- Email: [email protected]
Nicotine and the hallucinating brain: Effects on mismatch negativity (MMN) in schizophrenia
Psychiatry Research 196 (2012) 181–187
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Nicotine and the hallucinating brain: Effects on mismatch negativity (MMN) in schizophrenia Derek J. Fisher a, b, c, d,⁎, Bryan Grant e, Dylan M. Smith c, f, Giuseppe Borracci d, Alain Labelle c, d, Verner J. Knott b, c, d, e, f a
Department of Psychology, Mount Saint Vincent University, Halifax, Nova Scotia, Canada Department of Psychology, Carleton University, Ottawa, Ontario, Canada University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada d Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada e Department of Psychology, University of Ottawa, Ottawa, Ontario, Canada f Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada b c
a r t i c l e
i n f o
Article history: Received 30 May 2011 Received in revised form 23 January 2012 Accepted 25 January 2012 Keywords: MMN Mismatch negativity Schizophrenia Auditory hallucinations Nicotine Tobacco Auditory event-related potentials
a b s t r a c t Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6 mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Abnormally high smoking rates are seen in schizophrenia and have been reported to be as high as 88% (Kelly and McCreadie, 1999). While it is assumed nicotine self-medication is common in most psychiatric populations (Milailescu and Drucker-Colin, 2000; Newhouse et al., 2004; Singh et al., 2004), the smoking rate in schizophrenia is even higher than the rates found in mood (de Leon et al., 2002) and bipolar disorder (Uck et al., 2004). In addition, schizophrenia smokers appear to have higher daily cigarette consumption (Uck et al., 2004), prefer stronger cigarettes (Olincy et al., 1997), and extract more nicotine from each cigarette (Olincy et al., 1997; Strand and Nyback, 2005) than typical smokers (Kumari and Postma, 2005). ⁎ Corresponding author at: Department of Psychology, Mount Saint Vincent University, 166 Bedford Hwy., Halifax, Canada NS B3M 2J6. Tel.: +1 902 457 5503. E-mail addresses: derek.fi[email protected], [email protected] (D.J. Fisher). 0165-1781/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2012.01.026
Nicotine is the main psychoactive alkaloid in cigarettes and its effects on cognition, specifically working memory and attention, is of great interest. It is commonly believed that nicotine's ability to mediate selective attention, by acting as a stimulus barrier, screening irrelevant and distracting stimuli from the smoker's awareness, may lead to improved task performance and cognitive processing (Kassel, 1997). By doing this, it is believed that brain systems involved in the processing of irrelevant stimuli are freed up (Friedman and Horvath, 1974; Knott and Venables, 1978) and allocated to enhance processing of relevant, target stimuli, thus facilitating task performance (Kassel, 1997). Following from evidence suggesting that acute nicotine administration reverses nicotine withdrawal-related cognitive deficits, as well as producing true (i.e. non-withdrawal mediated) cognitive enhancement, it is thought that schizophrenia patients may use smoking as a way to self-medicate (Cadenhead and Braff, 1999; Kumari and Postma, 2005; Evans and Drobes, 2008). It has been proposed that the
182
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
mood and cognitive enhancement associated with nicotine from cigarettes may be reinforcing for schizophrenia patients, as the nicotine could provide temporary alleviation of negative symptoms (Janhunen and Ahtee, 2007), improve attention and recall, reduce extrapyramidal symptoms associated with anti-psychotic medication (Anfang and Pope, 1997), and aid in the gating out of irrelevant stimuli (such as auditory hallucinations) and focusing of attention (Kumari and Postma, 2005; Evans and Drobes, 2008). Evidence that smoking/nicotine may ameliorate abnormal cognition in schizophrenia has been found in studies that have shown acute treatment with nicotine normalizes spatial memory (Sacco et al., 2005) and sensory-gating deficits (Adler et al., 1993; Kumari et al., 2001), while it enhances sustained attention (Hong et al., 2011) and smooth pursuit eye-tracking (Tanabe et al., 2006). Sensory gating improvements with nicotine are thought to be related to the activation of the hippocampal α-7 subtype nAChRs, which have been shown to be deficient in post-mortem brains of patients and are known to be important for attentional control, learning, and memory (Leonard et al., 2002). Electroencephalography (EEG) non-invasively measures neuroelectric brain activity by recording electrical activity at the scalp and is able to detect subtle stages of information processing due to its superior temporal resolution (milliseconds). EEG derived event-related potential (ERP) components are elicited in response to the presentation of discrete stimuli (i.e. tones, light flashes); the amplitudes and latencies of ERP components allow for an objective assessment of the strength and timing of various cognitive processes, respectively (Hillyard and Kutas, 1983). One ERP component, the mismatch negativity (MMN), is an especially useful measure of automatic sensory perception as it does not require any behavioral response, and is elicited in the absence of attention to the stimuli (Näätänen, 2003). The MMN, a negative peak with a frontal-topography maximum amplitude and an expected peak latency of 90–250 ms, is elicited by any discriminable change in auditory stimulation (Näätänen, 1992). These auditory stimuli may deviate in any number of ways from the standard, with deviations in frequency, duration, intensity and location, among others, eliciting an MMN (Näätänen and Ahlo, 1997). It is thought that the MMN is generated following a comparison of the deviant stimulus with a well-formed sensory or ‘echoic’ memory trace of the standard auditory stimulus, and subsequent identification that the incoming auditory stimulus differs from the existing memory trace (Näätänen et al., 2007). Given the MMN's association with auditory sensory information processing, it follows that MMN generators are located bilaterally in the left and right supratemporal lobes, specifically in the auditory cortex. It is the orientation of these temporal generators, as well as the presence of MMN generators in the frontal lobes that results in MMN amplitude being maximal at fronto-central sites (Näätänen et al., 2007). In the majority of studies, the MMN is generated by randomly inserting a single low-probability (i.e. rare) deviant auditory stimulus into a train of repetitive (i.e. standard) sounds. The recently developed “Optimum-1” multi-feature MMN paradigm (Näätänen et al., 2004), however, elicits MMNs to five different pure-tone deviant types (frequency, duration, intensity, location and gap) in a relatively short period of time. Given the advantage in efficiency over the traditional oddball design, the multi-feature MMN paradigm has been employed recently in clinical research, notably in schizophrenia (Fisher et al., 2008a; Thönnessen et al., 2008). However, of these five deviant types, frequency, duration and intensity deviants (obtained from auditory oddball paradigms) are overall most often reported in MMN literature, leading to the development of the even shorter Optimal-3 (i.e. 3-deviant) version of the multi-feature MMN paradigm (Fisher et al., 2011a). MMN abnormalities are marked in schizophrenia (Näätänen and Kähkönen, 2009) and appear to be specific to this disorder, as no consistent MMN alterations have been observed in any of the other major
psychiatric disorders (Catts et al., 1995; Umbricht et al., 2003). Deficits in MMN generation were first reported by Shelley et al. (1991), who found significant reductions in MMN amplitude to a duration deviant paradigm in schizophrenia patients. Since this study, abundant corroborating research has confirmed a systematic and robust neurophysiological attenuation of the MMN amplitude in schizophrenia populations to duration and, to a lesser degree, frequency deviants (Javitt et al., 1995; Javitt et al., 1998; Michie, 2001; Umbricht and Krljes, 2005; Fisher et al., 2008a; Fisher et al., 2008b; Todd et al., 2008; Näätänen and Kähkönen, 2009; Dulude et al., 2010; Horton et al., 2011; Rasser et al., 2011). Recent efforts have attempted to characterize deficits to other deviant types, such as intensity. Todd et al. (2008) found that only patients examined early in the course of their illness demonstrate significant MMN reduction to intensity deviants, while patients with longer lengths of illness show no reduction in intensity MMNs vs. age matched controls. Fisher et al. (2008a) also reported an attenuated intensity MMN in chronic patients, but only in those with auditory hallucinations. Recently, studies examining MMN in schizophrenia have begun to look at the effects of the associated syndromes or symptoms, including whether AVHs make a unique contribution to the overall deficit in MMN generation (Oades et al., 1996; Hirayasu et al., 1998; Schall et al., 1999; Youn et al., 2002; Fisher et al., 2008a; Fisher et al., 2008b; Fisher et al., 2011b). Overall, these efforts have tended to focus on correlations between MMN amplitude and self-report measures of hallucinations with uneven results, though the three studies that did find significant correlations reported that as measures of hallucinations increase there is a corresponding decrease in MMN amplitude (Hirayasu et al., 1998; Youn et al., 2002; Fisher et al., 2011b). In one study that directly compared schizophrenia patients with clear, persistent auditory hallucinations to those with no auditory hallucinations, it was reported that hallucinating patients showed reduced MMN amplitude to duration (vs. healthy controls and non-hallucinating patients) and intensity deviants (vs. healthy controls), while non-hallucinating patients were not significantly different from healthy controls (Fisher et al., 2008a). These findings corroborate the suggestion that auditory hallucinations compete with incoming external stimuli for finite resources in the auditory cortex (Woodruff, 2004), resulting in reduced MMN amplitudes. The mismatch negativity, despite being predominantly moderated by ‘bottom-up’ processes, also appears to some degree, under specific conditions, sensitive to ‘top-down’ processes including the availability of attentional resources. High demand auditory processing tasks result in a significant decrease in MMN amplitude; as more resources are required for processing of a primary task, there is a corresponding drop-off in resources available to the MMN generator (Kramer et al., 1995). The lowered effectiveness of the generator is seen in the reduction of MMN amplitude. The revised ‘stimulus-filter’ hypothesis of smoking suggests that nicotine increases available processing resources, particularly those implicated in stimulus encoding, through its action on locus coeruleus noradrenergic cells (Kassel, 1997). If this is indeed the case, one might expect nicotine to enhance the processing of taskindependent stimuli without any decrement in primary task performance. In this way, administration of nicotine may free up resources in the auditory cortex in order to facilitate processing of auditory change detection (as indexed by the MMN), even in the presence of resource-demanding auditory hallucinations. Studies on the effects of smoking/nicotine on MMN in healthy controls have produced rather consistent findings. Positive effects of acute nicotine treatment have been shown in studies reporting moderate improvements in auditory MMN with increased MMN amplitude in smokers using a roving paradigm (Baldeweg et al., 2006), increased MMN amplitudes with a complex consonant–vowel deviant passive paradigm in smokers and non-smokers (Harkrider and Hedrick, 2005), increased MMN amplitudes with an interstimulus interval duration deviant paradigm in both smokers and non-smokers (Martin et al.,
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
