The cerebral cortex undergoes a protracted course of post-natal development during childhood and through young adulthood¹. In addition to progressive brain tissue changes, developmental changes in neurotransmitter availability likely precede or underlie these structural changes². There is strong evidence that pre-frontal cortex (PFC) microcircuitry is abnormal in neurodevelopmental disorders such as schizophrenia (SZ). Recent evidence suggests that dysregulation of the dopamine system in SZ could be secondary to a deficit in glutamate function². Alterations in the neurochemical profile in those at risk for psychosis are less consistent, but suggest these types of measures may be sensitive to heightened psychosis risk or transition to psychosis^3,4,5, and are related to volumetric gray matter reductions critical to the pathogenesis of the disorder⁶.20 typically developing (TD) youth, 13 individuals at clinical high risk (CR) for psychosis and 5 young patients with schizophrenia (SZ) participated. All participants were recruited from the Philadelphia Neurodevelopmental Cohort^7,8 and Brain Behavior Laboratory at the Unversity of Pennsylvania under approved IRB protocol. We employed a novel imaging technique—glutamate chemical exchange saturation transfer (GluCEST)⁹—to measure glutamate levels, in vivo, across the cerebrum, with a specific emphasis on regions of known volume loss in SZ and CR, including the olfactory system^10,11. An optimized within-subject acquisition and analysis pipeline was implemented as shown in Figures 1 & 2. Participants underwent both 3T and 7T MRI. At 3T, structural images were acquired and each subject’s image was segmented using FreeSurfer. At 7T, 2D GluCEST, B₀ and B₁ maps (5mm thickness) were collected in axial and mid-sagittal planes. Raw CEST images were acquired at varying saturation offset frequencies from ±1.5 to ±4.5 ppm (relative to water resonance) with a step size of ±0.3 ppm. GRE images at two echo times (TE1 = 4.24 ms; TE2 = 5.26 ms) were collected to compute the B₀ map. The B₁ map was generated from the two images obtained using square preparation pulses with flip angles 30° and 60°. Overall, acquisition time of CEST images, B₁ and B₀ field maps was approximately 15 minutes. The B₀ and B₁ corrected GluCEST contrasts were then averaged within automatically derived regions-of-interest (ROIs) from each individual’s high-resolution 3T structural MRI.In TD youth, GluCEST values varied throughout the cortex dependent on brain lobe. Parietal and occipital lobes show similar GluCEST values and both lobes show greater values than the frontal lobe. Glutamate values also differ between diagnostic groups. Typically developing subjects had the highest levels of GluCEST. Patients with schizophrenia had lower GluCEST values in frontal (15%), parietal (20%) and occipital (23%) lobes. Youth at risk for psychosis showed an intermediate pattern (Figure 3A, 3B, 3C). Exploratory analysis of specific regions-of-interest within each lobe (Figure 4) indicated regions specificity of GluCEST deficits in psychosis (e.g. Subcallosal cortex, medial orbitofrontal cortex), in particular for youth at-risk for developing psychosis.Our preliminary work indicates typically developing individuals have the highest glutamate values throughout the cortex while youth at clinical high risk for psychosis exhibit subtle, but significant, abnormalities in brain glutamate, similar to patients with schizophrenia. Given the clinical evidence implicating abnormal neurodevelopment in the pathogenesis of schizophrenia, and the potential utility of brain structure and function to predict illness vulnerability, GluCEST holds distinct promise for understanding neurodevelopmental contributions to schizophrenia pathophysiology. Adolescence is a critical developmental risk period, during which developmental anomalies or stressors can greatly increase the subsequent risk of schizophrenia¹². As such, early intervention requires valid and reliable methods of identifying youths at highest risk for developing psychosis.We suggest that, in addition to neuroanatomical and functional imaging methods, neurochemical metrics, such as GluCEST, be considered as markers of risk for psychosis.