Effect of low-frequency transcranial magnetic stimulation on an affective go/no-go task in patients with major depression: Role of stimulation site and depression severity☆
Introduction
Transcranial magnetic stimulation (TMS) is a non-invasive and well-tolerated means to stimulate the human brain (Pascual-Leone et al., 1999, Pascual-Leone et al., 2000). In psychiatry, repetitive TMS (rTMS) has been studied primarily as a potential antidepressant treatment. The mechanisms of action remain unclear, but many studies support an antidepressant effect of rTMS when applied over the dorsolateral prefrontal cortex (DLPFC; for review, see Holtzheimer et al., 2001, Burt et al., 2002, Gershon et al., 2003). However, effect sizes vary considerably between studies, and some have found no antidepressant properties of rTMS (e.g., Kimbrell et al., 1999, Loo et al., 2003a, Hausmann et al., 2004a). The heterogeneity of findings might largely be due to a high variability across depressed patients in their response to rTMS. Potentially relevant factors include the site of magnetic stimulation (left versus right DLPFC; Pascual-Leone et al., 1996b), pulse frequency (Pascual-Leone et al., 1994, Sachdev et al., 2002), stimulation intensity (Loo et al., 2001), clinical state (e.g., depressed or euthymic; George et al., 1996, Pascual-Leone et al., 1996a), depression subtype (e.g., psychotic features; Grunhaus et al., 2000), duration of depressive episode (Holtzheimer et al., 2004), age (Kozel et al., 2000, Janicak et al., 2002), previous response to rTMS (Dannon et al., 2000), metabolic brain state prior to TMS (Kimbrell et al., 1999, Teneback et al., 2001), and potential interactions between some of these factors. It seems important to study the factors influencing the response of depressed patients to rTMS, because their knowledge shows promise for optimizing treatment parameters and improving our understanding of the pathophysiology of major depression.
Previous studies have used different output measures to assess the response of depressed patients to rTMS. The most frequently used parameters are depression rating scales, such as the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1967) and the Beck Depression Inventory (Beck et al., 1996; for overview, see Burt et al., 2002, Gershon et al., 2003). Other response measures previously used in the study of depression include motor cortex excitability (Maeda and Pascual-Leone, 2003), metabolic changes (Catafau et al., 2001, Mottaghy et al., 2002, Loo et al., 2003b), and cognitive task performance (Hausmann et al., 2004b). In the present study, we adopted an affective go/no-go task (AGN task) to examine the response of depressed patients to rTMS. This task requires subjects to respond to stimuli of one valence (e.g., positive) while inhibiting responses to stimuli of the opposite valence (e.g., negative). Since response selection and inhibition are guided by emotional content, the task provides a means of studying the interface between cognition and emotion. We employed the AGN task, because it can be used to quantify neuropsychological deficits typically observed in depressed patients which, for instance, concern response selection and inhibition, the recognition of affect, and mood-congruent attentional bias (Rubinow and Post, 1992, Elliott, 1998, Murphy et al., 1999). In addition, the AGN task has been shown to involve the lateral prefrontal cortex (Elliott et al., 2000, Elliott et al., 2002), which is the common target region of therapeutic rTMS in mood disorders and is assumed to play a role in the pathophysiology of major depression (Mayberg, 2003, Phillips et al., 2003).
