcare resources. In this context, innovative interventions are needed urgently to delay AD onset and thereby give our healthcare systems time to prepare and provide meaningful care to our aging populations. This focused review discusses the crucial role of frontal gamma oscillations as a therapeutic target to delay or ameliorate cognitive decline in AD. Frontal gamma oscillations, including from prefrontal cortical areas, serve as a biomarker for working memory and other cognitive functions, and their impairment is observed before clinical symptoms manifest. This review evaluates evidence from animal models and human subjects to highlight the correlation between gamma wave abnormalities and cognitive deterioration. Furthermore, the review summarizes 11 clinical studies using neuromodulation techniques designed to stimulate gamma oscillations in mild cognitive impairment (MCI) and AD patients, including transcranial electrical stimulation, transcranial magnetic stimulation, and rhythmic sensory stimulation. These interventions have shown promise in mitigating early-stage cognitive decline, as evidenced by improved performance on memory tests, increased gamma oscillatory responses, and some have even shown reduced brain atrophy. These early studies suggest that treatments that strengthen frontal gamma oscillatory responses through neuromodulation are a promising approach to delay cognitive decline, that may serve as an adjunct to other therapies or as a standalone treatment in some populations.

Targeting Frontal Gamma Activity with Neurofeedback to Improve Working Memory in Schizophrenia.

Optimal working memory (WM), the mental ability to internally maintain and manipulate task-relevant information, requires coordinated activity of dorsal-lateral prefrontal cortical (DLPFC) neurons. More specifically, during delay periods of tasks with WM features, DLPFC microcircuits generate persistent, stimulus-specific higher-frequency (e.g., gamma) activity. This activity largely depends on recurrent connections between parvalbumin positive inhibitory interneurons and pyramidal neurons in more superficial DLPFC layers. Due to the size and organization of pyramidal neurons (especially apical dendrites), local field potentials generated by DLPFC microcircuits are strong enough to pass outside the skull and can be detected using electroencephalography (EEG). Since patients with schizophrenia (SCZ) exhibit both DLPFC and WM abnormalities, EEG markers of DLPFC microcircuit activity during WM may serve as effective biomarkers or treatment targets. In this review, we summarize converging evidence from primate and human studies for a critical role of DLPFC microcircuit activity during WM and in the pathophysiology of SCZ. We also present a meta-analysis of studies available in PubMed specifically comparing frontal gamma activity between participants with SCZ and healthy controls, to determine whether frontal gamma activity may be a valid biomarker or treatment target for patients with SCZ. We summarize the complex cognitive and neurophysiologic processes contributing to neural oscillations during tasks with WM features, and how such complexity has stalled the development of neurophysiologic biomarkers and treatment targets. Finally, we summarize promising results from early reports using neuromodulation to target DLPFC neural activity and improve cognitive function in participants with SCZ, including a study from our team demonstrating that gamma-EEG neurofeedback increases frontal gamma power and WM performance in participants with SCZ. From the evidence discussed in this review, we believe the emerging field of neuromodulation, which includes extrinsic (electrical or magnetic stimulation) and intrinsic (EEG neurofeedback) modalities, will, in the coming decade, provide promising treatment options targeting specific neurophysiologic properties of specific brain areas to improve cognitive and behavioral health for patients with SCZ.

Novel EEG-Based Neurofeedback System Targeting Frontal Gamma Activity of Schizophrenia Patients to Improve Working Memory.

Patients with schizophrenia (SCZ) exhibit working memory (WM) deficits that are associated with deficient dorsal-lateral prefrontal cortical activity, including decreased frontal gamma power. We thus hypothesized that training SCZ patients to increase frontal gamma activity would improve their WM performance. We administered electroencephalographic (EEG) neurofeedback (NFB) to 31 participants with SCZ for 12 weeks (24 sessions), which provides real-time visual and auditory feedback related to frontal gamma activity. The EEG-NFB training significantly improved EEG markers of optimal working memory, e.g., frontal P3 amplitude and gamma power. Based on these promising results, we developed a novel, EEGLAB/MATLAB-based brain-computer interface (BCI) that delivers F3-F4 gamma coherence NFB with a dynamic threshold to SCZ patients randomized in a double-blind, placebo-controlled clinical trial. The BCI significantly increased F3-F4 gamma coherence after 12 weeks (24 sessions) of training, according to data from the first 12 subjects ( n=6 /group) who completed gamma- or placebo-NFB training.

