3.4 NEURAL OSCILLATIONS AND EXCITATION/INHIBITION BALANCE IN SCHIZOPHRENIA: A DEVELOPMENTAL PERSPECTIVE

Abstract Background Schizophrenia (ScZ) is a neurodevelopmental disorder that characteristically emerges during the transition from adolescence to adulthood. However, the mechanisms that underlie the expression of psychotic symptoms and cognitive deficits during this developmental period are still unclear. In my presentation, I will summarize data from EEG/MEG-work that has investigated the maturational changes in in neuronal dynamics during adolescence as well as the possibility that aberrant rhythmic activity is present in clinical high-risk participants. Methods A sample of participants meeting CHR-criteria (n=100) from the ongoing Youth Mental Health Risk and Resilience (YouR) Study and 50 matched controls were recruited as well as a sample of n = 20 participants meeting first-episode psychosis (FEP) criteria. We examined auditory and visual-induced oscillations as well as resting-state Magnetoencephalographical (MEG)-data and obtained estimates of spectral power and phase-synchronization at source-level. MEG-recordings were accompanied by Magnetic Resonance Spectroscopy (MRS) measurements of GABA and Glutamate-levels in auditory and visual cortices. In addition, we examined the development of neural oscillations in a sample of n = 100 children and adolescents (age range: 12–21 years) during a working memory task and during spontaneous activity to identify critical periods for the development of neural dynamics. Results CHR-participants were significantly impaired in the generation of both auditory and visual gamma-band oscillations as well as characterized by an increase in broad-band, resting-state gamma-band power. The latter points towards an increase in excitability-levels of neural circuits which is supported by increased Glutamate-levels in sensory regions while GABA-levels were not different from controls. Similar patterns in both MEG- and MRS-parameters were observed in the FEP-group. Finally, our developmental data highlight that the transition from adolescence to adulthood is characterized by profound changes in both amplitude and synchrony dynamics, highlighting the possibility that critical period mechanisms that underlie the expression of psychosis are impaired in ScZ. Discussion Together, these data indicate that aberrant neural oscillations in ScZ highlight the crucial contribution of impaired neural dynamics that are likely to result from dysfunctional Excitation/Inhibition balance parameters. Moreover, the onset of schizophrenia during the transition from adolescence to adulthood suggests that critical period mechanisms that support the expression of high-frequency oscillations are impaired.


Stanford University
Background: In schizophrenia (SCH), proton MRS studies of the medial prefrontal cortex (MPFC) show elevated glutamine (Gln) or the combination of Glu and Gln (Glx) in unmedicated patients.Studies in healthy human subjects demonstrate ketamine-induced acute increases in MPFC Glu or Gln.Together, these findings raise the question of potential disturbances in excitation-inhibition balance in the illness, possibly arising from NMDA receptor deficits in GABAergic interneurons.We investigated these questions following acute ketamine administration by using repeated 15-minute MRS acquisitions of Glx and GABA with simultaneous EEG and comparing the results with the same modalities acquired in SCH.Methods: We enrolled 11 healthy volunteers (age 18-55) who were given a constant i.v.infusion of ketamine 0.5 mg/kg over 40 min during a combined EEG and 1H MRS study.Glx and GABA were acquired in the pregenual MPFC using a 3T GE system and a J-edited PRESS sequence.Sequential MRS acquisitions each of 15 min duration (90 min total) were obtained before, during, and following the infusion.EEG was recorded using an MRI-compatible 64-channel system with direct current BrainAmp MR amplifiers (Brain Products GmbH).Post-ketamine EEG data were analyzed in frontal electrodes for gamma and delta alterations.EEG and MRS data were also acquired in 12 patients with SCH with these systems.Results: Neurochemicals Glx and GABA showed acute increases within 15-30 minutes following the initiation of ketamine infusion, more pronounced for GABA (13% increase, p = .04by paired t test).Gamma amplitude in left and right frontal electrodes increased in the first 15-minute average after initiation of ketamine (p < .05),with no evidence of earlier gamma decrease.Left delta amplitude decreased linearly following ketamine (p < .01).Peak GABA concentration correlated inversely with average left delta amplitude in the immediately subsequent 15-minute acquisition.Data in SCH showed similar elevations in GABA and gamma amplitude.Discussion: These data show the feasibility of attaining time resolution of Glx and GABA changes in the several-minutes range with standard PRESS J-edited 1H MRS, and simultaneous sub-second resolution with EEG.There were no indications in these frontal electrodes of very early GABAergic inhibition leading to disinhibition of Glx, which may occur in other brain regions following ketamine administration.The GABA, Glx, and EEG alterations found here following ketamine administration are consistent with stable alterations reported in unmedicated patients with SCH and are compatible with an NMDA receptor deficit mechanism in the illness.They show homeostatic rebalancing at elevated levels as found in SCH itself.Excitation-inhibition rebalancing at abnormally elevated levels may pose a risk of neuronal damage that persists in untreated psychosis.