2009), and increased MMN amplitude and reduced latency to frequency deviants in non-smokers administered an acute dose of a nicotinic acetylcholine receptor (nAChR) agonist (Dunbar et al., 2007). There is limited literature exploring the moderating effects of nicotine on MMN in schizophrenia, with one study having used doubleblind transdermal administration of nicotine and reporting shortened MMN latencies in non-smoking healthy controls, but not in nonsmoking schizophrenia patients (Inami et al., 2007). These results were consistent with a previous study (Inami et al., 2005), where MMN latency was shortened in non-smoking healthy controls using a double-blind transdermal administration of nicotine. In a more recent study, Dulude et al. (2010) reported enhancement of duration MMN amplitude with a high dose (8 mg) of nicotine in patients with schizophrenia, while nicotine had no effect on frequency MMN. 1.1. Study objectives and hypotheses In schizophrenia, AVHs appear to usurp cognitive resources at the expense of resources that are normally directed at external reality monitoring (Woodruff, 2004), possibly due to a tonic "tuning" or processing preference to AVHs (Ford et al., 2009). As MMN amplitude in SZ is positively correlated with global functioning (Wynn et al., 2010), interventions that can address MMN deficits in schizophrenia, and particularly during AVHs, may represent a viable approach for understanding and treating cognitive deficits in this disorder, which impede daily functional living. In hallucinating patients, nicotine agonist actions at the α-7 nAChR receptor may be a mechanism that can normalize aberrant processing within the auditory cortex directly by inhibiting neuronal activation underlying AVHs and/or indirectly by enhancing the detection of changes in external acoustic stimulation. The aims of this study were two-fold: first, we wished to compare the effects of a single dose of nicotine (vs. placebo) on acoustic change detection (MMN) within a modified three-deviant (frequency, duration and intensity) multi-feature paradigm and self-reports of AVHs. Secondly, as MMN amplitude has been negatively correlated with AVH symptom intensity in three previous studies and given the high smoking rates seen in schizophrenia patients, we wished to probe the relationship between MMN amplitudes and AVH symptoms under conditions of nicotine administration. Specifically, we will test the hypothesis that in SZ patients, nicotine (relative to placebo) will increase frontal MMN amplitudes and reduce self-reported AVHs, with the degree of nicotine-induced increase in the MMN being associated with the degree of nicotine-induced reduction in AVHs. 2. Materials and methods 2.1. Participants Twelve patient volunteers, all presenting with a primary diagnosis of schizophrenia, were recruited from the Outpatient Schizophrenia Clinic of the Royal Ottawa Mental Health Centre (ROMHC). During an initial clinical interview (with the primary care physician) in which volunteers were assessed with respect to inclusion and exclusion criteria, both clinical history and ratings on the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1989) for schizophrenia were used for recruitment. For study inclusion, all patients reported a definite, consistent history of AHs over the course of their illness, exhibiting a score ≥ 3 (mild or greater hallucinatory experiences) on the hallucination item of the PANSS positive symptom scale. The tendency to experience AVHs was subsequently confirmed by a study investigator (DF), who rated the patients on the AVH subscale of the Psychotic Symptom Rating Scale (PSYRATS; Haddock et al., 1999). This 11-item, 5-point (0–4) rating scale assesses trait hallucinations across several dimensions, including frequency, duration and intensity of distress. Of the 12 participants, 7 were current smokers with an average consumption of 27.71 cigarettes per day (S.D. = 15.18; range = 8–50 cigs/day) and a Fagerström Test of Nicotine Dependence (FTND; Heatherton et al., 1991) score of 7.86 (S.D. = 2.42; range = 5–11), indicating high-to-very high addiction. A summary of participant characteristics is given in Table 1. 2.1.1. Inclusion criteria All patients were required to be primarily right-handed, as indicated by a score greater than 0.5 on the Edinburgh Handedness Inventory (EHI; Oldfield, 1971), between the ages of 18 and 65 (actual range: 28–57 y.o.), and to have a primary DSM-
183
Table 1 Summary of participant demographics and trait questionnaires (mean ± S.D.). Patients Age Years of education PSYRATS PANSS positive symptom PANSS negative symptom PANSS hallucination item PANSS general psychoticism
41.31 13.8 25.92 21.55 19.82 4.00 40.82
(9.66) (1.07) (6.84) (3.88) (5.40) (0.48) (9.18)
IV TR diagnosis of schizophrenia, paranoid subtype, as assessed with Structured Clinical Interview DSM-IV Psychotic Screen (SCID-P) by their primary care physician. Patients also had to be clinically stable for the 4 weeks prior to testing, having no significant changes in symptoms or medications. Patients' primary medication was limited to one of the atypical anti-psychotics. All participants were required to understand spoken and written English, although English did not need to be their first language. Normal hearing via audiometric assessment was a requirement and was evidenced by auditory sound pressure level (SPL) thresholds of 25 dB or less (using a ‘descending method of limits' procedure) to pure tones of 500 Hz, 1000 Hz, and 2000 Hz. 2.1.2. Exclusion criteria Participants were excluded if they met any of the following criteria: co-morbid Axis I disorder as defined by DSM-IV TR criteria; current history of drug abuse or dependence; head injury resulting in the loss of consciousness within the last year; a neurologic disorder including epilepsy; primary treatment with a first generation neuroleptic such as haloperidol; electro-convulsive therapy (ECT) treatment within the last year; significant cardiac illness; extrapyramidal symptoms (EPS) resulting in movement disorders which would disrupt the ERP recordings; or audiometric assessment significantly above 25 dB (SPL) on each level of pure tones. 2.2. Study design Patient participants were assessed within a randomized, double-blind, placebo controlled crossover design involving two test sessions, one with nicotine treatment and the other with placebo treatment. Randomly selected, half of the patients received the placebo first and nicotine second, while the other half received treatment in the reverse order. Sessions were separated by approximately 7 days, with antipsychotic/adjunct medications being kept constant during this time span. 2.3. Study procedure Testing was conducted around midday (11:00 am–2:00 pm) with participants being required to abstain from illicit drugs, medications, and alcohol beginning at midnight of the previous day. Participants were also instructed to abstain from both caffeine and cigarettes for at least an hour prior to the session. Upon arrival at the laboratory, following self-report of adherence to pre-testing abstinence, participants completed demographic questionnaires and underwent audiometric assessment. Following this, EEG electrodes were applied and nicotine or placebo gum was administered. Volunteers were assessed using a modified 3-deviant version (Fisher et al., 2011a) of the multi-feature MMN paradigm (Näätänen et al., 2004), during which they were instructed to view a silent, neutral emotive video and to ignore the presented auditory stimuli. All testing procedures were carried out in accordance with the Declaration of Helsinki and following the approval of the research ethics board of the Royal Ottawa Health Care Group. 2.3.1. Nicotine Nicotine was administered in the form of two pieces of cinnamon flavored nicotine polacrilex gum (Nicorette brand [Johnson & Johnson, Inc.]): one 4 mg (Nicorette Plus ®) and one 2 mg (Nicorette ®) piece. The 6 mg of nicotine was expected to produce a plasma nicotine concentration of ~ 15–30 ng/ml (Hukkanen et al., 2005), which is approximately equal to the amount one would expect from smoking a single cigarette of average nicotine yield. The placebo gum pieces were similar in taste, texture and size to the treatment gum, but contained no nicotine. Gum pieces in both conditions were chewed for a 25 minute period, as per the directions of the manufacturer (i.e., biting twice every 2 min and then ‘parking’ the gum between the teeth and cheek between bites). Peak blood nicotine levels are typically achieved after 25–30 min of the gum chewing; normal nicotine elimination half-life is approximately 120 min. Following testing, participants indicated the presence or absence of side effects to the nicotine treatment using the Checklist of Nicotine-Related Symptoms, which measures adverse events (Harkrider and Hedrick, 2005). Additionally, in order to determine the efficacy of the double-blind, patients were asked to indicate whether they thought they had received nicotine or placebo gum. Only three out of the ten patients asked were able to correctly determine whether they had received nicotine or placebo.
184
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
Patients also completed questionnaires relating to craving, using the 32-item Questionnaire on Smoking Urges (QSU; Tiffany and Drobes, 1992), and smoking withdrawal, using the Smoking Withdrawal Symptoms Checklist (SWSC; Hughes and Hatsukami, 1986), in order to monitor subjective effects of nicotine abstinence. 2.3.2. Auditory stimuli The auditory stimuli and task were exactly the same as the modified 3-stimulus version of the multi-feature MMN paradigm and have been previously described elsewhere (Fisher et al., 2011a). Briefly, the task presented only frequency, duration and intensity deviants within a sequence whereby every second tone was a standard (P = 0.5) and every other one was one of the three deviants (P = 0.17 each), with the exception of the first 15 tones, which were all standards. All stimuli were presented binaurally through headphones and at a sound pressure level (SPL) of 70 dB (with the exception of the intensity deviants) with equal phase intensity in each channel. The stimuli were presented in three sequences of 3 min each (366 stimuli) for a total of 9 min (1098 stimuli). 2.3.3. ERP recording and computation MMNs were extracted from EEG activity recorded with an electrode cap positioning Ag+/Ag+-Cl− ring electrodes at 32 scalp sites according to the 10–10 system of electrode placement, including three frontal scalp sites (midline [FZ], left [F3], right [F4]). Electrodes were also used to record left (LM) and right (RM) mastoid activity and electrodes were placed on the mid-forehead and nose to serve as ground and reference, respectively. Bipolar recordings of horizontal (HEOG) and vertical (VEOG) electrooculogram activity were taken from supra-/sub-orbital and external canthi sites, respectively. All electrode impedances were kept below 5 kΩ. Electrical activity was recorded using BrainVision Recorder software and a BrainVision Quickamp amplifier (Brain Products GmbH, Munich DE) with bandpass settings of 0.1 and 100 Hz, digitized at 500 Hz, and stored on hard-disk for later off-line analysis using BrainVision Analyzer software (Brain Products GmbH, Munich DE). EEG epochs (500 ms duration, beginning 100 ms pre-stimulus) were corrected for residual eye movement and eye blink activity using the Gratton and Coles algorithm, which operates in the time and frequency domain (Gratton et al., 1983); any corrected epochs with EEG voltages exceeding ± 100 μV were excluded from further analysis. Within the multi-feature paradigm, epochs were separately averaged for each standard and deviant stimulus type and then digitally filtered using a bandpass of 0.15–8 Hz (Leung et al., 2006) and a slope of 24 db/octave. The narrow band pass, previously used in studies of the multi-feature MMN (Fisher et al., 2008a, 2011a, 2011b), eliminates any extraneous high-frequency muscular or eye-twitch activity that may generate artifacts. MMN difference waveforms were derived from point-by-point digital subtraction of the standard stimulus values from those elicited by the deviant stimulus. MMN peaks were obtained by quantifying peak negative amplitudes within a window of 80–220 ms; this window was chosen based on a visual inspection of the waveforms. Prior to peak picking, individual visual assessment of the presence of the true MMN (as indicated by appropriate polarity inversion at mastoids) was conducted within each participant for each deviant type. MMN peaks for each individual participant were picked for each deviant type as the most negative point within the analysis window and output was the average within five voltage points (10 ms) to the left and right of the peak amplitude. MMN latency measurements were only measured at FZ, the site of maximum amplitude. 2.3.4. Hallucination state ratings (HSR) Upon completion of the MMN paradigm, patients completed a rating scale, similar to that used by Margo et al. (1981), asking them to indicate the nature of their hallucinations experienced during the recordings on 5 dimensions: 1) duration (1 = no AVHs, 7 = continuous AVHs); 2) loudness (1 = not audible, 7 = extremely loud); 3) clarity (1 = unintelligible, 7 = very clear); 4) distress (1 = not distressing, 5 = very distressing); and 5) control (1 = complete control over voices, 7 = no control over voices).
Where appropriate, Huynh–Feldt epsilon correction factors were applied to the degrees of freedom and the rounded adjusted degrees of freedom have been reported. Regardless of the presence or absence of significant main or interaction effects, planned comparisons involving within-group comparisons of drug effects on MMN amplitude with respect to laterality and region, as well as MMN latency, were carried out. Significant (p b 0.05) effects were followed-up with pairwise comparisons for greater specificity in reporting. In order to examine the correlations between treatment, MMN amplitude and state and trait hallucination severity, two-way Spearman's rho correlations were conducted between change (nicotine–placebo) in MMN amplitude at frontal sites and change (nicotine–placebo) in state hallucination measures (HSRs). Correlations between MMN amplitude change and trait (PSYRATS, PANSS) scores were also performed to describe any significant relationship with hallucination trait, positive symptom, negative symptom and general psychopathology scores. Similar analyses were performed for MMN latency. Finally, an exploratory analysis used two-way Spearman's rho correlations to investigate the relationship between nicotine use (cigarettes per day, FTND scores) and hallucinations (HSRs, PSYRATS).
3. Results 3.1. MMN amplitude There were no significant MMN amplitude differences across the treatment conditions (placebo vs. nicotine) for duration, intensity or frequency deviants, nor was there a significant difference in amplitude between MMN deviants (i.e. duration = intensity = frequency). 3.2. MMN latency A significant shortening of latency was found (Fig. 1) for intensity deviants in the nicotine condition (mean = 144.95 ms, S.E. ± 39.35), compared to the placebo condition (mean = 160.39 ms, S.E ± 36.13; P = 0.048). There were no main or interaction effects. 3.3. Hallucination state ratings A paired-samples t-test was used to investigate the change in scores of the patients' subjective ratings of their hallucinations during the task between placebo and treatment conditions, however nicotine did not significantly alter any dimension of AVH state. 3.4. Correlations Nicotine induced change in amplitude of intensity MMN at FZ was negatively correlated (i.e. MMN increases as HSR increases) with change in the clarity (ρs = −0.702, P = 0.024) of hallucinations (Fig. 2).
