To our knowledge, this is the first study to examine the time course of frontal-striatal-MDN activation during a PPI paradigm in an unmedicated schizophrenia-spectrum sample. Our main finding is that compared with healthy controls, schizophrenia patients showed diminished BOLD activation curves in the dorsolateral prefrontal cortex, caudate, putamen, and MDN during the attended PPI condition while the SPD patients tended to show greater-than-normal activation during the ignored PPI condition. Our findings indicate that while both schizophrenia-spectrum patient groups exhibit FST dysfunction during an attentional modulation of PPI, it is manifested somewhat differently in SPD and schizophrenia. The schizophrenia patients showed diminished
BOLD response activation in FST regions during the attended PPI condition suggesting they fail to activate this circuit to attend to a stimulus that is salient. In contrast, the SPD patients showed a pattern of enhanced
BOLD activation in FST regions during the ignored PPI condition suggesting they cannot ignore stimuli that are unimportant. Fronto-striatal circuits play a central role in modulating sustained attention and SPD patients display deficits in cognitive processing similar to those observed in schizophrenia (Siever and Davis 2004
). Consistent with prior theories of resource allocation in schizophrenia (e.g., Braff 1993
; Nuechterlein and Dawson 1984
), our findings suggest two different types of deficient FST resource allocation: the schizophrenia patients seem deficient in the ability to mobilize and allocate resources from the FST circuit, whereas the SPD patients seem to show a pattern of excessive FST resource allocation during non-salient stimuli.
Our finding of diminished FST activation in schizophrenia patients during an active attention PPI paradigm is consistent with prior FDG-PET (Hazlett and Buchsbaum 2001
; Hazlett et al 1998
) and fMRI studies examining brain activity during a PPI paradigm (Kumari et al 2003
). We previously reported lower relative glucose metabolism using FDG-PET in DLPFC in schizophrenia patients compared with healthy controls during an attention-to-prepulse paradigm with simultaneous startle eyeblink recording. We also reported that among healthy controls, greater PPI of the startle eyeblink response during the attended PPI condition was associated with greater relative glucose in DLPFC, whereas in schizophrenia patients this relationship was found in a much smaller region of PFC (Hazlett and Buchsbaum 2001
). Two prior whole-brain approach fMRI studies used a tactile PPI paradigm which showed greater activation of striatal and thalamic regions in healthy controls compared with medicated schizophrenia patients (Kumari et al 2003
). The Kumari et al. (2003)
study examined six patients all of whom were treated (doctor’s choice) with typical antipsychotics while the more recent study (Kumari et al 2007a
) examined patients on a range of doses of either typical or atypical (risperidone versus olanzapine) antipsychotics (10 in each of the three groups). It is important to note that unlike the present study and our previous fMRI study in healthy controls (Hazlett et al 2001
), Kumari et al. (Kumari et al 2003
) used a passive, uninstructed PPI paradigm. Nevertheless, the similar pattern of activation across both active and passive attention PPI paradigms in healthy individuals supports the involvement of FST circuitry during both passive- and active-attention modulation of PPI. Our finding of greater BOLD response activation in FST regions during the attended compared with the ignored PPI condition in the healthy controls and less differential activation in schizophrenia-spectrum patients is also consistent with the lesion and pharmacological studies examining the neural substrates modulating PPI in the rat as a schizophrenia model (e.g., Swerdlow et al 2001
Our finding in healthy controls of greater BOLD activation in the MDN during the attended than in the ignored PPI condition replicates our prior fMRI study with a 1.5T magnet in an independent sample of healthy individuals (Hazlett et al 2001
), suggesting this finding is reliable. The thalamus has been hypothesized to play a central role in the altered circuitry in schizophrenia (Andreasen et al 1996
) and particularly the MDN of the thalamus given it has direct connections with DLPFC and integrates incoming sensory information with higher cortical regions involved in planning response strategies. Consistent with several prior studies, we found that compared with healthy controls, schizophrenia patients showed lower overall MDN activation (e.g., Buchsbaum et al 1991
; Hazlett et al 1999
) yet, consistent with inefficient attentional processing in schizophrenia, the patients also showed greater left MDN activation during the ignore than the attend PPI condition. In contrast, the SPD patients showed greater-than-normal overall activation in the MDN and in particular, greater activation during the ignore PPI condition. The overactivation of the MDN in the SPD group during a sustained attention task may result from a compensatory mechanism or hypervigilance which is protective against the more severe negative symptoms of schizophrenia. However, hypervigilance may result in inappropriately heightened attention to irrelevant stimuli consistent with the paranoid, referential symptoms of SPD.