NEURAL OSCILLATIONS AND EXCITATION/ INHIBITION BALANCE IN SCHIZOPHRENIA: A DEVELOPMENTAL PERSPECTIVE
Peter Uhlhaas* ,1 1

Institute of Neuroscience & Psychology, University of Glasgow
Background: Schizophrenia (ScZ) is a neurodevelopmental disorder that characteristically emerges during the transition from adolescence to adulthood.However, the mechanisms that underlie the expression of psychotic symptoms and cognitive deficits during this developmental period are still unclear.In my presentation, I will summarize data from EEG/MEG-work that has investigated the maturational changes in in neuronal dynamics during adolescence as well as the possibility that aberrant rhythmic activity is present in clinical high-risk participants.Methods: A sample of participants meeting CHR-criteria (n=100) from the ongoing Youth Mental Health Risk and Resilience (YouR) Study and 50 matched controls were recruited as well as a sample of n = 20 participants meeting first-episode psychosis (FEP) criteria.We examined auditory and visual-induced oscillations as well as resting-state Magnetoencephalographical (MEG)-data and obtained estimates of spectral power and phase-synchronization at source-level.MEG-recordings were accompanied by Magnetic Resonance Spectroscopy (MRS) measurements of GABA and Glutamate-levels in auditory and visual cortices.In addition, we examined the development of neural oscillations in a sample of n = 100 children and adolescents (age range: 12-21 years) during a working memory task and during spontaneous activity to identify critical periods for the development of neural dynamics.Results: CHR-participants were significantly impaired in the generation of both auditory and visual gamma-band oscillations as well as characterized by an increase in broad-band, resting-state gamma-band power.The latter points towards an increase in excitability-levels of neural circuits which is supported by increased Glutamate-levels in sensory regions while GABAlevels were not different from controls.Similar patterns in both MEG-and MRS-parameters were observed in the FEP-group.Finally, our developmental data highlight that the transition from adolescence to adulthood is characterized by profound changes in both amplitude and synchrony dynamics, highlighting the possibility that critical period mechanisms that underlie the expression of psychosis are impaired in ScZ.Discussion: Together, these data indicate that aberrant neural oscillations in ScZ highlight the crucial contribution of impaired neural dynamics that are likely to result from dysfunctional Excitation/Inhibition balance parameters.Moreover, the onset of schizophrenia during the transition from adolescence to adulthood suggests that critical period mechanisms that support the expression of high-frequency oscillations are impaired.