2.3.5. Self-reports A physical symptoms checklist used by Harkrider and Hedrick (2005) was employed to measure the severity of nicotine-related adverse symptoms. Participants were instructed to indicate the severity of their symptoms on a five-point scale (0 = no symptoms, 4 = extreme symptoms). Symptoms included such events as heartpounding, headache, dizziness, and nausea. 2.3.6. Vital signs Systolic blood pressure (SBP), diastolic blood pressure (DBP) (mm Hg) and heart rate (HR; beats per min; bpm) were assessed before and after gum administration while participants were sitting (semi-reclined) without task involvement. 2.4. Data analysis Analyses of MMN amplitudes and latencies were carried out using the Statistical Package for the Social Sciences (SPSS; IBM Corp., Armonk, NY). MMN amplitudes were subjected to repeated measures general linear model (GLM) procedures with three within-subjects factors (treatment [placebo or nicotine], deviant [duration, pitch and intensity] and electrode site [limited to F3, FZ and F4]). MMN latencies, derived only from FZ (the site of maximum amplitude), were subjected to a similar analysis, however electrode site was not included as a factor.
Fig. 1. MMN latencies to duration, frequency and intensity deviants for nicotine and placebo treatment conditions.
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
185
4. Discussion
Fig. 2. Scatterplot illustrating the negative correlation (ρs = − 0.70, P = 0.024) between change (nicotine–placebo) in MMN amplitude to intensity deviants and change (nicotine–placebo) in subjective appraisal in AVH clarity.
Exploratory analysis of the link between AVHs and smoking behavior with a two-tailed Spearman's rho test (Fig. 3) showed that number of cigarettes smoked per day was positively correlated with PSYRATS scores (ρs = 0.76, P = 0.050).
3.5. Withdrawal/craving ratings A two-tailed paired samples t-test comparing placebo and nicotine session scores found no significant differences with respect to SWSC and QSU values.
3.6. Vital signs Paired sample t-tests were performed for each of systolic BP, diastolic BP and pulse values post-treatment, with findings showing that diastolic blood pressure significantly differed across treatments, t (d.f. = 11) = −2.53, P = 0.028. Specifically, diastolic BP was greater following nicotine administration (mean = 79.42, S.E. = 9.21) compared to placebo (mean = 71.54, S.E. = 12.30). There were no significant effects of treatment for systolic blood pressure or pulse.
Fig. 3. Scatterplot illustrating the positive correlation (ρs = 0.76, P = 0.50) between number of cigarettes smoked per day and AVH trait score (as measured by the PSYRATS).
In this study, the presumed enhancement of auditory sensory processing with nicotine in schizophrenia patients with persistent AVHs was explored using frequency, duration, and intensity MMN. We failed to detect any effects of nicotine on amplitude, although latency was significantly shortened to intensity deviants. Furthermore, it appears that nicotine-related increases in intensity MMN amplitude are associated with increases in subjective clarity of AVHs. The hypothesis that nicotine treatment would significantly increase MMN amplitudes compared to those during placebo condition was not met. Despite this, our null treatment findings regarding frequency MMN amplitude are in agreement with those from Inami et al. (2007), who also examined nicotine's effects in schizophrenial, albeit using a slightly different methodology (including using only inpatients, transdermal nicotine administration, and non-smokers). In addition to frequency MMN explored by Inami et al. (2007), this study also examined duration and intensity MMN, although both of these failed to exhibit a significant change in amplitude between treatment sessions. The findings of this study are in contrast to those of Dulude et al. (2010), who reported an enhancement of duration MMN amplitude following nicotine administration. It must be noted, however, that the previous study used a two-stimulus auditory oddball paradigm (vs. a modified multi-feature paradigm) with ideal study parameters to determine treatment differences, including a very low deviant probability (5%) and high dosage of nicotine (8 mg). Additionally, the differences observed may stem from the schizophrenia populations used; while Dulude et al. studied MMN in a general schizophrenia population, the present study specifically employed schizophrenia patients with current and persistent auditory hallucinations. MMN latency to intensity MMN significantly decreased (vs. placebo) in schizophrenia patients following acute nicotine treatment. This observation lends support to previously reported findings that MMN latency decreases following acute nicotine treatment (Baldeweg et al., 2006; Inami et al., 2007), although this is the first study to report a decrease in MMN latency in schizophrenia patients. Consistent with Inami et al. (2007), we found no change in latency to pitch deviants in schizophrenia following nicotine treatment, as well as no reduction in latency to duration deviants. It would seem nicotine can accelerate automatic processing of intensity deviants in patients, although why this effect is seen only in intensity deviants will need to be explored further in follow up studies. Frequency, intensity, and duration MMN appear to be activated by different neural generators and it is possible that nicotine at the current dose level (6 mg) differentially affects the cortical sources underlying intensity deviance detection (Giard et al., 1995). Applying the stimulus-filter hypothesis (Kassel, 1997), it is possible that acute nicotine administration normalizes neural systems specific for processing intensity deviants by helping schizophrenia patients to screen irrelevant stimuli (AVHs) from awareness; this would free up auditory cortical resources normally usurped by AVHs for the processing of change detection, as indexed by the MMN. In this way, screening out AVHs may result in increased processing resources for relevant stimuli (deviants) and, therefore, a shortening in intensity MMN latency. In addition to MMN amplitude and latency, subjective hallucination state rating scale scores were investigated to find potential subjective effects of nicotine over and above neurophysiologic measures. Contrary to our hypothesis, nicotine did not significantly affect any of the HSR ratings. This may, however, be due in part to the relatively modest hallucinatory activity experienced by participants, creating a floor effect that would minimize our ability to see treatment-related change. While there was a significant nicotine-related correlation between measures of MMN change and AVH change, it was in the opposite direction of that predicted in our hypotheses. Specifically, as frontal
186
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
midline intensity MMN amplitude increased, so did the perceived clarity of AVHs. Nicotine has been previously shown to enhance cortical excitability in the auditory cortex (Knapp and Domino, 1962; Harkrider and Champlin, 2001), the site of both MMN (Näätänen and Ahlo, 1997) and auditory hallucination generation (Woodruff, 2004). We suggest that, under such conditions of modest AVH activity, nicotine induces a general increase in auditory cortex activity, resulting in an enhanced MMN as well as increased subjective measures of AVH experience, particularly AVH clarity. Perhaps the most interesting, albeit exploratory, finding is that the number of cigarettes smoked per day is positively correlated with PSYRATS scores, suggesting that greater AVH trait scores are associated with greater tobacco consumption. This lends further credence to the suggestion that schizophrenia patients smoke as a form of selfmedication, particularly to gate out irrelevant stimuli (such as auditory hallucinations) and focus attention (Kumari and Postma, 2005; Evans and Drobes, 2008). Conversely, given our findings that nicotine exacerbates particular dimensions of AVH states while enhancing MMN, it may be that increased smoking may increase the propensity to experience AVHs. Certainly, further research must be undertaken to clarify this issue. Blood pressure and pulse were measured in this study to verify patients were symptomatic to nicotine treatment. It has been previously documented that nicotine increases both blood pressure and pulse (Sjoberg and Saint, 2011; Wignall and de Wit, 2011), and, consistent with these previous reports, we observed an increase in diastolic blood pressure following nicotine administration. This suggests adequate absorption of the drug and the use of a sufficiently high enough dose to exert central effects, indicating that the lack of MMN amplitude and HSR results are not due to an absence of nicotine's biological effects. There are a number of limitations in the study that temper the study findings. According to Evans and Drobes (2008), easy to perform tasks may sometimes fail to detect nicotine effects and so by incorporating a task with multiple difficulty levels, one can better assay the effects of nicotine. A related confounding issue with our study may have been that the distraction task during MMN recording might not have garnered enough attention from participants and they may have focused on the tones (despite instructions informing participants to ignore them and focus on the movie). Perhaps using a standardized visual performance task (as opposed to a video), where attention could be reliably and quantifiably directed on the distraction task, would be a more suitable methodological option that would ensure a pure memory-based MMN recording that is not contaminated by attention. Other limitations of this study were the lack of adjustment made to nicotine dosage based on participant body weight, as well as neglecting to account for individual differences in nicotinic absorption by analyzing blood samples of nicotine levels, which are variable in each person and can be modified by age and prolonged cigarette usage. In the future, the use of a nasal spray vehicle instead of gum may also prove to be a more effective route of administration, as a nasal spray more closely resembles the rapid absorption seen with smoke inhalation (Lerman and Niaura, 2002). The variability of smoking habits in participants could be a strong confounding factor on whether the treatment had much effect. For participants who smoke a great deal, the 6 mg dose may have had little to no effect, while it may have had a very strong effect on those who smoke very little. Future research should endeavor to separate patients into groups of high, low, and non-smokers to test the effects of 6 mg dose of nicotine on MMN generation or at the very least, use participants with similar smoking behavior. Lastly, the lack of biochemical confirmation of abstinence from caffeine, alcohol, cigarettes, and drugs remains a limitation of this study. In conclusion, our results show a nicotine-induced reduction of intensity MMN latency in schizophrenia with trait AVHs and illustrate previously unknown correlations between AVHs and deficits in MMN amplitude and their change with acute nicotine treatment. It
can be argued that these relationships are the result of nicotine's direct actions at nAChR receptor systems within the auditory cortex, which may have also led to reduced latency times. This study complements a previous report of nicotine-induced MMN latency reduction in schizophrenia (Inami et al., 2007). Acknowledgments We would like to thank Dr. Risto Näätänen and his lab for supplying the auditory stimuli used in this study. This project was supported by a Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral) from the Canadian Institutes of Health Research (CIHR) awarded to DF. References Adler, L.E., Hoffer, D.L., Wiser, A., Freedom, R., 1993. Normalization of auditory physiology by cigarette smoking in schizophrenia patients. The American Journal of Psychiatry 150, 1856–1861. Anfang, M.K., Pope Jr., H.G., 1997. Treatment of neuroleptic-induced akathisia with nicotine patches. Psychopharmacology 134, 153–156. Baldeweg, T., Wong, D., Stephan, K.E., 2006. Nicotinic modulation of human auditory sensory memory: evidence from mismatch negativity potentials. International Journal of Psychophysiology 59, 49–58. Cadenhead, K.S., Braff, D.L., 1999. Schizophrenia spectrum disorders. In: Dawson, M.E., Schell, A.M., Bohmelt, A.H. (Eds.), Startle Modification: Implications for Neuroscience, Cognitive Science, and Clinical Science. Cambridge University Press, Cambridge, pp. 231–244. Catts, S.V., Shelley, A.M., Ward, P.B., Liebert, B., McConaghy, N., Andrews, S., Michie, P.T., 1995. Brain potential evidence for an auditory sensory memory deficit in schizophrenia. The American Journal of Psychiatry 152, 213–219. de Leon, J., Diaz, F.J., Rogers, T., Browne, D., Dinsmore, L., 2002. Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders. Schizophrenia Research 56, 47–54. Dulude, L., Labelle, A., Knott, V.J., 2010. Acute nicotine alteration of sensory memory impairment in smokers with schizophrenia. Journal of Clinical Psychopharmacology 30, 541–548. Dunbar, G., Boeijinga, P.H., Demazières, A., Cisterni, C., Kuchibhatla, R., Wesnes, K., Luthringer, R., 2007. Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191, 919–929. Evans, D.E., Drobes, D.J., 2008. Nicotine self-mediation of cognitive-attentional processing. Addiction Biology 14, 32–42. Fisher, D.J., Labelle, A., Knott, V.J., 2008a. The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multifeature paradigm. Clinical Neurophysiology 119, 919–921. Fisher, D.J., Labelle, A., Knott, V.J., 2008b. Auditory hallucinations and the mismatch negativity: processing speech and non-speech sounds in schizophrenia. International Journal of Psychophysiology 70, 3–15. Fisher, D.J., Grant, B., Smith, D.M., Knott, V.J., 2011a. Effects of deviant probability on the ‘optimal’ multi-feature mismatch negativity (MMN) paradigm. International Journal of Psychophysiology 79, 311–315. Fisher, D.J., Grant, B., Smith, D.M., Borracci, G., Labelle, A., Knott, V.J., 2011b. Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified ‘optimal’ multi-feature paradigm. International Journal of Psychophysiology 81, 245–251. Ford, J.M., Roach, B.J., Jorgensen, K.W., Turner, J.A., Brown, G.G., Notestine, R., BischoffGrethe, A., Greve, D., Wible, C., Lauriello, J., Belger, A., Mueller, B.A., Calhoun, V., Preda, A., Keator, D., O'Leary, D.S., Lim, K.O., Glover, G., Potkin, S.G., FBIRN, Mathalon, D.H., 2009. Tuning in to the voices: a multisite fMRI study of auditory hallucinations. Schizophrenia Bulletin 35, 58–66. Friedman, J., Horvath, T., 1974. Tobacco smoking and a stimulus barrier. Nature 248, 455–456. Giard, M., Lavikainen, J., Reinikainen, K., Perria, F., Bertrand, O., Pernier, J., Näätänen, R., 1995. Separate representations of stimulus, frequency, intensity and duration in auditory sensory memory: an event-related potential and dipole-model analysis. Journal of Cognitive Neuroscience 7, 133–143. Gratton, G., Coles, M.G., Donchin, E., 1983. A new method for off-line removal of ocular artifact. Electroencephalography and Clinical Neurophysiology 55, 468–484. Haddock, G., McCarron, J., Tarrier, N., Faragher, E.B., 1999. Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychological Medicine 29, 879–888. Harkrider, A.W., Champlin, C.A., 2001. Acute effect of nicotine on non-smokers: II. MLRs and 40-Hz responses. Hearing Research 160, 89–98. Harkrider, A.W., Hedrick, M.S., 2005. Acute effect of nicotine on auditory gating in smokers and non-smokers. Hearing Research 202, 114–128. Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., Fagerström, K.O., 1991. The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86, 1119–1127. Hillyard, S.A., Kutas, M., 1983. Electrophysiology of cognitive processing. Annual Review of Psychology 34, 33–61.
