HIGHLIGHTS
Our translational research program leverages multimodal neuroimaging techniques, pharmacological modeling, and computationally advanced data analytics to better understand disease processes underlying psychosis spectrum disorders. We use structural and functional Magnetic Resonance Imaging (MRI), Diffusion Weighted Imaging (DWI), Arterial Spin Labeling imaging (ASL), and Magnetic Resonance Spectroscopy (MRS) to study the neurobiological substrates relevant in psychosis and evaluate the effects of psychotropic drugs on brain structure, function, and biochemistry.
Dissecting the Heterogeneity of Schizophrenia
Schizophrenia is a heterogeneous disorder that likely involves multiple underlying pathological mechanisms, which has plagued attempts to identify rational therapeutic targets. All available antipsychotic drugs act on the dopamine receptor, but clinical response is variable, with a third of patients being partial responders, and a third non-responders. Arguably, those who respond well to antipsychotic medications have primarily dopaminergic abnormalities but it is imperative to also characterize the specific underlying pathologies in those with poor response in order to unravel the heterogeneity of psychosis and effectively develop new treatments. To dissect this heterogeneity, we are conducting a study where we longitudinally follow antipsychotic medication-naive first episode psychosis patients for eight months and monitor the clinical response to antipsychotic medications. We use complimentary brain imaging techniques to track pathophysiological mechanisms and monitor changes that occur over time in response to treatment. Using several imaging modalities has the potential to interrogate different neurobiological aspects of treatment response and will offer greater opportunities for clustering the patterns and combinations of the underlying pathologies in those with poor response. Deconstructing the heterogeneity of psychosis has broad implications for the identification of specific targets for drug development, and to lay the groundwork needed to conduct therapeutic trials on patients characterized by their specific underlying psychopathology.
Discovery of Neurobiological Correlates of the Duration of Untreated Psychosis
It is becoming increasingly clear that longer duration of untreated psychosis (DUP), the time between initial symptom onset and first treatment, is associated with adverse clinical outcomes in patients suffering from psychosis spectrum disorders, and may even be a determinant of overall outcomes. Here, we enrolled a large group of antipsychotic medication-naïve first episode psychosis patients in a multimodal neuroimaging protocol to characterize structural, functional and neurometabolic alteration in context of the DUP. We have demonstrated a link between the DUP and both structural and functional connectivity in antipsychotic medication-naïve first-episode psychosis patients. Importantly, we found that connectivity mediated the relationship between longer DUP and poorer subsequent response to antipsychotic treatment, supporting the idea that untreated psychosis adversely affects the brain in a clinically relevant manner. Our data provide empirical support to the idea the DUP may have fundamental pathogenic effects on the natural history of psychosis.
Neuroimaging Markers of Clinical Response to Antipsychotic Treatment
In this project we used complementary imaging and postmortem data to permit the formulation of a comprehensive model for antipsychotic treatment response in patients suffering from a severe mental illness. Using multimodal neuroimaging, we identified markers for several different pathophysiological mechanisms underlying psychosis, including abnormalities in glutamate, brain connectivity, and neurodevelopment. In parallel, we have quantified morphological indices of neuronal integrity of glutamate neurons and synapses as well as the structural integrity of mitochondria in our postmortem work to provide a basis for the interpretation of the in vivo neuroimaging data. Early detection of drug response has the potential to yield specific treatment strategies that are tailored to the individual, thus improving both the quality of life of the patients and drastically reducing the costs associated with unsuccessful treatments strategies.
Identification of Factors Associated with White Matter Disease Progression
Schizophrenia is a complex disorder associated with subtle white matter abnormalities that progress over time. Alterations are associated with disease severity across symptom dimensions and worse overall outcomes, but no strategies exist to attenuate white matter disease progression. This is largely because the underlying pathophysiological processes remain unknown. Glutamate excess and inflammation may be contributing factors, but we do not know if there is a period early in the illness where these affect white matter or if they alter white matter across illness stages. Here, we use multimodal neuroimaging techniques that measure white matter structural integrity in context of glutamatergic and inflammatory markers to test the hypothesis that white matter integrity deficits increase as a function of illness stage, and that glutamate excess and inflammation contribute to white matter pathology. Identification of factors that contribute to progressive white matter deficits holds the promise to transform our mechanistic understanding and inform biomarkers for targeted drug development investigating the potential of glutamatergic or anti-inflammatory agents delaying or attenuating white matter decline in schizophrenia.
Characterizing Clinical Subtypes of Schizophrenia
The current clinical taxonomy of psychiatric disorders does not include characteristics that demarcate patterns of symptoms, illness severity, or prognostic features. The deficit syndrome is thought to be a more homogenous clinical subgroup within the syndrome of schizophrenia that is characterized by enduring negative symptoms. It is hypothesized that distinct pathophysiological processes underlie the subtypes, where the deficit syndrome reflects an early onset non-progressive developmental process, and the non-deficit form of the illness is characterized attenuated neuroplasticity. We used multimodal neuroimaging to determine unique neuropathological signatures of the subtypes and found that first episode psychosis patients without deficit features show elevated glutamate metabolism whereas patients who do display deficit features show alterations in resting state network topology and fronto-parietal network connectivity. Our findings add to the growing body of literature supporting a neurobiological distinction between two clinical subtypes of schizophrenia, which has the potential to be leveraged for patient stratification in clinical trials and development of novel treatments.
Ketamine as a Pharmacological Model for Psychosis
A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on ɣ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to schizophrenia pathophysiology. Subanesthetic doses of ketamine preferentially block NMDAR on GABAergic interneurons and have been shown to transiently induce a behavioral phenotype similar to that seen in psychosis. Here, we used ketamine as a pharmacological model in healthy volunteers and confirmed the hypothesis that experimentally induced NMDAR blockage would result in an increase of glutamate in the hippocampus and in fronto-temporal and temporo-parietal functional dysconnectivity, resembling abnormalities seen in the disorder. Our data empirically support that hippocampal glutamatergic elevation and resting state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia. The results of this study also have potential clinical implications. Medications attenuating the impact of hippocampal glutamatergic hyperactivity could conceivably diminish functional dysconnectivity and perhaps alleviate disease burden across symptom dimensions in this profoundly disabling neuropsychiatric disorder.