A Systematic Review of the Potential Use of Neurofeedback in Patients With Schizophrenia.

Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by positive symptoms (hallucinations and delusions), negative symptoms (anhedonia, social withdrawal) and marked cognitive deficits (memory, executive function, and attention). Current mainstays of treatment, including medications and psychotherapy, do not adequately address cognitive symptoms, which are essential for everyday functioning. However, recent advances in computational neurobiology have rekindled interest in neurofeedback (NF), a form of self-regulation or neuromodulation, in potentially alleviating cognitive symptoms in patients with SCZ. Therefore, we conducted a systematic review of the literature for NF studies in SCZ to identify lessons learned and to identify steps to move the field forward. Our findings reveal that NF studies to date consist mostly of case studies and small sample, single-group studies. Despite few randomized clinical trials, the results suggest that NF is feasible and that it leads to measurable changes in brain function. These findings indicate early proof-of-concept data that needs to be followed up by larger, randomized clinical trials, testing the efficacy of NF compared to well thought out placebos. We hope that such an undertaking by the field will lead to innovative solutions that address refractory symptoms and improve everyday functioning in patients with SCZ.

Modulation of frontal gamma oscillations improves working memory in schizophrenia.

Schizophrenia is a debilitating mental disorder that is associated with cognitive deficits. Impairments in cognition occur early in the course of illness and are associated with poor functional outcome, but have been difficult to treat with conventional treatments. Recent studies have implicated abnormal neural network dynamics and impaired connectivity in frontal brain regions as possible causes of cognitive deficits. For example, high-frequency, dorsal-lateral prefrontal oscillatory activity in the gamma range (30-50 Hz) is associated with impaired working memory in individuals with schizophrenia.In light of these findings, it may be possible to use EEG neurofeedback (EEG-NFB) to train individuals with schizophrenia to enhance frontal gamma activity to improve working memory and cognition. In a single-group, proof-of-concept study, 31 individuals with schizophrenia received 12 weeks of twice weekly EEG-NFB to enhance frontal gamma band response. EEG-NFB was well-tolerated, associated with increased gamma training threshold, and significant increases in frontal gamma power during an n-back working memory task. Additionally, EEG-NFB was associated with significant improvements in n-back performance and working memory, speed of processing, and reasoning and problem solving on neuropsychological tests. Change in gamma power was associated with change in cognition. Significant improvements in psychiatric symptoms were also found. These encouraging findings suggest EEG-NFB targeting frontal gamma activity may provide a novel effective approach to cognitive remediation in schizophrenia, although placebo-controlled trials are needed to assess the effects of non-treatment related factors.

Can compassion focused therapy enhance dual recovery for veterans?

In our clinical work with veterans experiencing serious mental illness and substance use disorders, we noticed specific challenges not commonly addressed with traditional dual recovery group therapy-including having overactive threat systems and feelings of shame and self-criticism. For a program development project at our Veterans Affairs Psychosocial Rehabilitation and Recovery Center, we designed and implemented a group therapy program based on Compassion Focused Therapy (CFT), a therapeutic model that directly addresses the aforementioned challenges (Gilbert, 2009b). Results from pre- and post-intervention measures suggested veterans gained compassion and mindfulness skills and experienced reduced depressive symptoms. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Self-reported asthma diagnosis and mental health: Findings from the Collaborative Psychiatric Epidemiology Surveys.

