Excess theta or decreased theta?

The increased theta in non-responders to rTMS in Arns (2011) is in line with previous studies demonstrating non-responders to antidepressant medication to exhibit increased theta (Iosifescu et al., 2009; Knott et al., 2000; Knott et al., 1996). Theta was most specifically increased in fronto-central locations and not specifically at frontal midline sites, whereas in Spronk et al. (2010) it was found that increased theta at Fz was associated with improved treatment outcome to antidepressant medication. Frontal midline theta has been localized to the medial prefrontal cortex and anterior cingulate (Asada et al., 1999; Ishii et al., 1999) and a recent meta-analysis has demonstrated that theta in the rostral anterior cingulate cortex is associated with improved response to antidepressant treatment (Pizzagalli, 2011). Hence, the findings from Arns (2011) point rather to a generalized increased theta in non-responders as opposed to frontal midline theta originating from the anterior cingulate in line with Knott et al. (2000; 1996) and Iosifescu et al. (2009).


Figure 4 is from a study by Hegerl et al. (2011) and demonstrates EEG Vigilance regulation in patients with depression (N=30) compared to matched controls (N=30). As can be seen from this figure there is a clear difference in EEG vigilance regulation for depressed patients as compared to matched controls. In line with the theory, depressed patients exhibit a hyperstable vigilance regulation expressed by increased A1 stages (parietal alpha) and decreased B2/3 and C stages (frontal theta) which is consistent with a study by Ulrich and Fürstenberg (1999) and other studies demonstrating increased parietal alpha in depression (Itil, 1983; Pollock & Schneider, 1990). Vogel (1970) described a ‘Monotonous High Alpha Waves’ pattern, with a simple autosomal dominance of inheritance. The description of this EEG pattern found by Vogel (‘Kontinuität’) is very similar to the ‘hyperrigid’ or ‘hyperstable’ EEG vigilance found by Hegerl et al. (2011) and hence suggests this indeed reflects a ‘trait’ like EEG vigilance regulation.

Figure 4: EEG Vigilance regulation over the time course of 15 minutes in depressed patients and healthy controls. Depressed patients demonstrate a hyperstable vigilance regulation, expressed by more A1 stages (parietal alpha) and fewer B2/3 and C stages (frontal theta). From: Hegerl et al. (2011).


Furthermore, increased pre-treatment alpha has been associated with improved treatment outcome to antidepressant medication (Bruder et al., 2001; Ulrich et al., 1984) and most antidepressants also result in a decrease of alpha activity (see Itil (1983) for an overview). Therefore, the sub-group of non-responders from chapter 10 characterized by frontal theta might hence be interpreted as a sub-group characterized by a decreased EEG vigilance regulation (Arns et al., 2010a; Hegerl et al., 2010), as opposed to the typically reported increased or hyperstable vigilance regulation (‘hyperstable’ parietal alpha) as pointed out above. Given that patients with a decreased EEG vigilance regulation respond better to stimulant medication (Manic Depression: Bschor et al., 2001; Hegerl et al., 2010; Schoenknecht et al., 2010; ADHD: Arns et al., 2008; Sander et al., 2010) it is tempting to speculate if this subgroup of non-responders might respond better to stimulant medication, or other vigilance stabilizing treatments. Stimulant medication has been applied successfully in a sub-group of depression with excess theta by Suffin and Emory (1995) which was replicated in a prospective randomized controlled trial (Debattista et al., 2010). Furthermore, a recent Cochrane review also found that psychostimulants have clinical effects in depression on mood and fatigue, altough there were very few controlled studies which could be included limiting the extent to which this finding genealizes (Candy, Jones, Williams, Tookman, & King, 2008). Therefore, along the same lines as discussed above in relation to sleep problems as the core pathophysiology of ADHD, future research should focus on investigating EEG vigilance regulation and the existence of sleep problems in this sub-group of non-responders in order to develop an appropriate treatment for these patients. Figure 4 also clearly demonstrates that for depression eyes closed EEG recordings of up to 15 minutes are required to reliably demonstrate differences in EEG vigilance regulation, which is the main reason why this was not tested in our data, which have been limited to 2 minutes eyes closed.


Summarizing, responders to antidepressant treatments such as antidepressants and rTMS are generally characterized by increased parieto-occipital alpha (or a ‘hyperstable’ vigilance regulation) and increased theta in the rostral anterior cingulate (Pizzagalli, 2011) reflected as frontal-midline theta (Spronk et al., 2010; Asada et al., 1999; Ishii et al., 1999). A sub-group of non-responders to antidepressant treatments are characterized by generalized increased frontal theta reflective of decreased EEG vigilance regulation. It is hypothesized that this latter group might be better responders to vigilance stabilizing treatments such as psychostimulants or sleep onset normalizing treatments such as melatonin. In this regard it is interesting to note that recently a new antidepressant has entered the market with affinity to the melatonine MT1/MT2 receptor named Agomelatine (Demyttenaera, In Press). A final sub-group of non-responders to (antidepressant) treatments are characterized by a slowed alpha peak frequency, which will be discussed in more detail below.