This is the first examination of theta current density and treatment response in MDD using a double-blind, placebo-controlled study design. We confirm results from previous unblinded studies showing that responders to treatment have elevated rACC theta current density compared to non-responders. Our results demonstrated some regional specificity as evidenced by the fact that the PCC, used as a control, did not show significant differences between groups.
In the medication group we confirm results from previous unblinded medication studies showing that elevated theta current density in rACC and mOFC predicts response to antidepressant medication, and extend those results to show response prediction using different medications (fluoxetine, venlafaxine) from those previously examined. Our results agree with previous neuroimaging studies of treatment response that used other modalities to evaluate rACC and mOFC activity. For example, elevated rACC and mOFC metabolism have been shown in both medication responders and sleep deprivation responders relative to non-responders (Mayberg et al., 1997
; Saxena et al., 2003
; Volk et al., 1997
; Wu et al., 1999
). Our results also agree with prior studies on LORETA and treatment response which reported elevated theta band current density in the rACC (Mulert et al., 2007b
; Pizzagalli et al., 2001
) and mOFC (Mulert et al., 2007b
) in antidepressant medication responders relative to non-responders.
Interestingly, neither rACC nor mOFC showed a significant difference between remitters and non-remitters. This finding appears to be at odds with Pizzagalli’s earlier report (2001) that rACC theta predicted degree of response. However, Pizzagalli did not look specifically at remission. In the current study, remitters showed numerically higher theta current density than non-responders, but lower theta current density than subjects who responded but did not remit. This suggests there may be a “window” of rACC activity associated with optimal response. More research is needed to understand the neurobiological differences between response and full remission with treatment.
Previous LORETA studies of MDD examined responders to nortriptyline, reboxetine, and citalopram. Reboxetine primarily affects norepinephrine, citalopram primarily affects serotonin, and nortriptyline exerts effects on both systems. While Mulert and colleagues did study an SSRI (citalopram), as well as reboxetine, their results were driven by the reboxetine group (Mulert et al., 2007b
); thus no prior report showed a significant relationship between regional theta current density and response to an SSRI. The present study extends these results to include the SSRI fluoxetine and the SNRI venlafaxine. Because we did not find a significant interaction of medication in our analysis, there was no evidence of a different biomarker effect between the SSRI and SNRI we studied.
In contrast to the present finding in the medication group, Pizzagalli and colleagues did not report mOFC differences between responders and non-responders (Pizzagalli et al., 2001
). However, they did not specifically hypothesize differences in this region and thus may have used a different statistical threshold. Other methodological differences also may have contributed to different findings for the mOFC. Pizzagalli and colleagues used the dual-reuptake inhibitor tricyclic antidepressant nortriptyline, which also has anticholinergic and histaminic effects (Taylor and Richelson, 1980
). In comparison, the SNRI venlafaxine used in the present study does not have these confounding other actions. Additionally, the prior report assessed response after 4-6 months, whereas our study assessed acute 8-week response. The Mulert group, which first found the mOFC differences, also used a shorter response assessment of 4 weeks.
Because theta current density in both rACC and mOFC predicted treatment response, it is not surprising that theta current density values in these regions were highly correlated. However, this result contrasts with a prior study (Pizzagalli et al., 2001
), which found a significant correlation of rACC and OFC theta current density in healthy controls, but did not find this correlation in depressed subjects. This discrepancy between studies may be explained by methodological differences listed above. The other group to show responder/non-responder differences in both rACC and mOFC theta did not report on the correlations in these areas (Mulert et al., 2007b
). Correlations between rACC and mOFC theta current density may reflect true correlations of brain activity in these areas, but it could arise as a result of the smoothness constraint of LORETA (Mulert et al., 2007b
). Support for this being a true physiologic phenomenon can be found in prior results from PET and single photon emission computed tomography (SPECT) studies of MDD, that showed metabolic and perfusion differences between responders and non-responders to sleep deprivation in both medial prefrontal cortex/OFC and anterior cingulate (Volk et al., 1997
; Wu et al., 1999
That current density values in these regions are related to treatment response is not surprising, given that both regions have been shown to have abnormal electrophysiological activity in depressed subjects compared to healthy controls (Korb et al., 2008
; Mientus et al., 2002
; Pizzagalli et al., 2001
; Pizzagalli et al., 2002
). The rACC is a region that processes emotion and attention (Lane et al., 1998
), and the mOFC processes emotion and reward (O’Doherty et al., 2001a
; O’Doherty et al., 2001b
; Rolls et al., 2008
). Prior reports have suggested that increased activity in these areas may point to a compensatory neural response to depression that renders a depressed patient more likely to improve in response to treatment with medication (Mayberg et al., 1997
; Pizzagalli et al., 2001
; Saxena et al., 2003
) and sleep deprivation (Volk et al., 1997
; Wu et al., 1999
). Our results are consistent with this model, and we demonstrate that even when subjects are blinded to treatment theta current density predicts response.