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187 Hirayasu, Y., Potts, G.F., O'Donnell, B.F., Kwon, J.S., Arakaki, H., Akdaq, S.J., Levitt, J.J., Shenton, M.E., McCarley, R.W., 1998. Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage. The American Journal of Psychiatry 155, 1281–1283. Hong, L.E., Schroeder, M., Ross, T.J., Buchholz, B., Salmeron, B.J., Wonodi, I., Thaker, G.K., Stein, E.A., 2011. Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia. Schizophrenia Bulletin 37, 416–425. Horton, J., Millar, A., Labelle, A., Knott, V.J., 2011. MMN responsivity to manipulations of frequency and duration deviants in chronic, clozapine-treated schizophrenia patients. Schizophrenia Research 126, 202–211. Hughes, J.R., Hatsukami, D., 1986. Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry 43, 289–294. Hukkanen, J., Jacob III, P., Benowitz, N.L., 2005. Metabolism and disposition kinetics of nicotine. Pharmacology Review 57, 79–115. Inami, R., Kirino, E., Inoue, R., Arai, H., 2005. Transdermal nicotine administration enhances automatic auditory processing reflected by mismatch negativity. Pharmacology, Biochemistry and Behaviour 80, 453–461. Inami, R., Kirino, E., Inoue, R., Suzuki, T., Arai, H., 2007. Nicotine effects on mismatch negativity in nonsmoking schizophrenic patients. Neuropsychobiology 56, 64–72. Janhunen, S., Ahtee, L., 2007. Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: implications for drug development. Neuroscience and Biobehavioural Reviews 31, 287–314. Javitt, D.C., Doneshka, P., Grochowski, S., Ritter, W., 1995. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Archives of General Psychiatry 52, 550–558. Javitt, D.C., Grochowski, S., Shelley, A.M., Ritter, W., 1998. Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval. Electroencephalography and Clinical Neurophysiology 108, 143–153. Kassel, J.D., 1997. Smoking and attention: a review and reformulation of the stimulusfilter hypothesis. Clinical Psychology Review 17, 451–478. Kay, S.R., Opler, L.A., Lindenmeyer, J.P., 1989. The positive and negative syndrome scale (PANSS): rationale and standardization. The British Journal of Psychiatry 155 (Suppl 7), 59–65. Kelly, C., McCreadie, R.G., 1999. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland. The American Journal of Psychiatry 156, 1751–1757. Knapp, D.E., Domino, E.F., 1962. Action of nicotine on the ascending reticular activating system. International Journal of Neuropharmacology 1, 333–351. Knott, V.J., Venables, P.H., 1978. Stimulus control and the cortical evoked response in smokers and non-smokers. Psychophysiology 15, 186–192. Kramer, A.F., Trejo, L.J., Humphrey, D., 1995. Assessment of mental workload with taskirrelevant auditory probes. Biological Psychology 40, 83–100. Kumari, V., Postma, P., 2005. Nicotine use in schizophrenia: the self medication hypotheses. Neuroscience and Biobehavioural Reviews 29, 1021–1034. Kumari, V., Soni, W., Sharma, T., 2001. Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Human Psychopharmacology and Clinical Experience 16, 321–326. Leonard, S., Gault, J., Hopkins, J., Logel, J., Vianzon, R., Short, M., Drebing, C., Berger, R., Venn, D., Sirota, P., Zerbe, G., Ollincy, A., Ross, R.G., Adler, L.E., Freedman, R., 2002. Association of promoter variants in the a7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrena. Archives of General Psychiatry 59, 1085–1096. Lerman, C., Niaura, R., 2002. Applying genetic approaches to the treatment of nicotine dependence. Oncogene 21, 7412–7420. Leung, S., Croft, R.J., Guille, V., Nathan, P.J., 2006. The effects of digital filtering on duration MMN. Presented at the 4th Conference on Mismatch Negativity and Its Clinical and Scientific Applications, Cambridge UK, April 22–26. Margo, A., Helmsley, D.R., Slade, P.D., 1981. The effects of varying auditory input on schizophrenia hallucinations. The British Journal of Psychiatry 139, 122–127. Martin, L.F., Davalos, D.B., Kisley, M.A., 2009. Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform. Nicotine & Tobacco Research 11, 698–706. Michie, P., 2001. What has MMN revealed about the auditory system in schizophrenia? International Journal of Psychophysiology 42, 177–194. Milailescu, S., Drucker-Colin, R., 2000. Nicotine and brain disorders. Acta Pharmacologica Sinica 21, 97–104. Näätänen, R., 1992. Attention and Brain Function. Lawrence Earlbaum Associates, Hillsdale, NJ. Näätänen, R., 2003. Mismatch negativity: clinical research and possible applications. International Journal of Psychophysiology 48, 179–188.
187
Näätänen, R., Ahlo, K., 1997. Mismatch negativity — the measure for central sound represenation accuracy. Audiology & Neuro-Otology 2, 341–353. Näätänen, R., Kähkönen, S., 2009. Central auditory dysfunction in schizophrenia as revealed by the mismatch negativity (MMN) and its magnetic equivalent MMNm: a review. The International Journal of Neuropsychopharmacology 12, 125–135. Näätänen, R., Pakarinen, S., Rinne, T., Takegata, R., 2004. The mismatch negativity (MMN) — towards the optimal paradigm. Clinical Neurophysiology 115, 140–144. Näätänen, R., Paavilainen, P., Rinne, T., Alho, K., 2007. The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clinical Neurophysiology 118, 2544–2590. Newhouse, P.A., Potter, A., Singh, A., 2004. Effects of nicotine stimulation on cognitive performance. Current Opinion in Pharmacology 4, 36–46. Oades, R., Zerbin, D., Dittman-Balcar, A., Eggers, C., 1996. Auditory event-related potential (ERP) and difference-wave topography in schizophrenia patients with/without active hallucinations and delusions: a comparison with young obsessive–compulsive disorder (OCD) and healthy subjects. International Journal of Psychophysiology 22, 185–214. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113. Olincy, A., Young, D.A., Freedman, R., 1997. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biological Psychiatry 42, 1–5. Rasser, P., Schall, V., Todd, J., Michie, P.T., Ward, P.B., Johnston, P., Helmbold, K., Case, V., Søyland, A., Tooney, P.A., Thompson, P.M., 2011. Gray matter deficits, mismatch negativity, and outcomes in schizophrenia. Schizophrenia Bulletin 37, 131–140. Sacco, K.A., Termine, A., Seval, A., Dudas, M.M., Vessichio, J.C., Krishnan-Sarin, S., Jatlow, P.I., Wexler, B.E., George, T.P., 2005. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Archives of General Psychiatry 62, 649–659. Schall, U., Catts, S.V., Karayanidis, F., Ward, P.B., 1999. Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow up. The International Journal of Neuropsychopharmacology 2, 83–93. Shelley, A.M., Ward, P.B., Catts, S.V., Michie, P.T., Andrews, S., McConaghy, N., 1991. Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biological Psychiatry 30, 1059–1062. Singh, A., Potter, A., Newhouse, P., 2004. Nicotinic acetylcholine receptor system and neuropsychiatric disorders. The Investigational Drugs Journal 7, 1096–1103. Sjoberg, N., Saint, D.A., 2011. A single 4 mg dose of nicotine decreases heart rate variability in healthy nonsmokers: implications for smoking cessation programs. Nicotine and Tobacco Research 13, 369–372. Strand, J.E., Nyback, H., 2005. Tobacco use in schizophrenia: a study of cotinine concentrations in the saliva of patients and controls. European Psychiatry 20, 50–54. Tanabe, J., Tregellas, J.R., Martin, L.F., Freedman, R., 2006. Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia. Biological Psychiatry 59, 754–761. Thönnessen, H., Zvyagintsev, M., Harke, K.C., Boers, F., Dammers, J., Norra, Ch., Mathiak, K., 2008. Optimized mismatch negativity paradigm reflects deficits in schizophrenia patients: a combined EEG and MEG study. Biological Psychology 77, 205–216. Tiffany, S.T., Drobes, D.J., 1992. The development and initial validation of a questionnaire on smoking urges. British Journal of Addiction 86, 1467–1476. Todd, J., Michie, P.T., Schall, U., Karayanidis, F., Yabe, H., Näätänen, R., 2008. Deviant matters: duration, frequency, and intensity deviants reveal different patterns of mismatch negativity reduction in early and late schizophrenia. Biological Psychiatry 63, 58–64. Uck, A., Polat, A., Bozkurt, O., Meteris, H., 2004. Cigarette smoking among patients with schizophrenia and bipolar disorders. Psychiatry and Clinical Neurosciences 58, 434–437. Umbricht, D., Krljes, S., 2005. Mismatch negativity in schizophrenia: a meta-analysis. Schizophrenia Research 76, 1–23. Umbricht, D., Javitt, D.C., Bates, J., Kane, J., Lieberman, J.A., 2003. How specific are deficits in mismatch negativity generation to schizophrenia? Biological Psychiatry 53, 1120–1131. Wignall, N.D., de Wit, H., 2011. Effects of nicotine on attention and inhibitory control in healthy nonsmokers. Experimental and Clinical Psychopharmacology 19, 183–191. Woodruff, P.W., 2004. Auditory hallucinations: insights and questions from neuroimaging. Cognitive Neuropsychiatry 9, 73–91. Wynn, S., Sugar, C., Horan, W., Kern, R., Green, M., 2010. Mismatch negativity, social cognition, and functioning in schizophrenia patients. Biological Psychiatry 67, 940–947. Youn, T., Park, H.-J., Kim, J.-J., Kim, M.S., Kwon, J.S., 2002. Altered hemispheric asymmetry and positive symptoms in schizophrenia: equivalent current dipole of auditory mismatch negativity. Schizophrenia Research 59, 253–260.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Nicotine and the hallucinating brain: Effects on mismatch negativity (MMN) in schizophrenia Derek J. Fisher a, b, c, d,⁎, Bryan Grant e, Dylan M. Smith c, f, Giuseppe Borracci d, Alain Labelle c, d, Verner J. Knott b, c, d, e, f a
Department of Psychology, Mount Saint Vincent University, Halifax, Nova Scotia, Canada Department of Psychology, Carleton University, Ottawa, Ontario, Canada University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada d Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada e Department of Psychology, University of Ottawa, Ottawa, Ontario, Canada f Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada b c
a r t i c l e
i n f o
Article history: Received 30 May 2011 Received in revised form 23 January 2012 Accepted 25 January 2012 Keywords: MMN Mismatch negativity Schizophrenia Auditory hallucinations Nicotine Tobacco Auditory event-related potentials
a b s t r a c t Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6 mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Abnormally high smoking rates are seen in schizophrenia and have been reported to be as high as 88% (Kelly and McCreadie, 1999). While it is assumed nicotine self-medication is common in most psychiatric populations (Milailescu and Drucker-Colin, 2000; Newhouse et al., 2004; Singh et al., 2004), the smoking rate in schizophrenia is even higher than the rates found in mood (de Leon et al., 2002) and bipolar disorder (Uck et al., 2004). In addition, schizophrenia smokers appear to have higher daily cigarette consumption (Uck et al., 2004), prefer stronger cigarettes (Olincy et al., 1997), and extract more nicotine from each cigarette (Olincy et al., 1997; Strand and Nyback, 2005) than typical smokers (Kumari and Postma, 2005). ⁎ Corresponding author at: Department of Psychology, Mount Saint Vincent University, 166 Bedford Hwy., Halifax, Canada NS B3M 2J6. Tel.: +1 902 457 5503. E-mail addresses: derek.fi[email protected], [email protected] (D.J. Fisher). 0165-1781/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2012.01.026
Nicotine is the main psychoactive alkaloid in cigarettes and its effects on cognition, specifically working memory and attention, is of great interest. It is commonly believed that nicotine's ability to mediate selective attention, by acting as a stimulus barrier, screening irrelevant and distracting stimuli from the smoker's awareness, may lead to improved task performance and cognitive processing (Kassel, 1997). By doing this, it is believed that brain systems involved in the processing of irrelevant stimuli are freed up (Friedman and Horvath, 1974; Knott and Venables, 1978) and allocated to enhance processing of relevant, target stimuli, thus facilitating task performance (Kassel, 1997). Following from evidence suggesting that acute nicotine administration reverses nicotine withdrawal-related cognitive deficits, as well as producing true (i.e. non-withdrawal mediated) cognitive enhancement, it is thought that schizophrenia patients may use smoking as a way to self-medicate (Cadenhead and Braff, 1999; Kumari and Postma, 2005; Evans and Drobes, 2008). It has been proposed that the
