Normal N400 in mood disorders

Biological Psychology 71 (2006) 74–79 www.elsevier.com/locate/biopsycho

Normal N400 in mood disorders Patricia Deldin a,*, Jennifer Keller b, Brooks R. Casas c, Jennifer Best d, John Gergen e, Gregory A. Miller e a

University of Michigan, 525 E University, 2252 East Hall, Ann Arbor, MI 48109, USA b Stanford University, USA c Harvard University, USA d University of Southern California, USA e University of Illinois at Urbana-Champaign and Provena Covenant Medical Center, Urbana, IL, USA Received 23 November 2004; accepted 12 February 2005 Available online 10 May 2005

Abstract Individuals diagnosed with major depression have been characterized as having a variety of cognitive problems based on a number of behavioral and psychophysiological measures, but it is not clear whether there is a consistent language processing abnormality in depression. Three studies sought to determine whether diverse mood disordered samples show abnormal semantic processing, as indexed by a failure to show increased N400 event-related brain potential amplitudes to passively viewed incongruent, relative to congruent sentence endings. Individuals with major depression (N = 50) or dysthymia (N = 14) had N400 amplitudes similar to those of controls (N = 41) in this sentence processing paradigm. These results are consistent with a small behavioral literature suggesting intact semantic processing in depression and further indicate that abnormal controlled processing in some tasks does not simply reflect a generalized deficit. # 2005 Elsevier B.V. All rights reserved. Keywords: Major depression; Language; Semantic processing; N400; ERP; Dysthymia

1. Normal N400 semantic processing in mood disorders Cognitive theories of major depression, a severe mood disorder characterized by emotional (e.g. depressed mood), physical (e.g. weight changes), and cognitive impairments (e.g. memory problems), suggest that depressed people tend to show deficits on tasks that require sustained attention and larger amounts of cognitive capacity but that they are unimpaired on tasks requiring little or no effort or resources (e.g. Ellis and Ashbrook, 1988; Hertel and colleagues including Hertel, 1994; Hertel and Hardin, 1990; Hertel and Rude, 1991). These theories have generated much research and some empirical support. For example, depressed individuals do not appear to have deficits in automatic, preattentive processing (for review, see Hartlage et al., 1993). In contrast, they have been found to have impairment * Corresponding author. Tel.: +1 734 769 6011; fax: +1 734 615 0573. E-mail address: [email protected] (P. Deldin). 0301-0511/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.biopsycho.2005.02.005

on controlled processing tasks such as recall tasks (for review, see Ellis and Ashbrook, 1988). One area of cognition that has rarely been studied in this context is language. This is a surprising omission given that imaging studies utilizing positron emission tomography (PET) demonstrate that at resting individuals diagnosed with major depressive disorder (MDD) demonstrate abnormal blood flow in a number of brain regions involved in language processing, including prefrontal cortex, anterior cingulate gyrus, insula, amygdala, caudate nucleus (Posner et al., 1988; Baxter et al., 1989; Petersen et al., 1989; Drevets et al., 1992; Drevets and Raichle, 1992; Yazici et al., 1992; Demonet et al., 1994; Mayberg et al., 1997; Posner and Raichle, 1997; Ogura et al., 1998; Tutus et al., 1998; Roskies et al., 2001; Mayberg and Fossati, in press). Determining the presence and nature of possible language difficulties, including semantic processing, is potentially helpful in identifying the bounds of what is often considered a generalized cognitive deficit in depression.