In addition to showing greater-than-normal overall activation in the MDN, the SPD group also showed overactivation in the putamen. Our finding of low
striatal activation in unmedicated schizophrenia patients and high
striatal activation in SPD patients is consistent with work showing greater relative glucose metabolism with FDG-PET in the putamen, an area rich in D2 receptors, in SPD patients in relation to schizophrenia patients and healthy controls (Shihabuddin et al 2001
). Given that these D2 receptors mediate dopaminergic inhibition of putamen activity, our findings are consistent with the idea of reduced dopaminergic activity in the putamen or lower susceptibility to dopaminergic up-regulation which hypothetically is protective against full-blown psychotic symptoms in SPD (Shihabuddin et al 2001
A subgroup of the participants in the present study had their startle eyeblink measured in the psychophysiology laboratory within one week of their fMRI scan and these results are published elsewhere (Hazlett et al 2007
). Consistent with several prior studies (Dawson et al 1993
; Filion 1993
; Hawk et al 2002
; Hazlett et al 1998
), the healthy controls showed greater prepulse inhibition of startle during the attended prepulse condition compared with the ignored prepulse condition. Compared with healthy controls, both of the schizophrenia-spectrum groups exhibited significantly less PPI during the attended prepulse. Previous studies have reported that schizophrenia-spectrum patients have deficient attentional modulation of PPI (Dawson et al 1993
; Hazlett et al 1998
, in press
). In the present study, our correlational results suggest that schizophrenia-spectrum related deficits in PPI during the attended prepulse are associated with deficient left caudate activation and not DLPFC, putamen, or MDN function. However, future work with a larger sample size is needed in order to fully examine PPI-FST activation associations within each of the diagnostic subgroups separately. Nevertheless, our finding of an association between PPI and caudate activity in a schizophrenia-spectrum sample is consistent with data from animal studies which consider the striatum to be important in the modulation of PPI (e.g., Swerdlow et al 2001
) and suggests that schizophrenia studies which measure striatal activity and PPI may ultimately help us target effective new treatments.
An unique feature of the present study is that we studied schizophrenia patients while off medication. All of the fMRI studies examining the underlying neural circuitry of PPI conducted to date have included medicated schizophrenia patients (Kumari et al 2003
) although a recent non-imaging study found the expected gating deficit in antipsychotic naïve patients (Kumari et al 2007b
). Our findings suggest that schizophrenia (5/13 neuroleptic naïve) and SPD patients (12/13 neuroleptic naïve) exhibit dysfunction in dorsolateral, caudate, putamen, and mediodorsal nucleus regions during an attention-to-prepulse paradigm and that group differences are not due to current medication. Medicated patients failed to show the expected PPI vs. symptom severity correlations shown in unmedicated patients (Duncan et al 2006
). Evidence from a double-blind study where schizophrenia patients were randomized to either 8-week treatment with amisulpride or olanzapine suggest that that the PPI-restoring effect of antipsychotics is likely attributed to a dopamine D2 receptor blockade (Quednow et al 2006
). Future schizophrenia work employing measures of striatal activity together with PPI may be useful in predicting treatment response. Also, larger sample sizes are needed in functional imaging studies examining PPI in order to determine whether neuroleptic naïve and previously-medicated schizophrenia patients differ in striatal function.
