Antipsychotic Drugs Alter Functional Connectivity between the Medial Frontal Cortex, Hippocampus, and Nucleus Accumbens as Measured by H215O PET

Abstract

To evaluate changes in functional connectivity as a result of treatment with antipsychotic drugs (APDs) in subjects with schizophrenia (SZ), we identified a limited number of regions that have been implicated in the mechanism of action of APDs and that are part of a neuronal network known to be modulated by dopamine (DA). These regions consisted of the nucleus accumbens (NAcc), the hippocampus (Hip), and the medial frontal cortex (MFC). SZ participants were blindly randomized into a haloperidol treatment group (n = 12) and an olanzapine treatment group (n = 17). Using PET with 15O, we evaluated changes in functional connectivity between these regions during rest and task performance at three treatment time points: (1) at baseline, after withdrawal of all psychotropic medication (2 weeks), (2) after 1 week on medication, and (3) after 6 weeks on medication. Results from the two treatment groups were combined during analysis to investigate the common effects of APDs on functional connectivity. We found that the functional connectivity between MFC and NAcc significantly increased at week one, and then significantly decreased from week one to week 6. The functional connectivity between MFC and Hip significantly decreased at week one and week 6 relative to baseline. Critically, the strength of the functional connectivity between the MFC and Hip after 1 week of treatment was predictive of treatment response. This pattern of changes may represent an important biomarker for indexing treatment response. The regulation by APDs of the balance between prefrontal and limbic inputs to the striatum may be crucial to restoring adaptive behavior.

Keywords: antipsychotic drugs; functional connectivity; hippocampus; medial frontal cortex; nucleus accumbens; schizophrenia.

Figure 1

rCBF changes relative to baseline with APD treatment after 1 and 6 weeks of treatment. Increases in activation are shown in red and decreases are shown in blue. No significant changes were seen in the placebo-treated group at week 1 for any task. In the APD-treated group, there were significant increases in activation in NAcc after treatment with APDs (arrows, horizontal sections). There was a significant decrease in activation in medial frontal areas that shifted rostrally and dorsally between week 1 and week 6 of treatment (arrows, sagittal and coronal sections). The activation decrease was most significant during the sensory motor (SMC) and decision (DEC) task conditions. Coronal slices y = 47 mm and horizontal slices z = −10 mm (Montreal Neurological Institute coordinate system).

Figure 2

rCBF changes relative to 1 week of APD treatment after 6 weeks of treatment. Increases in activation are shown in red, and decreases are shown in blue. The significant decrease in activation in medial frontal areas shifted between week 1 and week 6 of treatment. The shift was most significant during the decision task condition.

Figure 3

Functional connectivity between regions of interest (ROI) at three time points in antipsychotic drug treatment (vertical axis) while performing three tasks and combined for all tasks (horizontal axis). Graph nodes represent ROI; graph edge color indicates the significance of the connection between nodes (p-value), for all connections with p < 0.05. SZ0, baseline; SZ1, 1 week of antipsychotic drugs treatment; SZ6, 6 weeks of antipsychotic drug treatment; HIP, hippocampus; VS; ventral striatum/nucleus accumbens; MFC, medial frontal cortex.

Figure 4

Changes in functional connectivity between regions of interest (ROI) during combined tasks from baseline to week one of antipsychotic drug treatment (left), baseline to week six of antipsychotic drug treatment (center), and between weeks one and six of antipsychotic drug treatment (right). Graph nodes represent ROI; graph edge color indicates the significance of the connectivity change between nodes (p-value), for all connections with p < 0.05. SZ0, baseline; SZ1, 1 week of antipsychotic drugs treatment; SZ6, 6 weeks of antipsychotic drug treatment; HIP, hippocampus; VS; ventral striatum/nucleus accumbens; MFC, medial frontal cortex.

Figure 5

Functional connectivity model. Functional connectivity model of medial frontal cortex (MFC), and hippocampus (HIP) incorporating gabaergic (red), glutametergic (green) and dopaminergic (blue) projections with an emphasis on MFC and HIP projection interactions in nucleus accumbens (NAcc). VP, ventral pallidum; Thal, thalamus; VTA, ventral tegmental area.