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The present studies examined semantic processing utilizing the N400 component of the event-related brain potential (ERP) in major depression. N400 is a scalpnegative voltage deflection approximately 400 ms after the presentation of the terminal word of a sentence. N400 is typically enhanced in response to the presentation of context-incongruent sentence endings. Kutas and Hillyard (1980a,b) first reported N400 enhancement in a sentencereading paradigm. They noted that when the last word of a sentence was semantically incongruent (e.g. ‘The pizza was too hot to cry’), N400 was larger than when the final word was congruent (e.g. ‘The pizza was too hot to eat’). Kutas and Hillyard (1984) adapted Taylor’s (1953) ‘cloze probability’ paradigm, finding that the amplitude of N400 was inversely related to the subject’s expectancy for the terminal word. These findings have since been adapted to a number of other paradigms that tap participants’ contextual expectancies, typically showing robust semantic incongruence effects. In addition, they have been adapted to examine semantic processing in various types of psychopathology (e.g. schizophrenia; Adams et al., 1993; Niznikiewicz et al., 1997; Condray et al., 1999; Salisbury et al., 2000). Titone and Salisbury (2004) recently suggested that N400 amplitude is more affected by global than local context, suggesting that controlled processes may take priority over automatic processes in modulating N400 amplitude. Thus, given that individuals diagnosed with MDD have demonstrated controlled processing deficits and abnormal activation in brain regions associated with semantic processing, they may show abnormal N400 amplitude. The three studies reported here are the first to evaluate semantic processing in diagnosed mood disorder using the standard N400 semantic incongruence paradigm. They shared a common methodology and stimulus set but were conducted with distinct samples in different settings. Standard congruent and incongruent sentences used in previous, nonclinical N400 studies were presented to one community sample and two inpatient groups diagnosed with major depression, one community sample diagnosed with dysthymia (a more chronic, though less severe form of depression), and three groups of individuals with no history of mental illness. Based on the reviewed models and the fact that semantic processing is at least moderately demanding, the primary

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hypothesis was that individuals diagnosed with a mood disorder would fail to show N400 enhancement to semantically incongruent sentence endings. However, if mood disorders are not associated with a generalized deficit, rather, the deficits are tied to a specific cognitive process there may be no differences in the N400. Indeed, the one available semantic priming study using exclusively behavioral measures found no abnormality associated with depression (Georgieff et al., 1998). A secondary hypothesis was that N400 abnormality would vary with severity of depression. Cognitive deficits previously reported in the depression literature have often been related to the severity of the mood disorder (e.g. Deldin et al., 2001). Therefore, a group of participants diagnosed with dysthymia was included in one study in order to determine whether the deficits were specific to MDD.

2. Methods 2.1. Participants Individuals diagnosed with major depression were recruited from an acute inpatient psychiatry unit in a moderate-size mid-western city (studies 1 and 2) and from a community sample in a large eastern city (study 3, see Table 1). Non-patient comparison subjects were recruited from the local community via newspaper advertisements (studies 1–3). Table 1 provides demographic information. All mood disordered participants were diagnosed as having current major depressive episode (in the context of MDD, studies 1–3) or dysthymic disorder (study 3) using the structured clinical interview (SCID, First et al., 1995) for the DSM-III-R or DSM-IV by an advanced doctoral student or a doctoral-level clinical psychologist (PJD). In studies 1 and 2, the diagnostic interviews were completed by advanced doctoral students in clinical psychology closely supervised by a senior research clinician (GAM) in a practicum on inpatient diagnosis. Consensus was reached in a review of each diagnosis of MDD. In study 3, 25% of the tapes of the interviews were reviewed and inter-rater reliability was 100% for the control, MDD, and dysthymic groups, with interviews done by an experienced research clinician (PJD) or trained supervisees.

Table 1 Sample demographics Variable

N N medicated Sex (female) Age Education

Study 1

Study 2

Study 3

Nondepressed

MDD

Nondepressed

MDD

Nondepressed

MDD

Dysthymia

11 1a 8 31.7 (12.89) 14.8 (1.48)

17 13 14 35.1 (9.68) 14.1 (2.03)

10 0 6 28.0 (7.8) 14.3 (1.704)

14 12 8 44.9 (14.0) 15.8 (1.48)

20 0 10 37.3 (14.4) 15.9 (2.0)

19 5 9 39.1(13.7) 14.4 (2.0)

14 2 4 42.7 (13.4) 15.4 (2.7)

Note: Means (S.D.) are given for age, number of years of education, and handedness. With the exception of age in study 2 (F(1,20) = 10.56, p < .01), within a study no group difference exceeded p < .10. a One healthy control was taking hormone replacement therapy.

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Control, dysthymic, and community MDD participants were paid US$ 5–10 per hour for their participation. Inpatient MDD participants were not paid.

0.01–30 Hz analog band-pass filter. Data were sampled at 125 Hz (studies 1 and 2) or 512 Hz (study 3) for 1400 ms beginning 200 ms prior to the onset of the last word in each sentence.