182
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
mood and cognitive enhancement associated with nicotine from cigarettes may be reinforcing for schizophrenia patients, as the nicotine could provide temporary alleviation of negative symptoms (Janhunen and Ahtee, 2007), improve attention and recall, reduce extrapyramidal symptoms associated with anti-psychotic medication (Anfang and Pope, 1997), and aid in the gating out of irrelevant stimuli (such as auditory hallucinations) and focusing of attention (Kumari and Postma, 2005; Evans and Drobes, 2008). Evidence that smoking/nicotine may ameliorate abnormal cognition in schizophrenia has been found in studies that have shown acute treatment with nicotine normalizes spatial memory (Sacco et al., 2005) and sensory-gating deficits (Adler et al., 1993; Kumari et al., 2001), while it enhances sustained attention (Hong et al., 2011) and smooth pursuit eye-tracking (Tanabe et al., 2006). Sensory gating improvements with nicotine are thought to be related to the activation of the hippocampal α-7 subtype nAChRs, which have been shown to be deficient in post-mortem brains of patients and are known to be important for attentional control, learning, and memory (Leonard et al., 2002). Electroencephalography (EEG) non-invasively measures neuroelectric brain activity by recording electrical activity at the scalp and is able to detect subtle stages of information processing due to its superior temporal resolution (milliseconds). EEG derived event-related potential (ERP) components are elicited in response to the presentation of discrete stimuli (i.e. tones, light flashes); the amplitudes and latencies of ERP components allow for an objective assessment of the strength and timing of various cognitive processes, respectively (Hillyard and Kutas, 1983). One ERP component, the mismatch negativity (MMN), is an especially useful measure of automatic sensory perception as it does not require any behavioral response, and is elicited in the absence of attention to the stimuli (Näätänen, 2003). The MMN, a negative peak with a frontal-topography maximum amplitude and an expected peak latency of 90–250 ms, is elicited by any discriminable change in auditory stimulation (Näätänen, 1992). These auditory stimuli may deviate in any number of ways from the standard, with deviations in frequency, duration, intensity and location, among others, eliciting an MMN (Näätänen and Ahlo, 1997). It is thought that the MMN is generated following a comparison of the deviant stimulus with a well-formed sensory or ‘echoic’ memory trace of the standard auditory stimulus, and subsequent identification that the incoming auditory stimulus differs from the existing memory trace (Näätänen et al., 2007). Given the MMN's association with auditory sensory information processing, it follows that MMN generators are located bilaterally in the left and right supratemporal lobes, specifically in the auditory cortex. It is the orientation of these temporal generators, as well as the presence of MMN generators in the frontal lobes that results in MMN amplitude being maximal at fronto-central sites (Näätänen et al., 2007). In the majority of studies, the MMN is generated by randomly inserting a single low-probability (i.e. rare) deviant auditory stimulus into a train of repetitive (i.e. standard) sounds. The recently developed “Optimum-1” multi-feature MMN paradigm (Näätänen et al., 2004), however, elicits MMNs to five different pure-tone deviant types (frequency, duration, intensity, location and gap) in a relatively short period of time. Given the advantage in efficiency over the traditional oddball design, the multi-feature MMN paradigm has been employed recently in clinical research, notably in schizophrenia (Fisher et al., 2008a; Thönnessen et al., 2008). However, of these five deviant types, frequency, duration and intensity deviants (obtained from auditory oddball paradigms) are overall most often reported in MMN literature, leading to the development of the even shorter Optimal-3 (i.e. 3-deviant) version of the multi-feature MMN paradigm (Fisher et al., 2011a). MMN abnormalities are marked in schizophrenia (Näätänen and Kähkönen, 2009) and appear to be specific to this disorder, as no consistent MMN alterations have been observed in any of the other major
psychiatric disorders (Catts et al., 1995; Umbricht et al., 2003). Deficits in MMN generation were first reported by Shelley et al. (1991), who found significant reductions in MMN amplitude to a duration deviant paradigm in schizophrenia patients. Since this study, abundant corroborating research has confirmed a systematic and robust neurophysiological attenuation of the MMN amplitude in schizophrenia populations to duration and, to a lesser degree, frequency deviants (Javitt et al., 1995; Javitt et al., 1998; Michie, 2001; Umbricht and Krljes, 2005; Fisher et al., 2008a; Fisher et al., 2008b; Todd et al., 2008; Näätänen and Kähkönen, 2009; Dulude et al., 2010; Horton et al., 2011; Rasser et al., 2011). Recent efforts have attempted to characterize deficits to other deviant types, such as intensity. Todd et al. (2008) found that only patients examined early in the course of their illness demonstrate significant MMN reduction to intensity deviants, while patients with longer lengths of illness show no reduction in intensity MMNs vs. age matched controls. Fisher et al. (2008a) also reported an attenuated intensity MMN in chronic patients, but only in those with auditory hallucinations. Recently, studies examining MMN in schizophrenia have begun to look at the effects of the associated syndromes or symptoms, including whether AVHs make a unique contribution to the overall deficit in MMN generation (Oades et al., 1996; Hirayasu et al., 1998; Schall et al., 1999; Youn et al., 2002; Fisher et al., 2008a; Fisher et al., 2008b; Fisher et al., 2011b). Overall, these efforts have tended to focus on correlations between MMN amplitude and self-report measures of hallucinations with uneven results, though the three studies that did find significant correlations reported that as measures of hallucinations increase there is a corresponding decrease in MMN amplitude (Hirayasu et al., 1998; Youn et al., 2002; Fisher et al., 2011b). In one study that directly compared schizophrenia patients with clear, persistent auditory hallucinations to those with no auditory hallucinations, it was reported that hallucinating patients showed reduced MMN amplitude to duration (vs. healthy controls and non-hallucinating patients) and intensity deviants (vs. healthy controls), while non-hallucinating patients were not significantly different from healthy controls (Fisher et al., 2008a). These findings corroborate the suggestion that auditory hallucinations compete with incoming external stimuli for finite resources in the auditory cortex (Woodruff, 2004), resulting in reduced MMN amplitudes. The mismatch negativity, despite being predominantly moderated by ‘bottom-up’ processes, also appears to some degree, under specific conditions, sensitive to ‘top-down’ processes including the availability of attentional resources. High demand auditory processing tasks result in a significant decrease in MMN amplitude; as more resources are required for processing of a primary task, there is a corresponding drop-off in resources available to the MMN generator (Kramer et al., 1995). The lowered effectiveness of the generator is seen in the reduction of MMN amplitude. The revised ‘stimulus-filter’ hypothesis of smoking suggests that nicotine increases available processing resources, particularly those implicated in stimulus encoding, through its action on locus coeruleus noradrenergic cells (Kassel, 1997). If this is indeed the case, one might expect nicotine to enhance the processing of taskindependent stimuli without any decrement in primary task performance. In this way, administration of nicotine may free up resources in the auditory cortex in order to facilitate processing of auditory change detection (as indexed by the MMN), even in the presence of resource-demanding auditory hallucinations. Studies on the effects of smoking/nicotine on MMN in healthy controls have produced rather consistent findings. Positive effects of acute nicotine treatment have been shown in studies reporting moderate improvements in auditory MMN with increased MMN amplitude in smokers using a roving paradigm (Baldeweg et al., 2006), increased MMN amplitudes with a complex consonant–vowel deviant passive paradigm in smokers and non-smokers (Harkrider and Hedrick, 2005), increased MMN amplitudes with an interstimulus interval duration deviant paradigm in both smokers and non-smokers (Martin et al.,
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
2009), and increased MMN amplitude and reduced latency to frequency deviants in non-smokers administered an acute dose of a nicotinic acetylcholine receptor (nAChR) agonist (Dunbar et al., 2007). There is limited literature exploring the moderating effects of nicotine on MMN in schizophrenia, with one study having used doubleblind transdermal administration of nicotine and reporting shortened MMN latencies in non-smoking healthy controls, but not in nonsmoking schizophrenia patients (Inami et al., 2007). These results were consistent with a previous study (Inami et al., 2005), where MMN latency was shortened in non-smoking healthy controls using a double-blind transdermal administration of nicotine. In a more recent study, Dulude et al. (2010) reported enhancement of duration MMN amplitude with a high dose (8 mg) of nicotine in patients with schizophrenia, while nicotine had no effect on frequency MMN. 1.1. Study objectives and hypotheses In schizophrenia, AVHs appear to usurp cognitive resources at the expense of resources that are normally directed at external reality monitoring (Woodruff, 2004), possibly due to a tonic "tuning" or processing preference to AVHs (Ford et al., 2009). As MMN amplitude in SZ is positively correlated with global functioning (Wynn et al., 2010), interventions that can address MMN deficits in schizophrenia, and particularly during AVHs, may represent a viable approach for understanding and treating cognitive deficits in this disorder, which impede daily functional living. In hallucinating patients, nicotine agonist actions at the α-7 nAChR receptor may be a mechanism that can normalize aberrant processing within the auditory cortex directly by inhibiting neuronal activation underlying AVHs and/or indirectly by enhancing the detection of changes in external acoustic stimulation. The aims of this study were two-fold: first, we wished to compare the effects of a single dose of nicotine (vs. placebo) on acoustic change detection (MMN) within a modified three-deviant (frequency, duration and intensity) multi-feature paradigm and self-reports of AVHs. Secondly, as MMN amplitude has been negatively correlated with AVH symptom intensity in three previous studies and given the high smoking rates seen in schizophrenia patients, we wished to probe the relationship between MMN amplitudes and AVH symptoms under conditions of nicotine administration. Specifically, we will test the hypothesis that in SZ patients, nicotine (relative to placebo) will increase frontal MMN amplitudes and reduce self-reported AVHs, with the degree of nicotine-induced increase in the MMN being associated with the degree of nicotine-induced reduction in AVHs. 2. Materials and methods 2.1. Participants Twelve patient volunteers, all presenting with a primary diagnosis of schizophrenia, were recruited from the Outpatient Schizophrenia Clinic of the Royal Ottawa Mental Health Centre (ROMHC). During an initial clinical interview (with the primary care physician) in which volunteers were assessed with respect to inclusion and exclusion criteria, both clinical history and ratings on the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1989) for schizophrenia were used for recruitment. For study inclusion, all patients reported a definite, consistent history of AHs over the course of their illness, exhibiting a score ≥ 3 (mild or greater hallucinatory experiences) on the hallucination item of the PANSS positive symptom scale. The tendency to experience AVHs was subsequently confirmed by a study investigator (DF), who rated the patients on the AVH subscale of the Psychotic Symptom Rating Scale (PSYRATS; Haddock et al., 1999). This 11-item, 5-point (0–4) rating scale assesses trait hallucinations across several dimensions, including frequency, duration and intensity of distress. Of the 12 participants, 7 were current smokers with an average consumption of 27.71 cigarettes per day (S.D. = 15.18; range = 8–50 cigs/day) and a Fagerström Test of Nicotine Dependence (FTND; Heatherton et al., 1991) score of 7.86 (S.D. = 2.42; range = 5–11), indicating high-to-very high addiction. A summary of participant characteristics is given in Table 1. 2.1.1. Inclusion criteria All patients were required to be primarily right-handed, as indicated by a score greater than 0.5 on the Edinburgh Handedness Inventory (EHI; Oldfield, 1971), between the ages of 18 and 65 (actual range: 28–57 y.o.), and to have a primary DSM-
