Elsevier

Clinical Neurophysiology

Volume 120, Issue 9, September 2009, Pages 1667-1682
Clinical Neurophysiology

Spatio-temporal EEG waves in first episode schizophrenia

https://doi.org/10.1016/j.clinph.2009.06.020Get rights and content

Abstract

Objective

Schizophrenia is characterized by a deficit in context processing, with physiological correlates of hypofrontality and reduced amplitude P3b event-related potentials. We hypothesized an additional physiological correlate: differences in the spatio-temporal dynamics of cortical activity along the anterior–posterior axis of the scalp.

Methods

This study assessed latency topographies of spatio-temporal waves under task conditions that elicit the P3b. EEG was recorded during separate auditory and visual tasks. Event-related spatio-temporal waves were quantified from scalp EEG of subjects with first episode schizophrenia (FES) and matched controls.

Results

The P3b-related task conditions elicited a peak in spatio-temporal waves in the delta band at a similar latency to the P3b event-related potential. Subjects with FES had fewer episodes of anterior to posterior waves in the 2–4 Hz band compared to controls. Within the FES group, a tendency for fewer episodes of anterior to posterior waves was associated with high Psychomotor Poverty symptom factor scores.

Conclusions

Subjects with FES had altered global EEG dynamics along the anterior–posterior axis during task conditions involving context update.

Significance

The directional nature of this finding and its association with Psychomotor Poverty suggest this result is related to findings of hypofrontality in schizophrenia.

Introduction

The characteristic cognitive deficit in schizophrenia has been described as a reduced ability to integrate appropriate contexts into ongoing cognition (Frith, 1995, Servan-Schreiber et al., 1996, Phillips and Silverstein, 2003, Waters et al., 2004, Hemsley, 2005). The deficit in contextual integration can be measured in memory, attention and perceptual functioning (Cohen and Servanschreiber, 1992, Cohen et al., 1996, Silverstein et al., 1996). Promising work on the physiology of this deficit has been carried out using blood perfusion measures (PET, fMRI) of hypofrontality (Davidson and Heinrichs, 2003), the P3b ‘target’ event-related potential (ERP) (Ford et al., 1992) and functional measures of long-range cortical integration such as coherence (Tauscher et al., 1998) and synchrony (Lee et al., 2003).

However, application of these techniques to the study of schizophrenia does not, in general, allow brain activity to be imaged at the time-scale that individual cognitive events occur, that is, within a few hundred milliseconds. This is either because of the inherently slow time constant of measures such as PET and fMRI, the need to average over multiple trials in the case of P3b ERP amplitudes or MEG dipole modeling, or the requirement to analyse relatively long time series in the case of coherence. While some progress has been made to address this methodological issue (Ford et al., 1994, Schack et al., 1999a), further progress in the study of schizophrenia at this fine time-scale of brain activity can still be made. The present research uses a novel method to analyse spatio-temporal patterns in scalp EEG, which is not only suited to the study of global processes of cortical integration but is also applicable to the study of real time cognitive events.

Hypofrontality refers to reduced blood flow in frontal/prefrontal regions at rest or during tasks that activate these areas (Davidson and Heinrichs, 2003). Measurements of hypofrontality in schizophrenia have not always been consistent (Ingvar and Franzen, 1974, Andreasen et al., 1992, Gur and Gur, 1995, Ramsey et al., 2002), but a number of recent meta-analyses have confirmed the robustness of the association (Davidson and Heinrichs, 2003, Hill et al., 2004, Glahn et al., 2005). Hypofrontality in schizophrenia commonly involves hypoperfusion of dorsolateral prefrontal cortex (DLPFC), an effect found at the earliest stages of clinical presentation (Molina et al., 2003, Hill et al., 2004, Glahn et al., 2005). The DLPFC is strongly activated during context processing tasks in healthy controls (Barch et al., 2001, MacDonald et al., 2005). In schizophrenia, hypo-activation of DLPFC appears to be more evident during task activation than resting conditions (Davidson and Heinrichs, 2003, Hill et al., 2004), and this is likely related to the need for task-relevant engagement of appropriate brain centres (Snitz et al., 2005). Hypofrontality effects have been found during both visual Working Memory and auditory Oddball tasks (Shajahan et al., 1997, Glahn et al., 2005).