2.2. Physiological recording 2.3. Procedure The electroencephalogram (EEG) was recorded from nine International 10–20 system sites (Jasper, 1958): Fz, Cz, Pz, F3, C3, P3, F4, C4, and P4, referenced to the left mastoid (studies 1 and 2) or left earlobe (study 3). EEG recorded from the right mastoid or right earlobe was subsequently used to compute an average mastoid reference ([A1 + A2]/2; Miller et al., 1991). In studies 1 and 2, Beckman miniature Ag–AgCl electrodes were used for the EEG recording. In study 3, EEG was collected using a tin-electrode cap (Electro-Cap International Inc., Eaton, OH). For all three studies, two orthogonal channels of the electro-oculogram (EOG) recorded vertical and horizontal eye movements using electrodes placed near the outer canthi and at left supra- and suborbital sites. Impedances were kept below 10 kV. EEG was amplified using a Grass Model 12 (studies 1 and 2) or an S.A. Instruments Custom Bioamp (study 3) with a

After an initial interview that screened prospective participants for handedness, head injury, seizures, normal or corrected-to-normal vision, major medical illness, and developmental disabilities, eligible participants were given an individual lab tour and provided written consent prior to testing. Participants also completed a SCID interview. Participants then returned on a second day for the EEG. Following electrode application, participants were instructed to relax and focus on the screen in front of them. They were told that they would see words appear briefly on the screen, one at a time, and that the words formed sentences. They were asked to read the sentences silently. In studies 1 and 2, they were told that they would be asked questions about the sentences at the end of the session. Subjects were then presented with a block of 30 congruent and 30 incongruent sentences used in previous N400 studies (Kutas, personal

Fig. 1. Grand averages of site Fz, Cz, and Pz in response to the congruent and incongruent stimuli by study and group.

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communication, based on Kutas and Hillyard, 1980a,b). The sentences were the same across the three studies. 2.4. Stimuli The order of sentence type was random within the constraints that no more than four of the same sentenceending type (congruent, incongruent) occurred in a row. Sentences were six to eight words in length. Each word appeared on the screen for 200 ms, with 200 ms of blank screen between each word. 2600 ms occurred between the offset of the last word of a sentence and the onset of the next sentence.

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right) repeated-measures analysis of variance (ANOVA), supplemented with simple-effects ANOVAs and Newman– Keuls tests as needed to interpret effects significant at the twotailed, 0.05 level. Reported probability values reflect the Huynh and Feldt (1976) degrees of freedom correction. No systematic differences were obtained in exploratory analyses comparing medicated and unmedicated subsamples of patients with major depression. Initially analyzing the three studies separately maximized the chances of finding a confirmation of the primary hypothesis (failure of N400 enhancement in depression). Consistency of results of the three studies was evaluated using the Stouffer meta-analytic procedure (Bush et al., 1960).

2.5. Data reduction and analysis Eye movement correction procedures were performed (Gratton et al., 1983; Miller et al., 1988, for studies 1 and 2; James Long System, unpublished for study 3). Each participant’s EEG was manually inspected for the presence of residual eye movements or EMG artifact, and contaminated epochs were removed from the analysis. Withinsubject averages of ERP waveforms were computed for each site and sentence-ending type. N400 scores were computed as the average voltage between 300 and 600 ms deviated from a 200 ms prestimulus baseline. For each study, N400 scores were submitted to group (MDD versus nondepressed (studies 1–3) or MDD versus dysthymia versus nondepressed (study 3))  stimulus type (congruent versus incongruent)  caudality (frontal versus central versus parietal) and laterality (left versus center versus

3. Results Fig. 1 presents ERP grand averages for each study, and Table 2 provides ANOVA results. Only effects directly relevant to present hypothesis will be discussed: group, stimulus type, and group  stimulus type. In all seven groups across the three studies, N400 was larger in response to the incongruent versus congruent stimuli (exceeding at least the p < .10 threshold in six groups), confirming a successful congruence effect. In contrast, no group or group  stimulus type effects approached significance (all p > .4). In fact, as can be seen in Table 2, the difference between congruent and incongruent stimuli was very similar across mood disorder and control groups in the three studies.

Table 2 ANOVA results a. Group main effects Study

Groups

d.f.

F

p

1 2 3 3

Control and MDD Control and MDD Control and MDD Control, MDD and dysthymia

1, 1, 1, 2,

0.71 0.12 0.07 0.52

0.408 0.728 0.798 0.597

26 22 37 50

b. Stimulus type simple effects Study

Groups

d.f.

