was not a general reduction in power but one specific to the gamma band.

Spencer and colleagues (2003) took the next logical step and evaluated the gamma-band response to visual stimuli in schizophrenia, to determine whether high-frequency neural synchronization associated with the perception of visual gestalts is abnormal in schizophrenia patients. Previous studies of healthy individuals had reported enhancements of gamma-band power (Tallon-Baudry & Bertrand, 1999) and phase locking (Rodriguez et al., 1999) when gestalt objects are perceived. In the study by Spencer et al., individuals with schizophrenia and matched healthy people discriminated between square gestalt stimuli and non-square stimuli (square/no-square conditions). In schizophrenia patients, the early visual system gamma-band response to gestalt square stimuli was lacking. There were also abnormalities in gamma-band synchrony between brain regions, with schizophrenia patients showing decreasing rather than increasing gamma-band coherence between posterior visual regions and other brain regions after perceiving the visual gestalt stimuli. These findings support the hypothesis that schizophrenia is associated with a fundamental abnormality in cellular neural circuitry evinced as a failure of gamma-band synchronization, especially in the 40-Hz range.

Several ERPs have been related to the search for an electrophysiologic concomitant of an early sensory gating deficit in schizophrenia. These include, for example, the startle response, for which the size of a blink to an acoustic probe is measured. Schizophrenia patients appear to be unable to modify their large startle response when forewarned that a probe is coming, in contrast with controls (e.g., Braff et al., 1978).

Another ERP thought to be sensitive to an early sensory gating abnormality in schizophrenia is the P50. In the sensory gating paradigm, an auditory click is presented to a subject, eliciting a positive deflection about 50 msec after stimulus onset, the P50 component. After a brief interval (about 500 msec), a second click elicits a much smaller-amplitude P50 in normal adult subjects, who are said to show normal gating: the first stimulus inhibits, or closes the gate to, neu rophysiological processing of the second stimulus. Patients with schizophrenia, by contrast, show less reduction in P50 amplitude to the second click, which is referred to as a failure in gating (Freedman, Adler, Waldo, Oachtman, & Franks, 1983). This gating deficit occurs in about half the first-degree relatives of a schizophrenic patient, a finding suggesting that it may index a genetic factor in schizophrenia in the absence of overt psychotic symptoms (Waldo et al., 1991). Patients with affective disorder may show a gating deficit, but the deficit does not persist after successful treatment; in patients with schizophrenia, the deficit occurs in both medicated and unmedicated patients and persists after symptom remission (Adler et al., 1991; Freedman et al., 1983).

The gating effect is thought to take place in temporal lobe structures, possibly the medial temporal lobe (Adler, Waldo, & Freedman, 1985). P50 gating is enhanced by nicotinic cholinergic mechanisms, and it is possible that smoking in patients with schizophrenia is a form of self-medication. Freedman et al. (1994) have shown that blockade of the α ₇ -nicotinic receptor, localized to hippocampal neurons, causes loss of the inhibitory gating response to auditory stimuli in an animal model. The failure of inhibitory mechanisms to gate sensory input to higher-order processing might result in “sensory flooding,” which Freedman suggests may underlie many of the symptoms of schizophrenia.

Mismatch negativity (MMN) is a negative ERP that occurs about 0.2 sec after infrequent sounds (deviants) are presented in the sequence of repetitive sounds (standards). Deviant sounds may differ from the standards in a simple physical characteristic such as pitch, duration, intensity, or spatial location. Mismatch negativity is primarily evoked automatically, that is, without conscious attention. Its main source is thought to be in or near primary auditory cortex (Heschl gyrus) and to reflect the operations of sensory memory, a memory of past stimuli used by the auditory cortex in analysis of temporal patterns.

There is a consistent finding of a reduction in amplitude of MMN in chronically ill schizophrenia patients that appears to be traitlike and not

ameliorated by either typical (haloperidol) or atypical (clozapine) medication (Umbricht et al., 1998). A point of particular interest has been the finding that the MMN elicited by tones of different frequency (the pitch MMN) is normal in patients at the time of first hospitalization (Salisbury, Bonner-Jackson, Griggs, Shenton, & McCarley, 2001; confirmed by Umbricht, Javitt, Bates, Kane, & Lieberman, 2002), whereas the MMN elicited by the same stimuli is abnormal in chronic schizophrenia. This finding suggests that pitch MMN might index a postonset progression of brain abnormalities. Indeed, the prospective longitudinal study of Salisbury, McCarley, and colleagues (unpublished data) now has preliminary data showing that schizophrenia subjects without a MMN abnormality at first hospitalization develop an abnormality over the next 1.5 years.

In the same group of patients, the Heschl gyrus, the likely source of the MMN, demonstrates a progressive reduction in GM volume over the same time period (Kasai et al., 2003b). In participants with both MRI and MMN procedures, the degree of GM volume reduction was found to parallel the degree of MMN reduction, although the number of subjects examined is currently relatively small and this conclusion is tentative. Although the presence of postonset progression of abnormalities is controversial in the field, it is of obvious importance to our understanding of the disorder and of particular importance to the study of adolescents with onset of schizophrenia, because it would prompt a search for possible medication and/or psychosocial treatment that might ameliorate progression.

