Activation imaging is among the hottest growth areas in neuroscience, promoted largely by the increasing availability of MRI equipment capable of measuring blood-oxygen level-dependent contrast, which generally parallels metabolism and blood flow. This is the foundation of functional MRI (fMRI). Initial reports using positron emission tomography (PET) to study cerebral glucose metabolism or blood flow showed hypofrontality (reduced activity in the frontal lobes) either at rest or while patients attempted cognitive tasks. Other fMRI studies support this concept (Winterer and Weinberger, 2004).
A meta-analysis suggested this is the most robust neuroimaging finding distinguishing schizophrenia (Davidson and Heinrichs, 2003). Another meta-analysis of fMRI studies that used a specific working memory paradigm concluded that the pattern of activation abnormalities (including both decreases and increases) across complex networks including frontal lobe and other linked regions, is more informative (Glahn et al., 2005). Complicating these interpretations, some studies show underactivation, while others show overactivation in response to cognitive challenges. The latter findings are often interpreted as revealing inefficiency of the neural systems involved (Winterer and Weinberger, 2004). Future studies will likely employ more sophisticated designs to characterize the dynamic response of frontal lobe and related regions to challenges of varying complexity. This will effectively offer a graded stress test to see how these systems respond to changing demands.
Exciting new research combines activation imaging with pharmacological manipulations and/or genetic information. For example, Honey and colleagues (1999) showed normalization of frontoparietal fMRI activation in response to a working memory challenge. Patients with schizophrenia were switched from conventional antipsychotics to risperidone(Drug information on risperidone) (Risperdal).
Several studies have now shown effects of genetic polymorphisms on the patterns of activation elicited by cognitive challenges, and even complex four-way interactions between diagnosis, cognitive challenge condition, genotype and pharmacological manipulation. For example, a polymorphism in the gene coding for the enzyme catechol-O-methyltransferase (COMT) has a significant effect on the breakdown of dopamine(Drug information on dopamine). Patients with schizophrenia who have the form of this gene linked to lower prefrontal dopamine showed greater inefficiency of prefrontal activation response to cognitive challenge, and also altered change in this response when given amphetamine (Mattay et al., 2003).
Another report examined the gene DISC1 (disrupted in schizophrenia 1), which was previously associated with a higher incidence of psychopathology in a family study (Callicott et al., 2005). Overtransmission of a certain polymorphism (Ser704Cys) was associated with reduced gray matter volume, as well as deficits in performance and activation in fMRI experiments. Future imaging studies will characterize patients by their responses to specific cognitive and pharmacological challenges, considering the genetic variations that impact these responses.
Molecular Imaging
While many current hypotheses about the mechanisms of antipsychotic agents are linked to receptor-binding profiles observed in vitro, neuroimaging has been instrumental in advancing knowledge of receptor modulation in vivo. Early versions of the dopamine hypothesis (i.e., that there is excessive transmission of dopamine) were based on the observation that effective antipsychotic agents blocked dopamine D2 receptors. Molecular imaging studies using specific ligands to map dopamine receptor binding and other indices of dopamine metabolism show that the situation is not so simple.
In an excellent review of this literature, Abi-Dargham and Laruelle (2005) concluded that evidence supports a complex pattern of excessive D2 stimulation subcortically and decreased transmission (at D1 receptors) cortically, and suggested that this may be consistent with a primary abnormality in N-Methyl-D-aspartate transmission. Comparisons of first- and second-generation antipsychotics show that reduced extrapyramidal side effects (EPS) can be explained by lower D2 occupancy. However, it is possible that the 5-HT2a binding of some novel antipsychotic agents, together with D2 blockade, indirectly increase D1 transmission cortically and thereby have beneficial effects. Some PET studies also have examined the therapeutic window for D2 occupancy. There is some consensus that a D2 occupancy of approximately 50% may be necessary to achieve therapeutic efficacy for positive symptoms, while an occupancy greater than 80% may produce EPS (Kapur and Mamo, 2003).
