Psychotic disorders are readily identified by the so-called `positive symptoms' of hallucinations, delusions, and thought disorder. However, the severity of `negative symptoms' (e.g. amotivation, anhedonia, and facial expression deficits) are the best predictors of functional outcomes such as employment and independent housing. Antipsychotic medications are modestly effective in ameliorating these symptoms. We lack a consensus understanding of how these symptoms are mediated at the level of neural circuits. Without a biological `target' such as circuit pathophysiology, our ability to develop new interventions is critically hampered. Previous work from our laboratory and others have used task-free or `resting state' functional Magnetic Resonance Imaging (rsfMRI) to examine the neural correlates of negative symptom severity. Our preliminary data determined that negative symptom severity is correlated with dysconnectivity between the cerebellum and Dorso-Lateral Pre-Frontal Cortex (DLPFC). We empirically tested this network-symptom relationship using repetitive transcranial magnetic stimulation (rTMS) to manipulate network connectivity. We observed that rTMS induced increases in functional connectivity were strongly associated with improvement in negative symptom severity, consistent with the hypothesis that network connectivity mediates negative symptomology. We propose to test the hypothesis that cerebellar-DLPFC network dysconnectivity causes negative symptoms in schizophrenia. Using a within-subject, longitudinal experimental design, we will measure network connectivity and symptom severity before and after rTMS manipulation of cerebellar-DLPFC connectivity. We will quantify symptom severity via reporter based methods as well as rater-independent; objective measures that test amotivation, anhedonia, and facial expression. Our hypothesis is that reversal of network dysconnectivity will give rise to reduced negative symptom severity and the magnitude of network engagement will explain individual variance in symptomatic improvement. If successful, this project will establish a biological target for engagement by a variety of experimental methods towards the amelioration of these disabling, medication-resistant symptoms of psychotic disorders.

Public Health Relevance

Poor motivation, anhedonia, and difficulty expressing emotion are the so-called ?negative' symptoms of psychotic disorders that are closely linked to unemployment and poor quality of life. Existing medications do not significantly improve these symptoms and we lack an understanding of which brain circuits to target for future treatments. This study seeks to determine how brain activity gives rise to these disabling, medication- resistant symptoms.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Mcmullen, David
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Beth Israel Deaconess Medical Center
United States
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