منفی بودن کاهش یافته ناهماهنگی، شروع روان پریشی را به زمان قبل تر منتقل می کند

Background Individuals with an “At Risk Mental State” have a 20–30% chance of developing a psychotic disorder within two years; however it is difficult to predict which individuals will become ill on the basis of their clinical symptoms alone. We examined whether mismatch negativity (MMN) could help to identify those who are particularly likely to make a transition to psychosis. Method 41 cases meeting PACE criteria for the At Risk Mental State (ARMS) and 50 controls performed a duration-deviant passive auditory oddball task whilst their electroencephalogram was recorded. The amplitude of the MMN wave was compared between groups using linear regression. The ARMS subjects were then followed for 2 years to determine their clinical outcome. Results The MMN amplitude was significantly reduced in the ARMS group compared to controls. Of the at-risk subjects who completed followed up (n = 41), ten (24% of baseline sample) subsequently developed psychosis. The MMN amplitude in this subgroup was significantly smaller across all three recording sites (FZ, F3 and F4) than in the ARMS individuals who did not become psychotic. Conclusion: Among those with the ARMS, MMN amplitude reduction is associated with an increased likelihood of developing frank psychosis.

The prodrome is a critical stage in the development of psychosis in which initial symptoms first arise. The basis of the vulnerability to psychosis in this group is not clearly known, and whilst evidence shows that psychological and pharmacological interventions may improve outcomes (Bechdolf et al., 2005, McGorry et al., 2002, Morrison et al., 2007, Politi et al., n.d and Yung et al., n.d), treating high-risk subjects remains controversial since most of them are not destined to develop psychosis (Simon et al., n.d.). Indicated prevention is currently regarded as the most promising strategy to attenuate, delay, or even avert psychosis. Studies have found significant specificity regarding prediction of conversion using clinical and other variables (Cannon et al., 2008 and Velthorst et al., 2009), but only at the cost of sensitivity and vice versa. However a recent study by Ruhrmann et al (2010) introduced a risk modelling procedure with the use of prognostic indexes for a multivariate clinical staging approach to improve specificity and individual risk assessment to allow for better targeted and earlier interventions. The multivariate clinical staging approach of at-risk symptoms further demands neurobiological markers for early detection, and researchers have tried to find trait markers using several imaging techniques (Bramon et al., 2008, Fusar-Poli et al., 2011a, Howes et al., 2007 and Pantelis et al., 2003). Indeed, the better characterisation of the prodrome of psychosis by means of biological investigations is a prerequisite for both prevention and intervention (Broome et al., 2005b; Ruhrmann et al.; Ruhrmann et al., 2010;Yung et al., 2003 and Yung et al., 2004). Direct in-vivo measures of cortical activity observed in the human EEG are useful markers of brain dysfunction in psychosis (Schulze et al., 2007, Schulze et al., 2008, Shaikh et al., 2010 and Turetsky et al., 2007) and provide high temporal resolution (Bramon et al., 2005). The MMN, in particular, is a change in the EEG (an event related potential) that emerges when a novel stimulus infringes the regularity of the preceding ones. Auditory MMN can be elicited by different qualitative and quantitative types of deviance, including intensity, location, frequency, duration or pattern of auditory stimuli. The deviant type as well as the attentional condition may have substantial effects on the stability and replicability of MMN potentials. Duration deviants, similar to the ones used in this study, generally produce MMN amplitudes of better intraindividual stability and a task demanding focused attention minimizes measurement error (Kathmann et al., 1999). The MMN waveform is an early phenomenon, thought to reflect cortical activation in basic, pre-attentive stages of auditory information processing and perception (Näätänen et al., 1989). It is thought that the MMN signal originates in primary and secondary auditory cortex (Kreitschmann-Andermahr et al., 1999, Molholm et al., 2005 and Sams et al., 1991). From the work of Shelley et al. (1991) and subsequent replications (Baldeweg et al., 2002, Javitt et al., 1995 and Michie et al., 2002Umbricht and Krljes, 2005) it is well-established that MMN amplitude, especially duration-MMN, is reduced amongst patients with chronic schizophrenia and first episode psychosis (Hermens et al., 2010) A meta-analysis in established schizophrenia produced a large effect size (0.99), showing that these MMN amplitude deficits are severe and MMN to stimuli differing in duration appeared more impaired in schizophrenia than MMN to frequency deviants. Additional correlation analyses indicated that the frequency MMN performance may worsen with illness duration (Umbricht and Krljes, 2005). It has also been suggested that the unaffected relatives of patients display similar deficits and that therefore MMN may be a potential marker of genetic risk to develop psychosis (Jessen et al., 2001 and Michie et al., 2002). However, in our family study we were only able to find duration MMN reductions in our chronic patients while their symptom-free first-degree relatives had a normal MMN wave (Bramon et al., 2004). A recent study has also found that the unaffected first-degree relatives of schizophrenia patients do not show duration or pitch MMN deficits (Magno et al., 2008). It is thus unclear whether or not MMN deficit reflects liability for psychosis or clinical state related changes. Investigations in an at-risk sample with prodromal symptoms will clarify whether duration MMN is related to the disease itself (trait) and can distinguish at-risk subjects that subsequently develop psychosis. With regard to targeted prevention, a state marker would be helpful to the estimation of the individual stage and transition to psychosis. Alterated MMN is of particular interest in relation to psychosis, as this appears to be a marker of brain glutamate dysfunction (Javitt, 2000), which is a key pathophysiological feature of psychotic disorders (Kantrowitz and Javitt; Lin et al.; Marsman et al.). Moreover, recent research using MR spectroscopy indicates that brain glutamate levels are altered in ARMS subjects (Stone et al., 2009), and that this is associated with changes in the structure and function of the medial temporal and prefrontal cortex (Fusar-Poli et al.; Stone et al., 2009; Valli et al.), and a change in the relationship with striatal dopamine function (Stone et al.). Furthermore, the later onset of psychosis in ARMS subjects may be linked to progression of these glutamatergic abnormalities (Stone et al.). Brockhaus-Dumke et al (2005) reported that 43 cases with at-risk symptoms of psychosis displayed a trend for small reductions in MMN, with values intermediate between those in healthy controls and patients with schizophrenia. They did not examine the relationship between MMN and the subsequent onset of psychosis. However, a more recent study reported that the subgroup of ARMS subjects who went on to develop psychosis had reduced MMN amplitudes at presentation relative to the rest of the sample (Bodatsch et al., 2010). We set out to attempt to replicate this finding in an independent sample, using similar methods. Our first prediction, was that MMN would be reduced in the ARMS group as a whole, relative to controls. We then tested the hypothesis that, within the ARMS sample, the reduction in MMN would be greater in the subgroup of subjects who subsequently developed psychosis than in those who did not.