183
Table 1 Summary of participant demographics and trait questionnaires (mean ± S.D.). Patients Age Years of education PSYRATS PANSS positive symptom PANSS negative symptom PANSS hallucination item PANSS general psychoticism
41.31 13.8 25.92 21.55 19.82 4.00 40.82
(9.66) (1.07) (6.84) (3.88) (5.40) (0.48) (9.18)
IV TR diagnosis of schizophrenia, paranoid subtype, as assessed with Structured Clinical Interview DSM-IV Psychotic Screen (SCID-P) by their primary care physician. Patients also had to be clinically stable for the 4 weeks prior to testing, having no significant changes in symptoms or medications. Patients' primary medication was limited to one of the atypical anti-psychotics. All participants were required to understand spoken and written English, although English did not need to be their first language. Normal hearing via audiometric assessment was a requirement and was evidenced by auditory sound pressure level (SPL) thresholds of 25 dB or less (using a ‘descending method of limits' procedure) to pure tones of 500 Hz, 1000 Hz, and 2000 Hz. 2.1.2. Exclusion criteria Participants were excluded if they met any of the following criteria: co-morbid Axis I disorder as defined by DSM-IV TR criteria; current history of drug abuse or dependence; head injury resulting in the loss of consciousness within the last year; a neurologic disorder including epilepsy; primary treatment with a first generation neuroleptic such as haloperidol; electro-convulsive therapy (ECT) treatment within the last year; significant cardiac illness; extrapyramidal symptoms (EPS) resulting in movement disorders which would disrupt the ERP recordings; or audiometric assessment significantly above 25 dB (SPL) on each level of pure tones. 2.2. Study design Patient participants were assessed within a randomized, double-blind, placebo controlled crossover design involving two test sessions, one with nicotine treatment and the other with placebo treatment. Randomly selected, half of the patients received the placebo first and nicotine second, while the other half received treatment in the reverse order. Sessions were separated by approximately 7 days, with antipsychotic/adjunct medications being kept constant during this time span. 2.3. Study procedure Testing was conducted around midday (11:00 am–2:00 pm) with participants being required to abstain from illicit drugs, medications, and alcohol beginning at midnight of the previous day. Participants were also instructed to abstain from both caffeine and cigarettes for at least an hour prior to the session. Upon arrival at the laboratory, following self-report of adherence to pre-testing abstinence, participants completed demographic questionnaires and underwent audiometric assessment. Following this, EEG electrodes were applied and nicotine or placebo gum was administered. Volunteers were assessed using a modified 3-deviant version (Fisher et al., 2011a) of the multi-feature MMN paradigm (Näätänen et al., 2004), during which they were instructed to view a silent, neutral emotive video and to ignore the presented auditory stimuli. All testing procedures were carried out in accordance with the Declaration of Helsinki and following the approval of the research ethics board of the Royal Ottawa Health Care Group. 2.3.1. Nicotine Nicotine was administered in the form of two pieces of cinnamon flavored nicotine polacrilex gum (Nicorette brand [Johnson & Johnson, Inc.]): one 4 mg (Nicorette Plus ®) and one 2 mg (Nicorette ®) piece. The 6 mg of nicotine was expected to produce a plasma nicotine concentration of ~ 15–30 ng/ml (Hukkanen et al., 2005), which is approximately equal to the amount one would expect from smoking a single cigarette of average nicotine yield. The placebo gum pieces were similar in taste, texture and size to the treatment gum, but contained no nicotine. Gum pieces in both conditions were chewed for a 25 minute period, as per the directions of the manufacturer (i.e., biting twice every 2 min and then ‘parking’ the gum between the teeth and cheek between bites). Peak blood nicotine levels are typically achieved after 25–30 min of the gum chewing; normal nicotine elimination half-life is approximately 120 min. Following testing, participants indicated the presence or absence of side effects to the nicotine treatment using the Checklist of Nicotine-Related Symptoms, which measures adverse events (Harkrider and Hedrick, 2005). Additionally, in order to determine the efficacy of the double-blind, patients were asked to indicate whether they thought they had received nicotine or placebo gum. Only three out of the ten patients asked were able to correctly determine whether they had received nicotine or placebo.
184
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
Patients also completed questionnaires relating to craving, using the 32-item Questionnaire on Smoking Urges (QSU; Tiffany and Drobes, 1992), and smoking withdrawal, using the Smoking Withdrawal Symptoms Checklist (SWSC; Hughes and Hatsukami, 1986), in order to monitor subjective effects of nicotine abstinence. 2.3.2. Auditory stimuli The auditory stimuli and task were exactly the same as the modified 3-stimulus version of the multi-feature MMN paradigm and have been previously described elsewhere (Fisher et al., 2011a). Briefly, the task presented only frequency, duration and intensity deviants within a sequence whereby every second tone was a standard (P = 0.5) and every other one was one of the three deviants (P = 0.17 each), with the exception of the first 15 tones, which were all standards. All stimuli were presented binaurally through headphones and at a sound pressure level (SPL) of 70 dB (with the exception of the intensity deviants) with equal phase intensity in each channel. The stimuli were presented in three sequences of 3 min each (366 stimuli) for a total of 9 min (1098 stimuli). 2.3.3. ERP recording and computation MMNs were extracted from EEG activity recorded with an electrode cap positioning Ag+/Ag+-Cl− ring electrodes at 32 scalp sites according to the 10–10 system of electrode placement, including three frontal scalp sites (midline [FZ], left [F3], right [F4]). Electrodes were also used to record left (LM) and right (RM) mastoid activity and electrodes were placed on the mid-forehead and nose to serve as ground and reference, respectively. Bipolar recordings of horizontal (HEOG) and vertical (VEOG) electrooculogram activity were taken from supra-/sub-orbital and external canthi sites, respectively. All electrode impedances were kept below 5 kΩ. Electrical activity was recorded using BrainVision Recorder software and a BrainVision Quickamp amplifier (Brain Products GmbH, Munich DE) with bandpass settings of 0.1 and 100 Hz, digitized at 500 Hz, and stored on hard-disk for later off-line analysis using BrainVision Analyzer software (Brain Products GmbH, Munich DE). EEG epochs (500 ms duration, beginning 100 ms pre-stimulus) were corrected for residual eye movement and eye blink activity using the Gratton and Coles algorithm, which operates in the time and frequency domain (Gratton et al., 1983); any corrected epochs with EEG voltages exceeding ± 100 μV were excluded from further analysis. Within the multi-feature paradigm, epochs were separately averaged for each standard and deviant stimulus type and then digitally filtered using a bandpass of 0.15–8 Hz (Leung et al., 2006) and a slope of 24 db/octave. The narrow band pass, previously used in studies of the multi-feature MMN (Fisher et al., 2008a, 2011a, 2011b), eliminates any extraneous high-frequency muscular or eye-twitch activity that may generate artifacts. MMN difference waveforms were derived from point-by-point digital subtraction of the standard stimulus values from those elicited by the deviant stimulus. MMN peaks were obtained by quantifying peak negative amplitudes within a window of 80–220 ms; this window was chosen based on a visual inspection of the waveforms. Prior to peak picking, individual visual assessment of the presence of the true MMN (as indicated by appropriate polarity inversion at mastoids) was conducted within each participant for each deviant type. MMN peaks for each individual participant were picked for each deviant type as the most negative point within the analysis window and output was the average within five voltage points (10 ms) to the left and right of the peak amplitude. MMN latency measurements were only measured at FZ, the site of maximum amplitude. 2.3.4. Hallucination state ratings (HSR) Upon completion of the MMN paradigm, patients completed a rating scale, similar to that used by Margo et al. (1981), asking them to indicate the nature of their hallucinations experienced during the recordings on 5 dimensions: 1) duration (1 = no AVHs, 7 = continuous AVHs); 2) loudness (1 = not audible, 7 = extremely loud); 3) clarity (1 = unintelligible, 7 = very clear); 4) distress (1 = not distressing, 5 = very distressing); and 5) control (1 = complete control over voices, 7 = no control over voices).
Where appropriate, Huynh–Feldt epsilon correction factors were applied to the degrees of freedom and the rounded adjusted degrees of freedom have been reported. Regardless of the presence or absence of significant main or interaction effects, planned comparisons involving within-group comparisons of drug effects on MMN amplitude with respect to laterality and region, as well as MMN latency, were carried out. Significant (p b 0.05) effects were followed-up with pairwise comparisons for greater specificity in reporting. In order to examine the correlations between treatment, MMN amplitude and state and trait hallucination severity, two-way Spearman's rho correlations were conducted between change (nicotine–placebo) in MMN amplitude at frontal sites and change (nicotine–placebo) in state hallucination measures (HSRs). Correlations between MMN amplitude change and trait (PSYRATS, PANSS) scores were also performed to describe any significant relationship with hallucination trait, positive symptom, negative symptom and general psychopathology scores. Similar analyses were performed for MMN latency. Finally, an exploratory analysis used two-way Spearman's rho correlations to investigate the relationship between nicotine use (cigarettes per day, FTND scores) and hallucinations (HSRs, PSYRATS).
3. Results 3.1. MMN amplitude There were no significant MMN amplitude differences across the treatment conditions (placebo vs. nicotine) for duration, intensity or frequency deviants, nor was there a significant difference in amplitude between MMN deviants (i.e. duration = intensity = frequency). 3.2. MMN latency A significant shortening of latency was found (Fig. 1) for intensity deviants in the nicotine condition (mean = 144.95 ms, S.E. ± 39.35), compared to the placebo condition (mean = 160.39 ms, S.E ± 36.13; P = 0.048). There were no main or interaction effects. 3.3. Hallucination state ratings A paired-samples t-test was used to investigate the change in scores of the patients' subjective ratings of their hallucinations during the task between placebo and treatment conditions, however nicotine did not significantly alter any dimension of AVH state. 3.4. Correlations Nicotine induced change in amplitude of intensity MMN at FZ was negatively correlated (i.e. MMN increases as HSR increases) with change in the clarity (ρs = −0.702, P = 0.024) of hallucinations (Fig. 2).
