Research

The MMTI lab‘s focus is to develop novel tools and techniques to study the living human brain, and to apply these techniques to clinical studies to unravel pathology associated with severe mental illnesses and drug addiction.  Molecular imaging techniques based on Positron Emission Tomography (PET) and functional MRI imaging techniques are the primary focus. The lab includes a comprehensive team of experts in neurobiology, cognitive and experimental psychology, mathematical modeling, and image analysis, in addition to clinicians expert in the evaluation and recruitment of research participants.

SCHIZOPHRENIA AND PSYCHOSIS
In schizophrenia, we have examined multiple aspects of dopaminergic neurotransmission and their association to symptom domains. Over the last decade the work of the lab has contributed to the following major findings that have reshaped our thinking about dopaminergic pathology in schizophrenia [1].  

Amphetamine induced dopamine release measured with D2 antagonist radiotracers is increased in the striatum of patients with schizophrenia compared to controls. Dopamine “synthesis” measured with the accumulation of [18F]DOPA is also increased in the striatum [2].

There is subregional heterogeneity in the dopamine dysregulation within the striatum. The rostral caudate and the associative striatum generally show lower dopamine release capacity than the sensorimotor striatum in healthy participants [3], but not in patients with schizophrenia, due to a prominent increase in the associative striatum [4-6]. Similar evidence for the prominent role of DA dysregulation in the associative striatum also derives from studies in prodrome by other labs [5, 6].

While postsynaptic receptors and transporters do not show a reliably detectable altered expression either in the striatum or in extrastriatal regions of the brain in schizophrenia, there is evidence for a supersensitive responsivity, as we demonstrated that patients with comorbid substance use disorder (and who have reduced presynaptic release) show a relationship between magnitude of release and propensity for psychosis. This supersensitivity could be due to post-synaptic factors [7].

Dopamine release capacity in prefrontal cortical and other extrastriatal regions is decreased [8]. 

Other lines of work into the pathophysiology of schizophrenia have focused on deficits in working memory. For many years, functional neuroimaging studies of working memory have largely failed to identify a consistent neural correlate of working memory impairments in these patients [9, 10]. This has long been thought to be due to a non-monotonic (i.e., “inverted-U”) relationship between fMRI activation of dorsolateral prefrontal cortex and the memory load of the task being used [10, 11], which we recently provided the first direct evidence for in a large sample of both medicated and unmedicated patients [12].

Going forward, our work in schizophrenia aims to understand how an early emerging dopamine dysfunction can lead to specific symptom domains, and how alterations in striatal dopamine can alter functional connectivity between the striatum and other brain regions [e.g., 13]. One area currently under examination is the specific relationship to auditory hallucinations. Furthermore, the imbalance between striatal and extrastriatal regions is puzzling and raises the possibility that local factors within the striatum may modulate dopamine transmission in an opposite way to the extrastriatal regions. Our lab is currently exploring these modulatory systems. Other ongoing works seeks to use resting state functional connectivity MRI to investigate whether alterations in neuroanatomical projections observed in mouse models of schizophrenia with impacted dopamine function may be present in clinical samples of human patients.

SUBSTANCE ABUSE
A second hub of work in the lab relates to drug addiction, considered on its own. Our work recently helped clarify an important debate in the literature on whether cannabis users have low amphetamine induced dopamine release in the striatum [14]: we reported that blunted dopamine release is present, but appears to depend heavily on the severity of use [15]. This contrasts with most other drugs of abuse, such as alcohol, cocaine, or heroin, where deficits in dopamine function are typically more uniform within the study sample.

Our work in drug addiction is increasing. In parallel to the lab’s ongoing work in schizophrenia, we are exploring neurotransmitter systems that modulate dopamine transmission in addiction, and testing how these modulatory systems may affect cognition and drug use. Members of our group are also interested in understanding why drug-addicted individuals, despite the harmful consequences of their use, are often resistant to treatment. We use functional neuroimaging methods to shed light on this issue, with the goal to improve our understanding of the neurobiological mechanisms underlying insight and self-awareness [16]. The core knowledge gained from this research also can be applied to other psychiatric disorders, potentially including schizophrenia.   

To learn more about our current studies, click here.

NEUROIMAGING METHODS DEVELOPMENT 
In support of the clinical neuroimaging work described above, our lab also makes substantial investments in methods development for both Positron Emission Tomography and functional Magnetic Resonance Imaging. Examples of ongoing and recent projections involve novel methods for pharmacokinetic modeling of PET data, early studies with a new vesicular cholinergic transporter tracer, and the development of a variety of new methods for identifying and correction motion-induced and other artifacts in simultaneous multi-slice (aka, “multiband”) fMRI data.

1. Weinstein, J.J., et al., Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biol Psychiatry, 2016.
2. Howes, O.D., et al., The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry, 2012. 69(8): p. 776-86.
3. Martinez, D., et al., Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab, 2003. 23(3): p. 285-300.
4. Kegeles, L.S., et al., INcreased synaptic dopamine function in associative regions of the striatum in schizophrenia. Archives of General Psychiatry, 2010. 67(3): p. 231-239.
5. Mizrahi, R., et al., Increased stress-induced dopamine release in psychosis. Biol Psychiatry, 2012. 71(6): p. 561-7.
6. Howes, O.D., et al., Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry, 2009. 66(1): p. 13-20.
7. Thompson, J.L., et al., Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry, 2012.
8. Slifstein, M., et al., Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry, 2015. 72(4): p. 316-24.
9. Van Snellenberg, J.X., Working memory and long-term memory deficits in schizophrenia: is there a common substrate? Psychiatry Res, 2009. 174(2): p. 89-96.
10. Van Snellenberg, J.X., I.J. Torres, and A.E. Thornton, Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable. Neuropsychology, 2006. 20(5): p. 497-510.
11. Manoach, D.S., Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res, 2003. 60(2-3): p. 285-98.
12. Van Snellenberg, J.X., et al., Mechanisms of Working Memory Impairment in Schizophrenia. Biol Psychiatry, 2016. 80(8): p. 617-26.
13. Horga, G., et al., Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia. JAMA Psychiatry, 2016. 73(8): p. 862-70.
14. Ghazzaoui, R. and A. Abi-Dargham, Imaging dopamine transmission parameters in cannabis dependence. Prog Neuropsychopharmacol Biol Psychiatry, 2014. 52: p. 28-32.
15. van de Giessen, E., et al., Deficits in striatal dopamine release in cannabis dependence. Mol Psychiatry, 2017. 22(1): p. 68-75.
16. Moeller, S.J. and R.Z. Goldstein, Impaired self-awareness in human addiction: deficient attribution of personal relevance. Trends Cogn Sci, 2014. 18(12): p. 635-41.