The P3b ERP occurs in response to a rare target stimulus, such as an auditory tone. The P3b ERP is thought to index Working Memory processes in response to change in the environment, conceptualized in particular in terms of context updating (Donchin and Coles, 1988; cf. Verleger, 1988 and the P3b as context closure). Reduced P3b amplitudes are a highly consistent finding in schizophrenia (Ford et al., 1992, Brown et al., 2002, Jeon and Polich, 2003, Bramon et al., 2004), and have been interpreted as reflecting a disturbance of context processing and Working Memory updating (Ford et al., 1992, Ford, 1999). The P3b can be evoked in a number of sensory modalities, but P3b abnormalities in schizophrenia are most consistently demonstrated for the auditory and to a lesser extent the visual modality (Ford, 1999).

A number of studies have demonstrated that in schizophrenia negative symptoms are associated with hypofrontality (Sabri et al., 1997, Erkwoh et al., 1999). The P3b amplitude reduction seen in schizophrenia is also associated with negative symptoms, although less consistently so (Ford, 1999, Williams et al., 2000, Williams et al., 2003, Kawasaki et al., 2007). The related symptom factor of Psychomotor Poverty (Liddle, 1987, Harris et al., 1999) is negatively correlated with ventro-medial prefrontal cortex volume (Chua et al., 1997) and with left DLPFC hypoperfusion (Liddle et al., 1992, Kaplan et al., 1993). Psychomotor Poverty has been hypothesized to involve a functional disconnection between prefrontal–frontal regions and other brain systems (Friston, 1992). EEG measures of functional connectivity – between anterior and other cortical regions – could therefore bring evidence to bear upon this hypothesis.

The measures of hypofrontality and the P3b ERP involve related psychological functions. Both involve Working Memory and integration of context (Donchin and Coles, 1988, MacDonald et al., 2000), both have been linked to contextual processing deficits in schizophrenia (Ford, 1999, Snitz et al., 2005) and both have a relationship to negative symptoms (Chua et al., 1997, Sabri et al., 1997, Erkwoh et al., 1999, Ford, 1999). These correspondences have prompted some researchers to explore the link between the two measures. Right DLPFC and left inferior prefrontal perfusion are positively correlated with P3b amplitudes in subjects with schizophrenia (Blackwood et al., 1999, Molina et al., 2005). In another study, healthy subjects significantly activated frontal regions during an auditory Oddball task, whereas subjects with schizophrenia did not (Shajahan et al., 1997). These results suggest frontal and prefrontal alterations may be related to the reduced P3b amplitudes seen in schizophrenia (Molina et al., 2005). We propose that the temporal ordering of cortical events, measurable at the scalp, provides a link between these measures.

Most studies of the P3b ERP focus on amplitude and latency at individual electrode sites or the topography of the activity (amplitudes) across recording sites (Soltani and Knight, 2000). Studies of amplitude topography, as well as lesion and imaging studies, have identified a number of cortical regions involved in P3b generation, including the lateral frontal cortex, the temporo-parietal junction and the inferior parietal lobe (Soltani and Knight, 2000, Linden, 2005). However, knowledge of the cortical sites most activated by the P3b does not provide direct evidence for how these areas are connected functionally during P3b activation (Soltani and Knight, 2000). P3b latency topography, on the other hand, provides an index of the order in which different cortical sites are activated, independently of the amplitude of activation. In adult subjects, P3b latency topographies have been assessed from grand-averaged (i.e., group) ERP curves (Alexander et al., 2006c) and individual subject ERPs (Anderer et al., 1996). The P3b latency topography during auditory Oddball is anterior to posterior across the scalp, with a mean latency difference from anterior to posterior of approximately 20 ms (cf. Klimesch et al., 2007 on P3 latency during Stroop task). The observed latency topography may provide a functional link across the different regions thought to be involved in generation of the P3b.

The present study utilizes new measures of event-related dynamics in the EEG (Alexander et al., 2006c). Spatio-temporal waves of electrical activity measurable at the scalp are analogous to waves on a pond spreading from a dropped stone. In particular, wave activity is a measure of long spatial wavelength patterns in the EEG that propagate smoothly across the scalp (Alexander et al., 2006c). A number of studies, using a variety of analysis techniques, have shown propagating long spatial wavelength patterns in scalp EEG/MEG to be task/activity dependent, including Working Memory (Sauseng et al., 2002, Alexander et al., 2006a, Alexander et al., 2007, Alexander et al., 2008), listening to auditory tones (Ribary et al., 1991, Alexander et al., 2006c, Alexander et al., 2008), resting states (Ito et al., 2005, Ito et al., 2007, Manjarrez et al., 2007, Nolte et al., 2008) and sleep (Massimini et al., 2004).