Historically, asthma has had a mixed association with mental health. More research is needed to examine the associations between asthma and specific psychiatric disorders, and whether these associations hold true across racial groups in the general population of the United States. Using the Collaborative Psychiatric Epidemiology Surveys, we examined the associations between lifetime asthma and specific DSM-IV psychiatric disorders, adjusting for sociodemographic characteristics and smoking status. We found that when looking at the entire sample, self-reported diagnosis of asthma was associated with greater odds of reporting mood disorders (AOR: 1.36; 95% CI: 1.05-1.74). Asthma was not significantly associated with total anxiety disorders (AOR 1.25; 95% CI: 0.98-1.60), though it was specifically associated with generalized anxiety disorder. Asthma was associated with greater odds of having alcohol use disorders (AOR: 1.71; 95% CI: 1.24-2.37), but was not associated with total eating disorders (AOR:1.36; 95% CI: 1.17-2.51) (though it was significantly associated with higher odds for binge eating disorder, but lower odds of reporting bulimia). The strength and the significance of the associations between asthma and psychiatric disorders varied when stratified by race, underscoring the importance of examining race as a potential explanation for the mixed findings observed previously in the literature.

Assessing the Effectiveness of Neurofeedback Training in the Context of Clinical and Social Neuroscience.

Social neuroscience benefits from the experimental manipulation of neuronal activity. One possible manipulation, neurofeedback, is an operant conditioning-based technique in which individuals sense, interact with, and manage their own physiological and mental states. Neurofeedback has been applied to a wide variety of psychiatric illnesses, as well as to treat sub-clinical symptoms, and even to enhance performance in healthy populations. Despite growing interest, there persists a level of distrust and/or bias in the medical and research communities in the USA toward neurofeedback and other functional interventions. As a result, neurofeedback has been largely ignored, or disregarded within social neuroscience. We propose a systematic, empirically-based approach for assessing the effectiveness, and utility of neurofeedback. To that end, we use the term perturbative physiologic plasticity to suggest that biological systems function as an integrated whole that can be perturbed and guided, either directly or indirectly, into different physiological states. When the intention is to normalize the system, e.g., via neurofeedback, we describe it as self-directed neuroplasticity, whose outcome is persistent functional, structural, and behavioral changes. We argue that changes in physiological, neuropsychological, behavioral, interpersonal, and societal functioning following neurofeedback can serve as objective indices and as the metrics necessary for assessing levels of efficacy. In this chapter, we examine the effects of neurofeedback on functional connectivity in a few clinical disorders as case studies for this approach. We believe this broader perspective will open new avenues of investigation, especially within social neuroscience, to further elucidate the mechanisms and effectiveness of these types of interventions, and their relevance to basic research.

Is smoking tobacco associated with psychotic experiences across racial categories in the United States? Findings from the Collaborative Psychiatric Epidemiological Surveys.

Smoking tobacco has been associated with psychosis, though research has yet to fully examine the extent to which this association reaches into the sub-threshold range of the psychosis continuum within the US, and whether this association persists after accounting for co-occurring disorders. We analyzed data from three large racially-diverse surveys of the US population and found that current smokers were more likely to report a lifetime psychotic experience when compared with never smokers after adjusting for socio-demographics. But after controlling for anxiety, mood, and substance use disorders, these effects only remained strong and statistically significant for Asian-Americans.

Biological Motion induced mu suppression is reduced in Early Psychosis (EP) patients with active negative symptoms and Autism Spectrum Disorders (ASD).

There is evidence of genetic and neural system overlap in Autism Spectrum Disorder (ASD) and Early Psychosis (EP). Five datasets were pooled to compare mu suppression index (MSI), a proxy of mirror neuron activity, in EP, high functioning ASD, and healthy subjects (HS). ASDs and EPs with "active" negative symptoms showed significant differences in mu suppression, in response to Biological Motion/point-light display animation, compared to HS. Preliminary findings suggest that similar neural network deficits in ASD and EP could be driven by the expression of negative symptoms in the latter group of patients. These findings may aid future studies on EP and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.

Sleep disturbances are associated with psychotic experiences: Findings from the National Comorbidity Survey Replication.