2.3.5. Self-reports A physical symptoms checklist used by Harkrider and Hedrick (2005) was employed to measure the severity of nicotine-related adverse symptoms. Participants were instructed to indicate the severity of their symptoms on a five-point scale (0 = no symptoms, 4 = extreme symptoms). Symptoms included such events as heartpounding, headache, dizziness, and nausea. 2.3.6. Vital signs Systolic blood pressure (SBP), diastolic blood pressure (DBP) (mm Hg) and heart rate (HR; beats per min; bpm) were assessed before and after gum administration while participants were sitting (semi-reclined) without task involvement. 2.4. Data analysis Analyses of MMN amplitudes and latencies were carried out using the Statistical Package for the Social Sciences (SPSS; IBM Corp., Armonk, NY). MMN amplitudes were subjected to repeated measures general linear model (GLM) procedures with three within-subjects factors (treatment [placebo or nicotine], deviant [duration, pitch and intensity] and electrode site [limited to F3, FZ and F4]). MMN latencies, derived only from FZ (the site of maximum amplitude), were subjected to a similar analysis, however electrode site was not included as a factor.
Fig. 1. MMN latencies to duration, frequency and intensity deviants for nicotine and placebo treatment conditions.
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
185
4. Discussion
Fig. 2. Scatterplot illustrating the negative correlation (ρs = − 0.70, P = 0.024) between change (nicotine–placebo) in MMN amplitude to intensity deviants and change (nicotine–placebo) in subjective appraisal in AVH clarity.
Exploratory analysis of the link between AVHs and smoking behavior with a two-tailed Spearman's rho test (Fig. 3) showed that number of cigarettes smoked per day was positively correlated with PSYRATS scores (ρs = 0.76, P = 0.050).
3.5. Withdrawal/craving ratings A two-tailed paired samples t-test comparing placebo and nicotine session scores found no significant differences with respect to SWSC and QSU values.
3.6. Vital signs Paired sample t-tests were performed for each of systolic BP, diastolic BP and pulse values post-treatment, with findings showing that diastolic blood pressure significantly differed across treatments, t (d.f. = 11) = −2.53, P = 0.028. Specifically, diastolic BP was greater following nicotine administration (mean = 79.42, S.E. = 9.21) compared to placebo (mean = 71.54, S.E. = 12.30). There were no significant effects of treatment for systolic blood pressure or pulse.
Fig. 3. Scatterplot illustrating the positive correlation (ρs = 0.76, P = 0.50) between number of cigarettes smoked per day and AVH trait score (as measured by the PSYRATS).
In this study, the presumed enhancement of auditory sensory processing with nicotine in schizophrenia patients with persistent AVHs was explored using frequency, duration, and intensity MMN. We failed to detect any effects of nicotine on amplitude, although latency was significantly shortened to intensity deviants. Furthermore, it appears that nicotine-related increases in intensity MMN amplitude are associated with increases in subjective clarity of AVHs. The hypothesis that nicotine treatment would significantly increase MMN amplitudes compared to those during placebo condition was not met. Despite this, our null treatment findings regarding frequency MMN amplitude are in agreement with those from Inami et al. (2007), who also examined nicotine's effects in schizophrenial, albeit using a slightly different methodology (including using only inpatients, transdermal nicotine administration, and non-smokers). In addition to frequency MMN explored by Inami et al. (2007), this study also examined duration and intensity MMN, although both of these failed to exhibit a significant change in amplitude between treatment sessions. The findings of this study are in contrast to those of Dulude et al. (2010), who reported an enhancement of duration MMN amplitude following nicotine administration. It must be noted, however, that the previous study used a two-stimulus auditory oddball paradigm (vs. a modified multi-feature paradigm) with ideal study parameters to determine treatment differences, including a very low deviant probability (5%) and high dosage of nicotine (8 mg). Additionally, the differences observed may stem from the schizophrenia populations used; while Dulude et al. studied MMN in a general schizophrenia population, the present study specifically employed schizophrenia patients with current and persistent auditory hallucinations. MMN latency to intensity MMN significantly decreased (vs. placebo) in schizophrenia patients following acute nicotine treatment. This observation lends support to previously reported findings that MMN latency decreases following acute nicotine treatment (Baldeweg et al., 2006; Inami et al., 2007), although this is the first study to report a decrease in MMN latency in schizophrenia patients. Consistent with Inami et al. (2007), we found no change in latency to pitch deviants in schizophrenia following nicotine treatment, as well as no reduction in latency to duration deviants. It would seem nicotine can accelerate automatic processing of intensity deviants in patients, although why this effect is seen only in intensity deviants will need to be explored further in follow up studies. Frequency, intensity, and duration MMN appear to be activated by different neural generators and it is possible that nicotine at the current dose level (6 mg) differentially affects the cortical sources underlying intensity deviance detection (Giard et al., 1995). Applying the stimulus-filter hypothesis (Kassel, 1997), it is possible that acute nicotine administration normalizes neural systems specific for processing intensity deviants by helping schizophrenia patients to screen irrelevant stimuli (AVHs) from awareness; this would free up auditory cortical resources normally usurped by AVHs for the processing of change detection, as indexed by the MMN. In this way, screening out AVHs may result in increased processing resources for relevant stimuli (deviants) and, therefore, a shortening in intensity MMN latency. In addition to MMN amplitude and latency, subjective hallucination state rating scale scores were investigated to find potential subjective effects of nicotine over and above neurophysiologic measures. Contrary to our hypothesis, nicotine did not significantly affect any of the HSR ratings. This may, however, be due in part to the relatively modest hallucinatory activity experienced by participants, creating a floor effect that would minimize our ability to see treatment-related change. While there was a significant nicotine-related correlation between measures of MMN change and AVH change, it was in the opposite direction of that predicted in our hypotheses. Specifically, as frontal
186
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187
midline intensity MMN amplitude increased, so did the perceived clarity of AVHs. Nicotine has been previously shown to enhance cortical excitability in the auditory cortex (Knapp and Domino, 1962; Harkrider and Champlin, 2001), the site of both MMN (Näätänen and Ahlo, 1997) and auditory hallucination generation (Woodruff, 2004). We suggest that, under such conditions of modest AVH activity, nicotine induces a general increase in auditory cortex activity, resulting in an enhanced MMN as well as increased subjective measures of AVH experience, particularly AVH clarity. Perhaps the most interesting, albeit exploratory, finding is that the number of cigarettes smoked per day is positively correlated with PSYRATS scores, suggesting that greater AVH trait scores are associated with greater tobacco consumption. This lends further credence to the suggestion that schizophrenia patients smoke as a form of selfmedication, particularly to gate out irrelevant stimuli (such as auditory hallucinations) and focus attention (Kumari and Postma, 2005; Evans and Drobes, 2008). Conversely, given our findings that nicotine exacerbates particular dimensions of AVH states while enhancing MMN, it may be that increased smoking may increase the propensity to experience AVHs. Certainly, further research must be undertaken to clarify this issue. Blood pressure and pulse were measured in this study to verify patients were symptomatic to nicotine treatment. It has been previously documented that nicotine increases both blood pressure and pulse (Sjoberg and Saint, 2011; Wignall and de Wit, 2011), and, consistent with these previous reports, we observed an increase in diastolic blood pressure following nicotine administration. This suggests adequate absorption of the drug and the use of a sufficiently high enough dose to exert central effects, indicating that the lack of MMN amplitude and HSR results are not due to an absence of nicotine's biological effects. There are a number of limitations in the study that temper the study findings. According to Evans and Drobes (2008), easy to perform tasks may sometimes fail to detect nicotine effects and so by incorporating a task with multiple difficulty levels, one can better assay the effects of nicotine. A related confounding issue with our study may have been that the distraction task during MMN recording might not have garnered enough attention from participants and they may have focused on the tones (despite instructions informing participants to ignore them and focus on the movie). Perhaps using a standardized visual performance task (as opposed to a video), where attention could be reliably and quantifiably directed on the distraction task, would be a more suitable methodological option that would ensure a pure memory-based MMN recording that is not contaminated by attention. Other limitations of this study were the lack of adjustment made to nicotine dosage based on participant body weight, as well as neglecting to account for individual differences in nicotinic absorption by analyzing blood samples of nicotine levels, which are variable in each person and can be modified by age and prolonged cigarette usage. In the future, the use of a nasal spray vehicle instead of gum may also prove to be a more effective route of administration, as a nasal spray more closely resembles the rapid absorption seen with smoke inhalation (Lerman and Niaura, 2002). The variability of smoking habits in participants could be a strong confounding factor on whether the treatment had much effect. For participants who smoke a great deal, the 6 mg dose may have had little to no effect, while it may have had a very strong effect on those who smoke very little. Future research should endeavor to separate patients into groups of high, low, and non-smokers to test the effects of 6 mg dose of nicotine on MMN generation or at the very least, use participants with similar smoking behavior. Lastly, the lack of biochemical confirmation of abstinence from caffeine, alcohol, cigarettes, and drugs remains a limitation of this study. In conclusion, our results show a nicotine-induced reduction of intensity MMN latency in schizophrenia with trait AVHs and illustrate previously unknown correlations between AVHs and deficits in MMN amplitude and their change with acute nicotine treatment. It
can be argued that these relationships are the result of nicotine's direct actions at nAChR receptor systems within the auditory cortex, which may have also led to reduced latency times. This study complements a previous report of nicotine-induced MMN latency reduction in schizophrenia (Inami et al., 2007). Acknowledgments We would like to thank Dr. Risto Näätänen and his lab for supplying the auditory stimuli used in this study. This project was supported by a Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral) from the Canadian Institutes of Health Research (CIHR) awarded to DF. References Adler, L.E., Hoffer, D.L., Wiser, A., Freedom, R., 1993. Normalization of auditory physiology by cigarette smoking in schizophrenia patients. The American Journal of Psychiatry 150, 1856–1861. Anfang, M.K., Pope Jr., H.G., 1997. Treatment of neuroleptic-induced akathisia with nicotine patches. Psychopharmacology 134, 153–156. Baldeweg, T., Wong, D., Stephan, K.E., 2006. Nicotinic modulation of human auditory sensory memory: evidence from mismatch negativity potentials. International Journal of Psychophysiology 59, 49–58. Cadenhead, K.S., Braff, D.L., 1999. Schizophrenia spectrum disorders. In: Dawson, M.E., Schell, A.M., Bohmelt, A.H. (Eds.), Startle Modification: Implications for Neuroscience, Cognitive Science, and Clinical Science. Cambridge University Press, Cambridge, pp. 231–244. Catts, S.V., Shelley, A.M., Ward, P.B., Liebert, B., McConaghy, N., Andrews, S., Michie, P.T., 1995. Brain potential evidence for an auditory sensory memory deficit in schizophrenia. The American Journal of Psychiatry 152, 213–219. de Leon, J., Diaz, F.J., Rogers, T., Browne, D., Dinsmore, L., 2002. Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders. Schizophrenia Research 56, 47–54. Dulude, L., Labelle, A., Knott, V.J., 2010. Acute nicotine alteration of sensory memory impairment in smokers with schizophrenia. Journal of Clinical Psychopharmacology 30, 541–548. Dunbar, G., Boeijinga, P.H., Demazières, A., Cisterni, C., Kuchibhatla, R., Wesnes, K., Luthringer, R., 2007. Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191, 919–929. Evans, D.E., Drobes, D.J., 2008. Nicotine self-mediation of cognitive-attentional processing. Addiction Biology 14, 32–42. Fisher, D.J., Labelle, A., Knott, V.J., 2008a. The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multifeature paradigm. Clinical Neurophysiology 119, 919–921. Fisher, D.J., Labelle, A., Knott, V.J., 2008b. Auditory hallucinations and the mismatch negativity: processing speech and non-speech sounds in schizophrenia. International Journal of Psychophysiology 70, 3–15. Fisher, D.J., Grant, B., Smith, D.M., Knott, V.J., 2011a. Effects of deviant probability on the ‘optimal’ multi-feature mismatch negativity (MMN) paradigm. International Journal of Psychophysiology 79, 311–315. Fisher, D.J., Grant, B., Smith, D.M., Borracci, G., Labelle, A., Knott, V.J., 2011b. Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified ‘optimal’ multi-feature paradigm. International Journal of Psychophysiology 81, 245–251. Ford, J.M., Roach, B.J., Jorgensen, K.W., Turner, J.A., Brown, G.G., Notestine, R., BischoffGrethe, A., Greve, D., Wible, C., Lauriello, J., Belger, A., Mueller, B.A., Calhoun, V., Preda, A., Keator, D., O'Leary, D.S., Lim, K.O., Glover, G., Potkin, S.G., FBIRN, Mathalon, D.H., 2009. Tuning in to the voices: a multisite fMRI study of auditory hallucinations. Schizophrenia Bulletin 35, 58–66. Friedman, J., Horvath, T., 1974. Tobacco smoking and a stimulus barrier. Nature 248, 455–456. Giard, M., Lavikainen, J., Reinikainen, K., Perria, F., Bertrand, O., Pernier, J., Näätänen, R., 1995. Separate representations of stimulus, frequency, intensity and duration in auditory sensory memory: an event-related potential and dipole-model analysis. Journal of Cognitive Neuroscience 7, 133–143. Gratton, G., Coles, M.G., Donchin, E., 1983. A new method for off-line removal of ocular artifact. Electroencephalography and Clinical Neurophysiology 55, 468–484. Haddock, G., McCarron, J., Tarrier, N., Faragher, E.B., 1999. Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychological Medicine 29, 879–888. Harkrider, A.W., Champlin, C.A., 2001. Acute effect of nicotine on non-smokers: II. MLRs and 40-Hz responses. Hearing Research 160, 89–98. Harkrider, A.W., Hedrick, M.S., 2005. Acute effect of nicotine on auditory gating in smokers and non-smokers. Hearing Research 202, 114–128. Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., Fagerström, K.O., 1991. The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86, 1119–1127. Hillyard, S.A., Kutas, M., 1983. Electrophysiology of cognitive processing. Annual Review of Psychology 34, 33–61.