Measures of wave activity are sensitive to spatio-temporal dynamics that exist for only single cycle of wave propagation (Alexander et al., 2006c). This makes wave activity measures suitable for quantification in event-related paradigms, and for analysis of changes in the EEG occurring within a single trial. Wave activity is a measurement level description of scalp EEG. That is, wave activity measures do not model the cortical sources of the dynamical patterns (Nunez et al., 1997, Tallon-Baudry et al., 1999). Several considerations, summarized in the discussion section of Alexander et al. (2006c), show that wave activity cannot merely be the by-product of smearing of brain signals due to volume conduction effects. Chief among these considerations is that the detected waves are spatio-temporal. The spatial smearing of volume conduction effects is effectively instantaneous and so cannot account for latency gradients of phase, measurable across the scalp. Latency gradients during episodes of wave activity are highly correlated with the measured spatial gradients of phase (Alexander et al., 2006c). In short, volume conduction effects act as a low-pass spatial filter on cortical signals, and so do not constitute a barrier to detecting low spatial frequency spatio-temporal waves.

Previous studies with a variety of clinical groups have shown wave activity measures to be at least as sensitive as EEG power measures or ERP amplitudes, as indicated by effect size statistics (Alexander et al., 2006a, Alexander et al., 2007, Alexander et al., 2008). Wave measures have been used to differentiate ADHD subjects from controls and have also been used to demonstrate differences in brain function during development in carriers of the apolipoprotein ε4 allele (Alexander et al., 2007, Alexander et al., 2008). A result of particular relevance to the present study is the finding that elderly subjects with subjective memory complaints show differences compared to matched controls in the global direction of wave propagation at around the time of the P2/N2 ERPs, during a 1-back Working Memory task (Alexander et al., 2006a). Similar directional wave propagation effects have been found in healthy subjects for event-related changes during a memory task (Sauseng et al., 2002). Measures of the direction of wave activity propagation therefore open a new possibility of exploring functional connectivity in schizophrenia because they reveal the temporal order of activation across the global EEG array.

The average latency of the P3b is ∼360 ms in a population of adults between 20 and 50 years old (Anderer et al., 1996). Time–frequency analysis of P3b-related power in adult subjects reveals a peak in the delta band (∼320 ms post-stimulus, ∼3 Hz; Alexander et al., 2006c), consistent with previous research (Basar-Eroglu et al., 1992, Demiralp et al., 2001). The measure of wave activity also reveals a P3b-related peak, not present in background trials, with a population maxima at ∼375 ms, ∼2.8 Hz post-stimulus (Alexander et al., 2006c). The peak wave in activity therefore has slightly longer latency than the average latency of the P3b component in the ERP wave, but is substantially earlier than the N4 ERP component.

Of interest to present research is that the P3b-related peak in wave activity in adults typically (but not exclusively) involves waves propagating in the anterior to posterior direction (Alexander et al., 2006c). This single trial measure is therefore consistent with the averaged latency topography of the P3b ERP in adults (Anderer et al., 1996, Alexander et al., 2006c). P3b-related wave activity provides a potential index of large-scale functional connectivity between anterior and posterior regions of cortex during context update. To extend the previous analogy about waves on a pond, toy boats a different positions on a pond may bob up by characteristic heights when perturbed by a wave (EEG/ERP amplitude), but may also bob up in a characteristic order (activation latency). Due to previous findings of hypofrontality and P3b abnormalities in schizophrenia, we were particularly interested in delta-band wave activity that appears earliest over the anterior region of the scalp and spreads posteriorly. We hypothesized that in schizophrenia, these delta-band waves will be altered in relation to the anterior–posterior axis of propagation on the scalp.

People with schizophrenia usually present with positive symptoms in late adolescence or early adulthood (Kaiser and Gruzelier, 1999; Bramon et al., 2004, Table 1). This timing is thought to arise from the increase in myelination during late development (Benes, 1989, Whitford et al., 2007). These developmental processes may exacerbate existing abnormalities, for example, in the DLPFC (Randall, 1980, Randall, 1983, Weinberger, 1987, Lewis et al., 2004, Eastwood and Harrison, 2005). The peak in event-related wave activity associated with the P3b ERP has a lower frequency in a population with mean age 12 years, arising at ∼1 Hz rather than the 2–3 Hz peak seen 25–50 year old adults (Alexander et al., 2006c, Alexander et al., 2008). Preliminary results suggest the transition in P3b-related peak frequency for wave activity occurs smoothly with increasing mean age of the subjects (Alexander et al., 2006b). In order to address potential developmental influences on wave trajectories, the present study will focus on a range of frequencies in the delta band.