Sleep disturbances have been linked to psychotic experiences in the general adult populations of multiple countries, but this association has yet to be confirmed in the United States using robust diagnostic measures. We analyzed a subsample (n=2304) of the National Comorbidity Survey Replication, and found that when compared with those who did not report any sleep problems, individuals with sleep disturbances lasting two weeks or longer over the past 12months were significantly more likely to report at least one psychotic experience during that same time frame. Specifically, difficulty falling asleep, waking up during the night, early morning awakenings, and feeling sleepy during the day were each associated with greater odds of reporting psychotic experiences over the past year after controlling for socio-demographic variables. However, only difficulty falling asleep and early morning awakenings were still significant after adjusting for DSM comorbid disorders. Reporting three or four types of sleep disturbances was especially predictive of psychotic experiences. Our findings underscore the importance of detecting and reducing sleep problems among individuals who report PE.

Effects of intranasal oxytocin on neural processing within a socially relevant neural circuit.

Dysregulation of the Mirror Neuron System (MNS) in schizophrenia (SCZ) may underlie the cognitive and behavioral manifestations of social dysfunction associated with that disorder. In healthy subjects intranasal (IN) oxytocin (OT) improves neural processing in the MNS and is associated with improved social cognition. OT's brain effects can be measured through its modulation of the MNS by suppressing EEG mu-band electrical activity (8-13Hz) in response to motion perception. Although IN OT's effects on social cognition have been tested in SCZ, OT's impact on the MNS has not been evaluated to date. Therefore, we designed a study to investigate the effects of two different OT doses on biological motion-induced mu suppression in SCZ and healthy subjects. EEG recordings were taken after each subject received a single IN administration of placebo, OT-24IU and OT-48IU in randomized order in a double-blind crossover design. The results provide support for OT's regulation of the MNS in both healthy and SCZ subjects, with the optimal dose dependent on diagnostic group and sex of subject. A statistically significant response was seen in SCZ males only, indicating a heightened sensitivity to those effects, although sex hormone related effects cannot be ruled out. In general, OT appears to have positive effects on neural circuitry that supports social cognition and socially adaptive behaviors.

Teaching Spanish to veterans with psychiatric disabilities: A creative approach to rehabilitation and recovery.

TOPIC: A Spanish course was heuristically designed to serve as a context to bring together components of various therapies and was offered to veterans with psychiatric disabilities enrolled in a psychosocial rehabilitation and recovery center. PURPOSE: Bilingualism has been associated with enhanced cognitive function and deserves more attention in psychiatric rehabilitation research. Developing opportunities for language instruction to potentially improve cognitive and community integration is explored. SOURCES USED: Relevant studies were reviewed to inform the design of the Spanish course and feedback was elicited from veterans who took the course. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Dialoguing with veterans can yield innovative and recovery-oriented changes to services, and may increase consumer satisfaction. Since leisure, social, and educational activities can draw from a person's interests and strengths, incorporating elements of therapies into these activities may create less stigmatizing and more engaging forms of treatment.

Biomarkers in psychosis: an approach to early identification and individualized treatment.

Numerous biomarkers for somatic disorders are used in routine medical practice. Yet, despite remarkable advances in mental health research, we are not able to identify biomarkers with established clinical utility for mental disorders such as schizophrenia. While identification and characterization of biomarkers are crucial first steps in this process, their predictive diagnostic and treatment utility need to be better developed for clinical practice. The heterogeneity of psychotic disorders etiologically, pathologically and symptomatically presents both a challenge and an opportunity for the use of biomarkers in clinical practice. Simply said, a single biomarker might not exist that necessitates the search for a biomarker profile. In this review we discuss research findings in light of such an approach. We summarize some examples of emerging biomarkers in early psychosis research and delineate how these can be applied to a clinical setting to inform treatment on an individual basis fostering a personalized treatment approach.

A developmental look at the attentional system in the at risk and first episode of psychosis: age related changes in attention along the psychosis spectrum.