Group differences in dorsolateral prefrontal cortex activation were observed during the prepulse+startle condition (when the startle stimulus was presented 120 ms following onset of the tone prepulse) and the prepulse alone condition. The healthy controls showed similar DLPFC activation during the prepulse+startle and startle alone condition (averaged across attend/ignore and hemisphere factors). In contrast, the schizophrenia patients showed much greater DLPFC activation during the prepulse+startle condition than the prepulse alone condition suggesting that they were more distracted by the startle stimulus. Startle inhibition has been explained in terms of sensorimotor gating, or perceptual filtering which involves the concept of the reduction of processing of and distraction by irrelevant or repetitive stimuli (Braff et al 1978
). Graham’s (Graham 1975
) concept of protection of processing resources is similar but it goes a step further by predicting differential processing of the prepulse as a function of startle inhibition. In Graham’s theory, the onset of the prepulse initiates two processes, one serving to identify the prepulse, and the other serving to protect the processing of the prepulse from interruption by the startle stimulus. The degree to which this protective mechanism is activated determines the extent of startle inhibition. It is interesting that in our study, the startle stimulus effect was only observed in the DLPFC and not in the other regions examined (caudate, putamen, MDN). Interestingly, in healthy volunteers, fMRI startle habituation effects are very prominent in the thalamus (McDowell et al 2006
) and it is possible that this habituation mechanism is absent in our SPD group.
Limitations of this study include the small sample size. While our findings are promising and our study is the first to examine unmedicated patients, it will be important to replicate the findings in a larger sample. Our sample size of 13 unmedicated schizophrenia patients is larger than prior fMRI work examining PPI in medicated schizophrenia patients (n=10 and n=6 patients in Kumari et al 2003
, respectively). We were unable to carry out fMRI and psychophysiological recordings of PPI in the same session. However, our prior work examining simultaneous PPI during FDG-PET showed a similar pattern of greater PFC activation with greater PPI during the attended prepulse in the healthy controls suggesting the pattern is stable. Also, prior work has shown that startle eyeblink during an attended prepulse has good test-retest reliability (Hawk et al 2002
Our method used hand-tracing of caudate and other structures on each participant’s anatomical MRI which is time-consuming. However, to match our earlier studies on the caudate, e.g., (Buchsbaum et al 1986
), we examined the correlation between our hand-tracings and a stereotaxic box at xyz 12,12,12 (Talairach and Tournoux 1988
). A 5×5 pixel box placed in the caudate with root-mean-square assessment of fMRI activity yielded both a significant difference between attend minus ignore conditions in patients with schizophrenia (−8.12, sd=20.25) and normal controls (3.35, sd= 6.48; t-1.95, df=24, p
=0.032, 1-tailed). The correlation between hand-traced root-mean-square and stereotaxic box was 0.49, p
=0.012. This indicates that an entirely automated method can yield a single score for patient characterization on the attentional dimension which may be useful in future studies for predicting neuroleptic response and following neuroleptic action. Given a recent double-blind, randomized controlled trial showed that olanzapine effectively increased PPI in schizophrenia but risperidone and haloperidol had no such effects (Wynn et al 2007
), it will be important for future studies to determine the underlying neural substrates so that pharmacological treatments can be targeted.
In conclusion, this study found that activation of frontal-striatal-MDN circuitry during an active attention PPI paradigm is abnormal in both schizophrenia and SPD patients and likely underlies deficient modulation of PPI in these groups. Schizophrenia patients showed an overall pattern of failing to activate key FST regions during the attend PPI while SPD patients tended to over-activate FST regions during the ignore PPI condition. Our findings suggest that either one of these patterns of FST circuitry dysfunction may in turn, lead to deficient attentional modulation of PPI which has reliably been reported in both SPD and schizophrenia patients (Dawson et al 1993
; Hazlett et al 1998
, in press
). Although generally consistent with the SPM analysis, our findings were more robust using our hypothesis-driven region-of-interest MANOVA approach highlighting the strength of this statistical strategy. Our findings build upon prior rodent models delineating the neural circuitry modulating PPI and provide important implications for future PPI research. For example, combining PPI and fMRI measures of FST activation in future medication trials may be a useful strategy for new targeted region-of-interest based pharmacological treatments and predicting treatment response in schizophrenia.