They used a drug model of psychosis to relate presymptomatic physiology to symptom outcome. Ketamine induces transient psychotic symptoms in healthy volunteers and exacerbates existing symptoms in patients. They assessed brain responses, separately under placebo and ketamine treatments, in healthy volunteers across four cognitive challenges, each theoretically related to a symptom of psychosis. Two of the tasks (verbal working memory and attention) are associated with negative symptoms, which may result from social and cognitive disengagement attributable to reduced processing capacity of prefrontal cortex, leading to difficulties in concentration and maintaining task set. They predicted that prefrontal activity during the attention and working memory tasks would be associated with vulnerability to negative symptoms under ketamine.
A failure to monitor "inner speech" may provide a mechanism leading to auditory hallucinations, whereby self-generated speech is misattributed externally. Comparing verbal self-monitoring (imagining speech spoken by another person) with inner speech (minimal self-monitoring) increases prefrontal and temporal cortex activation in patients with auditory hallucinations. Ketamine produces auditory illusory experiences similar to the heightened auditory and visual awareness described by patients during the prodromal phase, and it has been suggested that these contribute to the development of hallucinations. The authors predicted that prefrontal and temporal cortex activation during a self-monitoring task would be associated with vulnerability to the auditory illusory experiences under ketamine.
Finally, a sentence completion task was used to engage brain regions associated with semantic processing. Thought disorder involves difficulty in constraining semantic threads of language, making speech disjointed and chaotic, as also observed under ketamine. In patients, the requirement to generate an appropriate semantic response to complete a sentence is associated with increased activation of left frontal and temporal cortex. They predicted that frontotemporal responses to a sentence completion task would predict vulnerability to thought disorder induced by ketamine.
They in fact found that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration. Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine. Bilateral frontal responses to an attention task were also predictive of negative symptoms. Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences. A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia. These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.
Thursday, July 03, 2008
Brain markers that predict vulnerability to psychosis.
Honey et al. offer an interesting study in the Journal for Neuroscience. As indicated in these slightly edited clips from text and abstract: