These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.

Previous studies have shown that changes in brain functionClinicians long have observed a lag time of several weeks between the initiation of antidepressant treatment and clinical response for many patients (Hyman and Nestler 1996;Katz et al. 1996). Some individuals do have early symptomatic improvement, and this has been reported to predict further improvement over the next several weeks (Nierenberg et al. 1995). Reports have suggested that some physiologic changes are seen shortly after initiation of treatment (Sulser 1989;Beck 1995;Dahmen et al. 1997). No clinically practical physiologic predictor of treatment response has yet been identified with these techniques, however, and the relationship of early physiologic changes to eventual clinical outcome remains incompletely understood.Quantitative electroencephalography (QEEG) has been used as a physiologic measure in efforts to address these questions. Prior work with "pharmaco-EEG" techniques has shown that the administration of antidepressant compounds yields reproducible changes in EEG activity in healthy control subjects within a few hours of dosing (Saletu et al. 1982(Saletu et al. , 1983(Saletu et al. , 1986(Saletu et al. , 1987(Saletu et al. , 1987 Grunberger 1985, 1988;Sannita et al. 1983;Sannita 1990; Early Prefrontal Changes in Depression 121Itil et al. 1984;Herrmann et al. 1991;Luthringer et al. 1996). The relationship of these immediate EEG changes in control subjects to eventual clinical response in a depressed population is unclear. Other QEEG work with depressed subjects has found that changes from baseline in theta power early in the course of treatment may characterize groups of depressed patients who are more likely to respond to antidepressant treatment (Ulrich et al. 1994). Unfortunately, the overlap in the value of these changes between responder and nonresponder groups precluded the use of this measure in response prediction for individual subjects, and prior research did not indicate how to relate changes in theta power to other measures of regional brain activity (e.g., regional cerebral blood flow or metabolism). We previously have shown that absolute and relative power are complementary measures of brain activity (Leuchter et al. 1993). A relatively new QEEG measure, "cordance," combines information from both absolute and relative power measures (Leuchter et al. 1994a(Leuchter et al. , 1994b. The algorithm yields two indicators: a categorical value ("concordant" or "discordant" state) and a numerical value for each electrode. In an earlier report with the categorical measure , we observed that depressed subjects exhibiting the concordant state prior to treatment had better treatment outcomes when treated with fluoxetine than did subjects with the discordant state. In this report, we use the num*erical values of cordance, because they allow examination of changes in regional brain activity with treatment. In validation against data collected simultaneously with [H 2 15O]-positron emission tomography (PET), cordance values in the the...

Experiments were conducted to elucidate the role of the cholinergic neurotransmitter system in arousal and the orienting of attention to peripheral targets. Rhesus monkeys and humans fixated a visual stimulus and responded to the onset of visual targets presented randomly in two visual field locations. The target was preceded by a valid cue (cue and target at the same location), an invalid cue (cue and target to opposite locations), a double cue (cues to both spatial locations, target to one), or, the cue was omitted (no-cue, target to either location). Reaction times (RTs) to the onset of the target were recorded. For monkeys, systemic injections of nicotine (0.003-0.012 mg/kg) or atropine (0.001-0.01 mg/kg), but not saline control injections, reduced mean RTs for all trials, indicating general behavioral stimulation. In addition, nicotine significantly reduced RTs for invalid trials but had little additional effect on those for valid, double, or no-cue trials. Virtually identical effects were observed for human chronic tobacco smokers in performing the same task following cigarette smoking. Injections of atropine in monkeys had no effect on RTs for valid or invalid trials but significantly slowed RTs in double-cue trials that did not require the orienting of attention. These results suggest that in both species, the nicotinic cholinergic system may play a role in automatic sensory orienting. In addition, the muscarinic system may play a role in alerting to visual stimuli in monkeys.

Experiments were conducted to elucidate the role of the noradrenergic neurotransmitter system in arousal and the orienting of attention. Rhesus monkeys were trained to perform a peripherally cued, covert orienting task for juice reward, and their manual reaction times (RTs) to visual stimuli were measured. The effects of parenteral injections of the alpha-2 adrenergic agonists clonidine and guanfacine, and normal saline were compared on the covert task. We assessed 1) overall error rates, 2) the difference in RTs between validly and invalidly cued trials (validity effect), 3) the difference in RTs between neutral and no-cue trials (alerting effect), 4) target location (visual field), and 5) cue-target interval. Changes in noradrenaline levels produced by clonidine (and to a lesser extent guanfacine) significantly decreased the alerting effect, and lowered RTs to stimuli in the left visual field, but did not change the validity effect, suggesting that noradrenaline is involved in maintaining non-spatial, sensory readiness to external cues but not in the shifting of the attentional focus.

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