D.J. Fisher et al. / Psychiatry Research 196 (2012) 181–187 Hirayasu, Y., Potts, G.F., O'Donnell, B.F., Kwon, J.S., Arakaki, H., Akdaq, S.J., Levitt, J.J., Shenton, M.E., McCarley, R.W., 1998. Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage. The American Journal of Psychiatry 155, 1281–1283. Hong, L.E., Schroeder, M., Ross, T.J., Buchholz, B., Salmeron, B.J., Wonodi, I., Thaker, G.K., Stein, E.A., 2011. Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia. Schizophrenia Bulletin 37, 416–425. Horton, J., Millar, A., Labelle, A., Knott, V.J., 2011. MMN responsivity to manipulations of frequency and duration deviants in chronic, clozapine-treated schizophrenia patients. Schizophrenia Research 126, 202–211. Hughes, J.R., Hatsukami, D., 1986. Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry 43, 289–294. Hukkanen, J., Jacob III, P., Benowitz, N.L., 2005. Metabolism and disposition kinetics of nicotine. Pharmacology Review 57, 79–115. Inami, R., Kirino, E., Inoue, R., Arai, H., 2005. Transdermal nicotine administration enhances automatic auditory processing reflected by mismatch negativity. Pharmacology, Biochemistry and Behaviour 80, 453–461. Inami, R., Kirino, E., Inoue, R., Suzuki, T., Arai, H., 2007. Nicotine effects on mismatch negativity in nonsmoking schizophrenic patients. Neuropsychobiology 56, 64–72. Janhunen, S., Ahtee, L., 2007. Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: implications for drug development. Neuroscience and Biobehavioural Reviews 31, 287–314. Javitt, D.C., Doneshka, P., Grochowski, S., Ritter, W., 1995. Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Archives of General Psychiatry 52, 550–558. Javitt, D.C., Grochowski, S., Shelley, A.M., Ritter, W., 1998. Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval. Electroencephalography and Clinical Neurophysiology 108, 143–153. Kassel, J.D., 1997. Smoking and attention: a review and reformulation of the stimulusfilter hypothesis. Clinical Psychology Review 17, 451–478. Kay, S.R., Opler, L.A., Lindenmeyer, J.P., 1989. The positive and negative syndrome scale (PANSS): rationale and standardization. The British Journal of Psychiatry 155 (Suppl 7), 59–65. Kelly, C., McCreadie, R.G., 1999. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland. The American Journal of Psychiatry 156, 1751–1757. Knapp, D.E., Domino, E.F., 1962. Action of nicotine on the ascending reticular activating system. International Journal of Neuropharmacology 1, 333–351. Knott, V.J., Venables, P.H., 1978. Stimulus control and the cortical evoked response in smokers and non-smokers. Psychophysiology 15, 186–192. Kramer, A.F., Trejo, L.J., Humphrey, D., 1995. Assessment of mental workload with taskirrelevant auditory probes. Biological Psychology 40, 83–100. Kumari, V., Postma, P., 2005. Nicotine use in schizophrenia: the self medication hypotheses. Neuroscience and Biobehavioural Reviews 29, 1021–1034. Kumari, V., Soni, W., Sharma, T., 2001. Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Human Psychopharmacology and Clinical Experience 16, 321–326. Leonard, S., Gault, J., Hopkins, J., Logel, J., Vianzon, R., Short, M., Drebing, C., Berger, R., Venn, D., Sirota, P., Zerbe, G., Ollincy, A., Ross, R.G., Adler, L.E., Freedman, R., 2002. Association of promoter variants in the a7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrena. Archives of General Psychiatry 59, 1085–1096. Lerman, C., Niaura, R., 2002. Applying genetic approaches to the treatment of nicotine dependence. Oncogene 21, 7412–7420. Leung, S., Croft, R.J., Guille, V., Nathan, P.J., 2006. The effects of digital filtering on duration MMN. Presented at the 4th Conference on Mismatch Negativity and Its Clinical and Scientific Applications, Cambridge UK, April 22–26. Margo, A., Helmsley, D.R., Slade, P.D., 1981. The effects of varying auditory input on schizophrenia hallucinations. The British Journal of Psychiatry 139, 122–127. Martin, L.F., Davalos, D.B., Kisley, M.A., 2009. Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform. Nicotine & Tobacco Research 11, 698–706. Michie, P., 2001. What has MMN revealed about the auditory system in schizophrenia? International Journal of Psychophysiology 42, 177–194. Milailescu, S., Drucker-Colin, R., 2000. Nicotine and brain disorders. Acta Pharmacologica Sinica 21, 97–104. Näätänen, R., 1992. Attention and Brain Function. Lawrence Earlbaum Associates, Hillsdale, NJ. Näätänen, R., 2003. Mismatch negativity: clinical research and possible applications. International Journal of Psychophysiology 48, 179–188.
187
Näätänen, R., Ahlo, K., 1997. Mismatch negativity — the measure for central sound represenation accuracy. Audiology & Neuro-Otology 2, 341–353. Näätänen, R., Kähkönen, S., 2009. Central auditory dysfunction in schizophrenia as revealed by the mismatch negativity (MMN) and its magnetic equivalent MMNm: a review. The International Journal of Neuropsychopharmacology 12, 125–135. Näätänen, R., Pakarinen, S., Rinne, T., Takegata, R., 2004. The mismatch negativity (MMN) — towards the optimal paradigm. Clinical Neurophysiology 115, 140–144. Näätänen, R., Paavilainen, P., Rinne, T., Alho, K., 2007. The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clinical Neurophysiology 118, 2544–2590. Newhouse, P.A., Potter, A., Singh, A., 2004. Effects of nicotine stimulation on cognitive performance. Current Opinion in Pharmacology 4, 36–46. Oades, R., Zerbin, D., Dittman-Balcar, A., Eggers, C., 1996. Auditory event-related potential (ERP) and difference-wave topography in schizophrenia patients with/without active hallucinations and delusions: a comparison with young obsessive–compulsive disorder (OCD) and healthy subjects. International Journal of Psychophysiology 22, 185–214. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113. Olincy, A., Young, D.A., Freedman, R., 1997. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biological Psychiatry 42, 1–5. Rasser, P., Schall, V., Todd, J., Michie, P.T., Ward, P.B., Johnston, P., Helmbold, K., Case, V., Søyland, A., Tooney, P.A., Thompson, P.M., 2011. Gray matter deficits, mismatch negativity, and outcomes in schizophrenia. Schizophrenia Bulletin 37, 131–140. Sacco, K.A., Termine, A., Seval, A., Dudas, M.M., Vessichio, J.C., Krishnan-Sarin, S., Jatlow, P.I., Wexler, B.E., George, T.P., 2005. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Archives of General Psychiatry 62, 649–659. Schall, U., Catts, S.V., Karayanidis, F., Ward, P.B., 1999. Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow up. The International Journal of Neuropsychopharmacology 2, 83–93. Shelley, A.M., Ward, P.B., Catts, S.V., Michie, P.T., Andrews, S., McConaghy, N., 1991. Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biological Psychiatry 30, 1059–1062. Singh, A., Potter, A., Newhouse, P., 2004. Nicotinic acetylcholine receptor system and neuropsychiatric disorders. The Investigational Drugs Journal 7, 1096–1103. Sjoberg, N., Saint, D.A., 2011. A single 4 mg dose of nicotine decreases heart rate variability in healthy nonsmokers: implications for smoking cessation programs. Nicotine and Tobacco Research 13, 369–372. Strand, J.E., Nyback, H., 2005. Tobacco use in schizophrenia: a study of cotinine concentrations in the saliva of patients and controls. European Psychiatry 20, 50–54. Tanabe, J., Tregellas, J.R., Martin, L.F., Freedman, R., 2006. Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia. Biological Psychiatry 59, 754–761. Thönnessen, H., Zvyagintsev, M., Harke, K.C., Boers, F., Dammers, J., Norra, Ch., Mathiak, K., 2008. Optimized mismatch negativity paradigm reflects deficits in schizophrenia patients: a combined EEG and MEG study. Biological Psychology 77, 205–216. Tiffany, S.T., Drobes, D.J., 1992. The development and initial validation of a questionnaire on smoking urges. British Journal of Addiction 86, 1467–1476. Todd, J., Michie, P.T., Schall, U., Karayanidis, F., Yabe, H., Näätänen, R., 2008. Deviant matters: duration, frequency, and intensity deviants reveal different patterns of mismatch negativity reduction in early and late schizophrenia. Biological Psychiatry 63, 58–64. Uck, A., Polat, A., Bozkurt, O., Meteris, H., 2004. Cigarette smoking among patients with schizophrenia and bipolar disorders. Psychiatry and Clinical Neurosciences 58, 434–437. Umbricht, D., Krljes, S., 2005. Mismatch negativity in schizophrenia: a meta-analysis. Schizophrenia Research 76, 1–23. Umbricht, D., Javitt, D.C., Bates, J., Kane, J., Lieberman, J.A., 2003. How specific are deficits in mismatch negativity generation to schizophrenia? Biological Psychiatry 53, 1120–1131. Wignall, N.D., de Wit, H., 2011. Effects of nicotine on attention and inhibitory control in healthy nonsmokers. Experimental and Clinical Psychopharmacology 19, 183–191. Woodruff, P.W., 2004. Auditory hallucinations: insights and questions from neuroimaging. Cognitive Neuropsychiatry 9, 73–91. Wynn, S., Sugar, C., Horan, W., Kern, R., Green, M., 2010. Mismatch negativity, social cognition, and functioning in schizophrenia patients. Biological Psychiatry 67, 940–947. Youn, T., Park, H.-J., Kim, J.-J., Kim, M.S., Kwon, J.S., 2002. Altered hemispheric asymmetry and positive symptoms in schizophrenia: equivalent current dipole of auditory mismatch negativity. Schizophrenia Research 59, 253–260.