INNOVATIVE APPROACHES TO EARLY IDENTIFICATION AND TREATMENT: USING MOBILE HEALTH TECHNOLOGY TO IMPROVE OUTCOMES IN PSYCHOSIS Laura Tully University of California, Davis
Overall Abstract: Smartphone and internet based applications that promote symptom tracking, treatment engagement, and self-management have the potential to improve mental health outcomes and reduce cost of care.This is especially important in the treatment of psychosis, as longterm clinical outcomes to commonly available treatments remain poor and financial costs are high.The speakers in this symposium will present novel approaches using mobile health technology to promote rapid identification and referral (Dr.Niendam), access to treatment (Dr.Hidalgo-Mazzei), treatment engagement and symptom tracking (Dr.Tully), and functional recovery (Dr.Alvarez-Jimenez) for individuals experiencing psychosis.Dr. Niendam will present initial results of a community-based clusterrandomized controlled trial aiming to increase identification rates of individuals with psychosis and reduce Duration of Untreated Psychosis.Twenty-two school, community, and primary care sites in Sacramento, California were randomized to either standard community education and clinician-based referral versus standard education plus electronic (tablet) screening for psychosis symptoms.Results show electronic screening is feasible across various community settings and significantly increases identification rates compared to clinician-based identification alone.Dr. Hidalgo-Mazzei will present data examining the feasibility of delivering a psychoeducational treatment program that promotes self-management in bipolar disorder.The SIMPLe platform is accessible from any internet enabled device and provides symptom monitoring and personalized psychoeducation content in Spanish, Italian, and French.Data from a large open trial with over 300 participants from across the globe demonstrate how mobile technologies can increase access to care by extending effective interventions to many people at low cost.Dr. Tully will present data on the feasibility, validity, and predictive utility of a consumer smartphone application ("app") plus provider web-based Dashboard as an add-on treatment tool in Early Psychosis outpatient programs in Northern California.Data demonstrate that consumers and providers in community-based outpatient clinics are responsive to integrating smartphone technology into treatment services.Consumers willingly use the app to track their symptoms; symptom data gathered via the app appears to be a valid reflection of symptoms experienced over time and can predict symptom exacerbations two weeks later.Dr. Alvarez-Jimenez will present data demonstrating the feasibility, acceptability, and efficacy of two novel online social media based platforms designed to promote functional recovery in Ultra High Risk and First Episode Individuals.Results indicate online social media platforms are safe, engaging, and improve social functioning in both populations -a domain that is often neglected in most treatment approaches.Chantel Garrett is the founder of Strong365.org,a website providing consumer and family-focused psychoeducation materials related to psychosis in 103 languages.She also has lived experience as a family member of a loved one with schizophrenia.As discussant, she will speak from her expertise as both a developer and consumer of internet-based and mobile technologies to elucidate how mobile health materials can impact provision of mental health care, and facilitate discussion of the barriers and future directions for the field.Implementation of technology-based care across diverse cultures and languages will also be discussed.

ENHANCING EARLY PSYCHOSIS TREATMENT USING SMARTPHONE TECHNOLOGY: INTEGRATION OF A MOBILE HEALTH PLATFORM IN FOUR EARLY PSYCHOSIS PROGRAMS
Laura Tully* ,1 , Ana-Maria Iosif 1 , Lauren Zakskorn 1 , Divya Kumar 1 , Kathleen Nye 1 , Aqsa Zia 1 , Jennifer Denton 1 , Katherine Pierce 1 , Taylor Fedechko 1 , Tara Niendam 1 1 University of California, Davis Background: Mobile health applications offer ecologically valid, data-rich methods of modeling daily symptoms and functioning, which could inform treatment delivery and facilitate early intervention in individuals with psychosis.To date, most studies evaluate adoption of technology independent of care providers.However, successful implementation and long-term adoption of mobile technology likely also requires integration into outpatient settings as an add-on tool to enhance treatment.We implemented a smartphone "app" plus clinician Dashboard as an add-on treatment tool in the UC Davis Early Psychosis (EP) Programs and tested feasibility, validity, and predictive utility of symptom tracking via the app as part of EP care.A subsequent pilot study examined barriers to implementation within two additional community outpatient settings in Northern California.Methods: Study 1 implemented the platform within the UC Davis EP Programs.For up to 14 months, EP clients completed daily and weekly surveys examining mood, symptoms, and treatment relevant factors via the app, as well as monthly in-person clinical assessments using the BPRS.Clinicians discussed symptom ratings and surveys during treatment sessions using the Dashboard.We examined client enrollment and survey completion to determine feasibility, and relationships between BPRS and weekly symptom ratings to evaluate validity of self-report symptom data collected via the app.Analysis of predictive utility determined if weekly self-report symptoms predicted symptom exacerbations 2 weeks later.Study 2 expanded recruitment to 2 additional community-based EP outpatient clinics.EP clients and their clinicians used the platform as part of