Recent multimodal imaging (Wible et al., 2001) has demonstrated the presence of a deficiency of fMRI activation (BOLD) in schizophrenia to the mismatch stimulus within Heschl's gyrus and nearby posterior superior temporal gyrus.

Because MMN may reflect, in part, N-methyl-d -aspartate (NMDA)-mediated activity, a speculation about the reason for progression is that NMDA-mediated excitotoxity might cause both a reduction in the neuropil (dendritic regression) and a concomitant reduction in the MMN in the months following first hospitalization. Only further work will determine whether this specula tion is valid. It is noteworthy that the MMN abnormalities present in schizophrenic psychosis are not present in manic psychosis.

The P300 is an ERP that occurs when a low-probability event is detected and consciously processed. Typically, subjects are asked to count a low-probability tone that is interspersed with a more frequently occurring stimulus. The P300 differs from the typical MMN paradigm in that the stimuli are presented at a slower rate (typically around one per second) and the subject is actively and consciously attending and processing the stimuli, whereas the MMN stimuli are not consciously processed. P300 is larger when the stimulus is rare. Whereas MMN is thought to reflect sensory memory, by definition preconscious, P300 is thought to reflect an updating of the conscious information-processing stream and of expectancy.

Reduction of the P300 amplitude at midline sites is the most frequently replicated abnormality in schizophrenia, although P300 reduction is also found in some other disorders. This widespread P300 reduction also appears to be traitlike and an enduring feature of the disease. For example, Ford and colleagues (1994) demonstrated that although P300 showed moderate amplitude increases with symptom resolution, it did not approach normal values during these periods of remission. Umbricht et al. (1998) have reported that atypical antipsychotic treatment led to a significant increase of P300 amplitudes in patients with schizophrenia.

In addition to the midline P300 reduction, both chronically ill and first-episode schizophrenic subjects display an asymmetry in P300 with smaller voltage over the left temporal lobe than over the right. The more pronounced this left temporal P300 amplitude abnormality, the more pronounced is the extent of psychopathology, as reflected in thought disorder and paranoid delusions (e.g., McCarley et al., 1993, 2002). It is possible the increased delusions reflect a failure of veridical updating of cognitive schemata. This left temporal deficit is not found in affective (manic) psychosis.

There are likely several bilateral brain generators responsible for the P300, with a generator in the superior temporal gyrus (STG) likely under

lying the left temporal deficit, since, in schizophrenia, the greater the reduction in GM volume in posterior STG, the greater the reduction in P300 amplitude at left temporal sites in both chronic and first-episode schizophrenia patients. It is of note that the posterior STG, on the left in right-handed individuals, is an area intimately related to language processing and thinking (it includes part of Wernicke's area), and an area where volume reductions are associated with increased thought disorder and severity of auditory hallucinations.

Brain activity reflected in ERPs recorded during performance of information-processing tasks can be used to help isolate the component or stage of information-processing that is impaired in schizophrenia. A series of ERP studies of children and adolescents with schizophrenia, conducted by the UCLA Childhood Onset Schizophrenia program, are summarized below (see Strandburg et al., 1994a and Asarnow, Brown, & Strandburg, 1995 for reviews). These studies examined ERP components while children and adolescents with schizophrenia performed tasks like the span of apprehension (Span; Strandburg, Marsh, Brown, Asarnow, & Guthrie, 1984) and a continuous performance test (CPT; Strandburg et al., 1990). Several decades of studying mental chronometry with ERPs has produced a lexicon of ERP components with well-established neurocognitive correlates (Hillyard & Kutas, 1983). These ERP components can be used to help identify the stages of information processing that are impaired in schizophrenia.

The UCLA ERP studies have focused primarily on four components: contingent negative variation (CNV), hemispheric asymmetry in the amplitude of the P1/N1 component complex, processing negativity (Np), and a late positive component (P300). The CNV measures orienting, preparation, and readiness to respond to an expected stimulus. There are at least two separate generators of the CNV: an early frontal component believed to be an orienting response to warning stimuli, and a later central component associated with preparedness for stimuli-processing and response (Rohrbaugh et al., 1986).

Healthy individuals typically have larger visual P1/N1 components over the right cerebral hemisphere. Many of the UCLA studies compared hemispheric laterality between healthy and schizophrenia individuals. Differences in lateralization during visual information-processing tasks could reflect either differences in the strategic use of processing capacity of the hemispheres or a lateralized neural deficit.