To our knowledge, this is the first report to examine the relationship between rACC or mOFC current density and response to placebo. We found no association seen between activity in these two areas and placebo response. Although there was no significant relationship between theta current density and placebo response, we cannot conclude that the rACC and mOFC biomarkers worked differently for subjects treated with medication and those treated with placebo. There was not a significant interaction between type of treatment (active medication vs. placebo) and response indicating that the relationship between theta current density and response was not significantly different between the two groups. Contributing to this lack of differentiation, may be the fact that many patients probably have the capacity to respond either to medication or placebo, and some patients who appear to respond to medication may in fact be “placebo responders” in whom medication is not responsible for the clinical improvement seen. While a previous study demonstrated that subjects treated with placebo and medication showed different patterns of change in surface recorded QEEG (Leuchter et al., 2002
), these differences did not emerge until late in the course of treatment. In another study, our group did detect pretreatment QEEG differences between placebo responders and medication responders (Leuchter et al., 2004
), but these differences also did not involve source localization techniques. Current source density prior to, or early in the course of treatment, might not show these same differences. Further examination of the differences in brain function between placebo and medication responders may help elucidate mechanisms of clinical improvement in MDD.
It is interesting to note that both elevated rACC theta current density in the present study, and elevated rACC glucose metabolism as reported in previous studies, are related to improved response. These two measures have been compared directly in depressed and healthy subjects, and it has been shown that rACC theta current density correlates positively with glucose metabolism (Pizzagalli et al., 2003
), suggesting an association between elevated theta current density and elevated neural activity in this region. In the mOFC, however, the relationship of theta current density to glucose metabolism is less clear, because a previous report did not find a significant correlation in this region (Pizzagalli et al., 2003
). mOFC theta current density may be functionally related to rACC theta current density, as these areas have been shown to be physically and functionally connected (Kringelbach and Rolls, 2004
; Ongur and Price, 2000
). The present findings could be consistent with a more complex pattern of interaction between mOFC and rACC activity, such as a cortico-cortical feedback loop. Unfortunately this possibility cannot be determined definitively with LORETA, because it does not directly measure theta activity in the mOFC or rACC, but rather computes a low-resolution estimate from surface measurements. However, patterns of activity could be studied explicitly using activation paradigms or brain imaging methods that facilitate examination of time-dependent interactions between brain regions.
Examination of the distribution of surface theta activity revealed elevated frontal midline relative power in responders relative to non-responders, although this did not reach significance. The distribution of differences has a similar topography to a low-alpha/high-theta spectral component identified by Tenke & Kayser (2005)
using an entirely different approach to EEG generators. Because LORETA is a linear algorithm, this low-alpha/high-theta component would likely have been localized by LORETA as theta arising from rACC and mOFC. It is also interesting to note that the midline frontal theta rhythm has been shown to be generated by alternate activity of the ACC and medial prefrontal cortex (Asada et al., 1999
). While we did not explicitly study the midline frontal theta rhythm, the similar topographies and brain regions involved may offer a salient context for considering the present findings.
While neither rACC nor mOFC theta current density predicted response to placebo treatment, other neurophysiologic markers might do so. In a prior report, baseline frontocentral QEEG theta cordance was shown to predict response to placebo treatment (Leuchter et al., 2004
). The fact that we did not find a relationship between rACC or mOFC theta current density and placebo response suggests that different features of the EEG contain different information about neural activity and how it relates to response. This is supported by the fact that theta current density in the rACC — a relatively deep cortical structure — correlates with glucose metabolism (Pizzagalli et al., 2003
), while cordance has stronger correlations with perfusion in more superficial cortices (Leuchter et al., 1999
This study has several limitations that should be acknowledged. One limitation is that subjects were treated with fixed medication dosage. Subjects who did not respond at this dosage, but who might have responded to a higher dosage, were still classified as non-responders to that agent. Similarly, the outcome measures of response and remission were determined only at 8 weeks. Some non-responders might have responded after a longer period of treatment, and some responders may have remitted, but these subjects’ longer-term outcome data were not available. Further research is necessary to examine potential moderators of the relationship between theta current density and response and remission, as well as specificity of the biomarker for different medications. It should be noted that our methods make use of a cross-spectrum, which results in an un-scaled measure of coherence rather than a direct computation of amplitude. While LORETA has limitations, as do all EEG source localization methods, we nonetheless interpret elevated rACC theta current density as elevated neural activity due to evidence that rACC theta current density correlates with glucose metabolism.
Converging evidence from different methods and modalities suggests that ACC and mOFC activity may predict treatment response in MDD, and that an inexpensive, non-invasive, neurophysiologic method like LORETA may be particularly useful in monitoring these areas. In a clinical setting, low rACC and mOFC theta current density might indicate risk for non-response. The findings to date warrant consideration of directly examining the clinical utility of LORETA methods in treatment of MDD.