In schizophrenia, disconnection theories posit the breakdown of specialized network systems (Friston, 1999). This phenomenon has been explored using measures of phase locking in EEG activity, chiefly in the 40 Hz band (Lee et al., 2003, Symond et al., 2005, Flynn et al., 2008). EEG coherence has been used to measure the functional coupling between of brain regions under pairs of electrodes (Shaw et al., 1978, Thatcher et al., 1986). A small number of studies have assessed resting delta-band coherence in schizophrenia, with findings of higher interhemispheric (Nagase et al., 1992) and intra-hemispheric (Wada et al., 1998), but lower frontal (Tauscher et al., 1998) delta-band coherence. The latter finding was interpreted in terms of DLPFC dysfunction. In general, these coherence findings arise in the absence of power differences. Most studies applying coherence measures to schizophrenia have only utilized the measured coherence amplitude and not coherence phase. The latter would enable the spatio-temporal functional connectivity of different brain regions to be assessed (Nolte et al., 2008). Wave activity measures also tap aspects of spatio-temporal functional connectivity, but unlike measures of coherence phase, measures of wave activity are sensitive to spatio-temporal dynamics within a single cycle of wave propagation (Alexander et al., 2006c). By contrast, studies of EEG coherence in schizophrenia are largely confined to resting EEG due to the relatively long time-series required for analysis (Nagase et al., 1992, Tauscher et al., 1998, Wada et al., 1998).

Building on previous findings of P3b ERP abnormalities and hypofrontality in schizophrenia, we hypothesized that the FES group would differ from the control group on the measure of anterior–posterior wave trajectories at P3b-related times and frequencies during an auditory Oddball task. That is, global scalp waves in FES should differ along the anterior–posterior axis in the delta band at latencies between 300 and 450 ms post-stimulus during target trials. If the relationship between hypofrontality and symptom profiles is also born out in the wave activity measures, then fewer episodes of global anterior–posterior wave trajectories should be predictive of higher Psychomotor Poverty symptom factor scores within the FES group. To test the generality of these findings, subjects were also assessed using a 1-back visual Working Memory task, which is known to elicit a robust P3b in the target condition.

Section snippets

Subjects

Fourty-six patients with FES (16 female, 30 male; age range 14.1–25.6 years; mean 20.2; SD 2.91), were recruited for the Brain Resource International Database (BRID; www.brainresource.com) from early Psychosis units in Adelaide and Sydney, Australia.

The FES patients were receiving a variety of second-generation neuroleptic medications at the time of the study, including amisulpride, clozapine, olanzapine, risperidone and quetapine. Patients’ medication dosages were converted into chlorpromazine

Single trial exemplars

Data from a single trial during auditory Oddball (target condition) are shown in Fig. 1. These data are from a 25 year old control subject. Data for each electrode during this trial were band-pass filtered at 2.4 Hz, using a 2-cycle Morlet wavelet. Fig. 1A shows the filtered time-series for each electrode. The plot shows a maximum positive-going component at electrode Pz, at approximately 310 ms post-stimulus. The same data are represented in Fig. 1B, with electrode voltages shown on a colour

Summary and significance of results

This is the first study using EEG measures of the trajectory of scalp waves to show differences between subjects with FES and matched controls. The consistent group difference to target stimuli was a decrease in the anterior–posterior component in the higher delta band. The group difference occurred at ∼400 ms post-stimulus, ∼3 Hz. The observed effect has generality across auditory and visual modalities. This finding appears not to be specific to the gender nor the age at first episode of

Disclosure of financial interests

D.M.A. has an intellectual property agreement with the BRC which specifies equal ownership of the method for measurement of phase gradients. G.J.F. has received Research Funding from Bristol-Myers Squibb and Janssen-Cilag. A.W.F.H. has received speaker fees from Bristol-Myers Squibb Australia and Astra Zeneca Australia and travel assistance from Janssen-Cilag Australia. He has been involved in research funded by Organon Australia and has developed educational packages with Wellmark. C.A.G. owns

Acknowledgements

We acknowledge the support of the Brain Resource International Database (under the auspices of Brain Resource; www.brainresource.com) for use of the clinical and normative data. We also thank the individuals who gave their time to participate in the database. Access to the database for scientific purposes is administered independently via the scientific network (BRAINnet; www.brainresource.com), which is coordinated independently of the commercial operations of Brain Resource.

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