The Np is a family of negative components that occur within the first 400 msec after the onset of a stimulus, indicating the degree to which attentional and perceptual resources have been allocated to stimulus processing. Because the Np waves occur contemporaneously with other components (P1, N1, and P2), they are best seen in difference potentials resulting from the subtraction of non-attend ERPs from attend ERPs (Hillyard & Hansen, 1986; Naatanan, 1982). Finally, as described above, the P300 is a frequently studied index of the recognition of stimulus significance in relation to task demands.

Table 5.2 summarizes by component the ERP results from six UCLA studies of children or adults with schizophrenia. In all the studies summarized in this table there were large and robust performance differences between groups in both the accuracy and reaction times of signal detection responses. Thus, the behavioral paradigms were successful in eliciting information-processing deficits in these patients.

The CNV differences between normals and schizophrenics were not consistently found across studies. In the span task (which includes a warning interval) all possible results were obtained (normals > schizophrenics; normals = schizophrenics; and normals < schizophrenics). For the CNV-like negative wave occurring in the CPT task, no group differences were found in either experiment. Because the warning interval was short and the wave was largest frontally, the CNVs in both tasks were most likely the early wave related to orienting. Thus, differences in prestimulus orienting do not seem to reliably ac

count for the poor performance of schizophrenics on these tasks. There are mixed results in CNV experiments on adults with schizophrenia, although most studies found smaller CNVs in schizophrenics (Pritchard, 1986). A longer warning interval than that used in the UCLA experiments (500 msec in the span and 1250 msec ISI in the CNV) may be required to detect preparatory abnormalities in schizophrenia.

In every study summarized in Table 5.2 in which processing negativities were measured, Nps were found to be smaller in schizophrenics. This deficit was seen in both children and adults, with both the span and CPT (Strandburg et al., 1994c) tasks. In contrast, a group of children with ADHD studied while they performed a CPT task showed no evidence of a smaller Np. Diminished Np amplitude is the earliest consistent ERP index of schizophrenia-related information-processing deficit in the UCLA studies. These results suggest impaired allocation of attentional and perceptual resources.

Most studies of processing negativities during channel selective attention tasks (Nd) find that adults with schizophrenia produce less attentional-related endogenous negative activity than do normal controls (see reviews by Cohen, 1990, and Pritchard, 1986). The UCLA results compliment this finding in adults by using a discriminative processing task and extend these findings to childhood-and adolescent-onset schizophrenia. Reductions in the amplitude of Np in schizophrenia result from im-pairments in executive functions responsible for the maintenance of an attentional trace (Baribeau-Braun, Picton, & Gosselin, 1983; Michie, Fox, Ward, Catts, & McConaghy, 1990). Baribeau-Braun et al. (1983) observed normal Nd activity with rapid stimulus presentation rates, but reduced amplitudes with slower rates, findings suggesting that the neural substrates of Nd are intact but improperly regulated in schizophrenia. Individuals with frontal lobe lesions resemble individuals with schizophrenia in this regard, in that both groups do not show increased Np to attended stimuli in auditory selection tasks (Knight, Hillyard, Woods, & Neville 1981).

As noted earlier, reduced amplitude P300 in schizophrenic adults has been consistently found using a wide variety of experimental paradigms (Pritchard et al., 1986). As can be seen in Table 5.2, the UCLA studies also consistently observed smaller P300 amplitude in studies of both schizophrenic children and adults, in the span, CPT, and idiom recognition tasks. P300 latency was also measured in two of these studies. Although prolonged P300 latency was found in one study (Strandburg et al., 1994c), no differences were found in another (Strandburg et al., 1994b). The majority of ERP studies have reported normal P300 latency in schizophrenics (Pritchard, 1986).

Absence of right-lateralized P1/N1 amplitude in visual ERPs has been a consistent finding in all five of the UCLA studies that used the CPT and span tasks. Abnormally lateralized electrophysiological responses, related either to lateralized dysfunction in schizophrenia or a pathology-related difference in information-processing strategy, is a consistent aspect of both adult-and childhood-onset schizophrenia. These results are consistent with abnormal patterns of hemispheric laterality in schizophrenics (e.g., Tucker & Williamson, 1984).

In summary, ERP studies of schizophrenic adults and children performing discriminative processing tasks suggest that the earliest reliable electrophysiological correlate of impaired discriminative processing in schizophrenia is the Np component. It appears that children and adolescents with schizophrenia are deficient in the allocation of attentional resources necessary for efficient and accurate discriminative processing. Although diminished amplitude processing negativities have been observed in ADHD in auditory paradigms (Loiselle, Stamm, Maitinsky, & Whipple, 1980; Satterfield, Schell, Nicholar, Satterfield, & Freese, 1990), Np was found to be normal in ADHD children during the UCLA CPT task (Strandburg et al., 1994a). Diminished Np visual processing may be specific to schizophrenic pathology. Later ERP abnormalities in schizophrenia (e.g., diminished amplitude P300) may be a “downstream” product of the uncertainty in stimulus recognition created by previous discriminative difficulties, or they may be one of additional neurocognitive deficits. Abnormalities in later ERP components are not specific to schizophrenia, having been reported in