F

p

Congruent

1 1 2 2 3 3 3

Control MDD Control MDD Control MDD Dysthymia

1, 1, 1, 1, 1, 1, 1,

5.04 4.88 3.54 0.86 9.27 3.77 15.22

0.039 0.052 0.082 0.377 0.007 0.070 0.002

2.79 2.33 3.97 3.44 1.48 1.16 2.29

16 10 13 9 19 17 13

Incongruent 2.07 1.63 2.67 2.38 0.27 0.35 0.14

Incongruent–congruent 0.72 0.70 1.30 1.06 1.75 1.51 2.15

c. Group  stimulus type interaction Study

Groups

1 2 3 3

Control, Control, Control, Control,

MDD MDD MDD MDD, dysthymia

d.f.

F

p

1, 1, 1, 2,

0.01 0.04 0.07 0.21

0.97 0.85 0.80 0.81

26 22 37 50

Note: Significant and marginally significant p values are bolded and italicized, respectively. Congruent and incongruent refer to the average values (mV) for each group’s N400 score for congruent and incongruent sentence endings, and incongruent–congruent shows the difference between groups.

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3.1. Control participants As expected, control participants produced larger N400 scores to the incongruent sentence endings. The statistical robustness of this pattern reflected sample size (study 2: p < .09, study 1: p < .04, study 3: p < .007, metaanalytically combined: p < .0003). 3.2. MDD participants Participants diagnosed with MDD also showed larger N400 scores in response to incongruent sentence endings. This difference was marginally significant in two of the individual studies and significant when the studies were meta-analytically combined ( p < .02). 3.3. Dysthymic participants The dysthymia group in study 3 showed robust enhancement of N400 for incongruence ( p < .002). In fact, this group demonstrated the largest mean difference between the congruent and incongruent N400 area scores.

4. Discussion Three studies examined one aspect of semantic processing utilizing the N400 component of the ERP in three independent groups of participants who were in a current major depressive episode, one group of participants who were diagnosed with dysthymic disorder, and three independent groups of psychiatrically healthy participants. The goal of these studies (N = 105) was to determine whether participants who are mood disordered show abnormal semantic processing, as indexed by the N400, in a passive sentence processing paradigm, and whether this varied with severity of depression. As expected, psychiatrically healthy participants showed a consistent enhancement of N400 in response to incongruent sentence endings in every study. Importantly, no study found evidence that mood disordered individuals differ from healthy controls during this semantic processing task. These results are consistent with the one available behavioral semantic priming study, which came to the same conclusion (Georgieff et al., 1998). Cognitive differences have sometimes been attributed to severity of the depression, but in the present samples patients with severe, acute depression (current MDE in MDD) and those with dysthymia had similar N400 results. It is important to note that other aspects of language processing could still be found to be dysfunctional in individuals diagnosed with major depression or other mood disorders and this study does not rule out that possibility. For example, schizophrenics have been shown to have normal N400’s in similar passive semantic processing tasks (Mitchell et al., 1991; Andrews et al., 1993). In contrast,

when asked to behaviorally respond to incongruent and congruent sentence endings they have shown abnormal N400 amplitudes (Nestor et al., 1997; Strandburg et al., 1997). Thus, the conclusions of normal semantic processing in this study is limited to the cognitive processes associated with passive sentence reading. In summary, results of the three similar but independent studies provide consistent psychophysiological evidence of normal semantic processing in depression as indexed by the N400 during a passive, sentence viewing task. Although null findings can be difficult to interpret definitively, the consistency of present findings is noteworthy. Furthermore, these findings cannot be attributed to a lack of power. With an average incongruence effect of 1.25 mV across the four depressive groups versus 1.28 mV across the three control groups, the difference is below the noise level of the EEG amplifiers. Thus, arbitrarily large sample sizes would be very unlikely to find impaired semantic congruence processing in depression as indexed by the N400. Furthermore, such a small voltage difference could have no conceivable functional significance. The conclusion that this aspect of language processing is spared in depression improves the case for the cognitive specificity of other types of impairment in depression, although considerable additional work will be needed to determine fully the boundaries and mechanism(s) of that impairment.

Acknowledgements This research was supported by NIMH grants F31 MH10191 to Patricia J. Deldin, F31 MH11758 to Jennifer Keller, and R01 MH39628 to Gregory A. Miller. The authors would like to thank Susan Clancy and Brandy Isaacks for help with data collection.

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