Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.

BACKGROUND: The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia. METHODS: Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging during working memory. We conducted between-group contrasts of task-evoked, univariate activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present. RESULTS: We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis. CONCLUSIONS: These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.

RATIONALE: Dopamine is abundant in the prefrontal cortex and striatum, regions implicated in working memory processes. Monkey studies suggest that subpopulations of prefrontal neurons are sensitive to component processes of working memory, and that dopaminergic actions at D1 and D2 receptors differentially affect these neurons. However, it is not known to what extent the effects of dopaminergic stimulation may differ in human subjects across the processing stages of working memory, and whether these effects are found throughout the network of task-related brain regions. OBJECTIVE: In this study we tested the effects of the D2 dopamine agonist bromocriptine during the performance of a delayed recognition task using functional magnetic resonance imaging (fMRI). METHODS: We measured blood oxygenation level dependent (BOLD) signals as subjects performed a spatial and object delayed recognition task. Subjects were scanned twice, once following 1.25 mg of bromocriptine and once following lactose placebo in a randomized double-blind design. Using an event-related design allowed for separate investigation of encoding, delay, and response period effects of dopaminergic stimulation. RESULTS: A group analysis revealed that bromocriptine treatment decreased activity in the task network at encoding and increased activity at response. There was no clear pattern of change in the delay period network. Across subjects, these BOLD signal changes were accompanied by reductions in accuracy and increases in response time during delayed recognition for spatial and object information. CONCLUSIONS: Decreased activity during encoding suggests that hyperdopaminergic stimulation may have reduced stimulus encoding processes, contributing to impaired performance.

Working memory is an important cognitive process dependent on a network of prefrontal and posterior cortical regions. In this study we tested the effects of the mixed D1-D2 dopamine receptor agonist pergolide on component processes of human working memory using functional magnetic resonance imaging (fMRI). An event-related trial design allowed separation of the effects on encoding, maintenance, and retrieval processes. Subjects were tested with spatial and object memoranda to investigate modality-specific effects of dopaminergic stimulation. We also measured baseline working memory capacity as previous studies have shown that effects of dopamine agonists vary with working memory span. Pergolide improved reaction time for high-span subjects and impaired reaction time for low-span subjects. This span-dependent change in behavior was accompanied by span-dependent changes in delay-related activity in the premotor cortex. We also found evidence for modality-specific effects of pergolide only during the response period. Pergolide increased activity for spatial memoranda and decreased activity for object memoranda in task-related regions including the prefrontal and parietal cortices.