INTRODUCTION: Neurodevelopmental processes of adolescence, when superimposed on a vulnerable brain, may produce additive effects reflecting the subthreshold psychotic symptoms, cognitive, and functional deterioration that are the hallmark of the early stages of schizophrenia. METHODS: As part of a longitudinal study, we investigated Continuous Performance Task, Identical Pairs Version (CPT-IP) performance in a sample of 301 participants (at risk for psychosis: 109; first episode-FE: 90; and controls: 102). Performance across groups was compared using d' of fast and slow, spatial and verbal conditions over two time points. Age effects were investigated using a regression model. RESULTS: Across all four CPT-IP conditions FE patients performed significantly worse than controls while AR individuals significantly differed from healthy subjects in the verbal condition. Age-related performance associations across groups significantly differed in the slow verbal condition because the FE sample did not show a significant association with increasing age like the AR and NC samples. CPT performance was stable over time. CONCLUSIONS: Sustained attention in the putative prodrome of psychosis is not only impaired but associated with age. Research focusing on cognitive and neurobiological age-related changes can help to address fundamental questions about the nature of the disorder, including whether the underlying pathophysiology of early psychosis is static or deteriorating.

Ethical implications for clinical practice and future research in "at risk" individuals.

The last 15 years have witnessed a shift in schizophrenia research with increasing interest in earlier stages of illness with the hope of early intervention and ultimately prevention of psychotic illness. Large-scale longitudinal studies have identified clinical and biological risk factors associated with increased risk of psychotic conversion, which together with symptomatic and demographic risk factors may improve the power of prediction algorithms for psychotic transition. Despite these advances, 45-70% of at risk subjects in most samples do not convert to frank psychosis, but continue to function well below their age matched counterparts. The issue is of utmost importance in light of the upcoming DSM-V and the possible inclusion of the attenuated psychotic symptoms syndrome (APSS) diagnosis, with clinical and ethical implications. Clinical considerations include feasibility of reliably diagnosing the at risk state in non-academic medical centers, variable psychotic conversion rates, a non-uniform definition of conversion and extensive debate about treatment for individuals with an ill-defined outcome. On the ethical side, diagnosing APSS could lead to unnecessary prescribing of antipsychotics with long-term deleterious consequences, slow research by providing a false sense of comfort in the diagnosis, and have psychosocial implications for those who receive a diagnosis. Thus it may be prudent to engage at risk populations early and to use broad-spectrum treatments with low risk benefit ratios to relieve functional impairments, while simultaneously studying all subsets of the at risk population.

Association of impaired EEG mu wave suppression, negative symptoms and social functioning in biological motion processing in first episode of psychosis.

BACKGROUND: Event related desynchronization (ERD) of mu waves, or mu suppression, over sensorimotor cortex has been observed in response to self-generated movement, viewing movement, or imaging movement. Mu suppression is especially pronounced when the movement has social relevance and is being generated by a biological entity indicating successful social adaptation. And since social adaptation problems are common in schizophrenia, the authors designed a study to test mu wave suppression in a first episode of psychosis population. METHODS: A total of 32 subjects (first episode of psychosis patients N=20; healthy comparison subjects N=12) aged 13-34 watched movement videos with and without socially relevant cues, executed by biological or non-biological agents. Scalp electrode EEG recordings of mu rhythm (8-13 Hz) over sensorimotor cortex during the session were used to calculate mu wave suppression. Average mu suppression was compared within and between groups, as well as correlations between mu suppression and clinical measures. RESULTS: First episode patients showed significantly reduced mu wave suppression over sensorimotor cortex when viewing biological motion, compared to healthy subjects. In addition, negative symptom burden and poor social adjustment correlated with impaired mu wave suppression. CONCLUSIONS: Our finding provides the first description of impaired event related desynchronization of mu waves in response to biological motion and its correlation with negative symptoms and social adjustment in the first episode of psychosis. Future studies can be conducted to determine if mu wave suppression represents an endophenotype with potential applications in biological treatments of negative symptoms and social functioning deficits in schizophrenia.