Using the AGN task, the present study aimed to further explore two of the above-mentioned factors potentially modulating rTMS outcome, namely the site of stimulation and the clinical state of the patient. With respect to the site of stimulation, the predominant hypothesis in the field is that depressed patients benefit from high-frequency (fast) rTMS over the left DLPFC and low-frequency (slow) rTMS over the right DLPFC (Burt et al., 2002, Gershon et al., 2003). This hypothesis is closely linked to the ‘imbalance’ hypothesis of depression, which postulates that a relative hypoactivity in the left relative to the right prefrontal cortex plays a critical role in the pathophysiology of depression (Sackeim et al., 1982). Fast left prefrontal rTMS might enhance and slow right prefrontal rTMS might reduce the activity in the targeted brain areas, thus restoring normal balance between the hemispheres. This view is consistent with various lesion (Morris et al., 1996, Paradiso et al., 1999), rTMS (Pascual-Leone et al., 1996a, George et al., 1999, Klein et al., 1999), and functional neuroimaging studies (Ebert et al., 1991, Sackeim et al., 1993, Kocmur et al., 1998, Mottaghy et al., 2002) associating depression with prefrontal asymmetry in favor of the right hemisphere. However, there are also a considerable number of studies that do not support the above hypothesis. For instance, a recent meta-analysis of functional neuroimaging studies did not find a significant difference between left and right prefrontal activity in depressed patients (Nikolaus et al., 2000; see also Iidaka et al., 1997, Tutus et al., 1998). Moreover, some rTMS studies observed unexpected effects, with better treatment response to slow than to fast rTMS over the left DLPFC (Kimbrell et al., 1999, Padberg et al., 1999). Because of these divergent findings, the asymmetry hypothesis of depression remains a matter of debate, and it seems desirable to further assess the assumption of beneficial effects of fast rTMS over the left DLPFC and slow rTMS over the right DLPFC (Burt et al., 2002). Since most work has focused on these two, potentially beneficial combinations of site and frequency of prefrontal rTMS, there is a lack of investigations that compare different stimulation sites for a given TMS frequency. In the present study, we administered slow (1 Hz) rTMS to the left and right DLPFC as well as the mesial occipital cortex (active control) prior to AGN task performance in order to examine the influence of stimulation site and depression severity on the response to TMS. We applied rTMS in one short (10-min) session per stimulation site to focus on the acute effects of rTMS and to avoid sustained adverse effects potentially induced in patients with major depression by left prefrontal rTMS at 1 Hz, as would be predicted by the above hypothesis. To determine the influence of the clinical state of patients with major depression on rTMS outcome, we compared acutely depressed with improved (i.e., partially or completely remitted) patients. The inclusion of partially remitted patients allowed the study of the gradual changes of rTMS effects with improving HRSD scores. Based on the imbalance theory of depression, we anticipated improved AGN task performance following right prefrontal rTMS at 1 Hz in acutely depressed patients and we hypothesized that this beneficial effect would disappear with improving HRSD scores.
Section snippets
Participants
All patients participating in this study were recruited from the psychiatric outpatient clinic of the University of Sao Paulo, Brazil. In all cases, the diagnosis of unipolar major depressive disorder was established using the Structured Clinical Interview for DSM-IV Axis I Disorders (First et al., 1995) and case note review. All patients had a history of at least three previous major depressive episodes, were right-handed and had not had a change of psychotropic medication within 2 weeks of
Task performance at baseline prior to rTMS
The total number of errors was 36.0 (± 13.2; mean ± S.D.) in the acutely depressed group and 24.4 (± 9.2) in the improved group (Fig. 2A). The comparison between groups revealed a significantly better performance in improved patients (t-test for independent groups; t = 2.2, P = 0.04). The average difference between the two groups was 11.6 errors. In addition to this group difference, we observed a significant correlation between task performance and HRSD scores independent of group (Fig. 2B; Pearson r =
Discussion
We found that the AGN task performance correlated with depression severity (HRSD score) in acutely depressed and improved (i.e., partially or completely remitted) patients. One session of slow rTMS over the right DLPFC enhanced the AGN task performance in acutely depressed patients. This beneficial effect declined with decreasing depression severity (HRSD score) and tended to reverse in the improved group. Slow rTMS over the left DLPFC had no significant effect on performance in the depressed
Acknowledgments
This work was supported by a grant within the Postdoctoral Program of the German Academic Exchange Service (DAAD, D/02/46858) to F.B., a grant within the Harvard Medical School Scholars in Clinical Sciences Program (NIH K30 HL004095-03) to F.F., a Heisenberg grant from the German Research Foundation to G.N. (DFG, 304/4-1), and grant K24 RR018875 from the National Institutes of Health (NCRR) to A.P.-L.
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2021, Clinical NeurophysiologyCitation Excerpt :In the neurotypical brain, previous studies have provided evidence for a balanced excitatory/inhibitory relationship involving GABAergic inhibition and glutamate receptor-mediated excitation (Yizhar et al., 2011). Impairments of this balance in the genu are linked to deficits of cognition and social behaviour in SCZ (Rowland et al., 2016; Yizhar et al., 2011) and of cognition and emotion in MDD (Bermpohl et al., 2006; Killgore et al., 2007). Interestingly, there are a number of overlapping phenotypic features also related to impaired GABAergic inhibitory neurotransmission, such as bilateral motor incoordination and disorganized thought in SCZ (McCormick et al., 2012) and anhedonia and cognitive deficits in MDD (Crestani et al., 1999; Shen et al., 2010).
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The study was carried out at the Psychiatry and Psychology Institute, University of Sao Paulo, Brazil.
- 1
Present address: Functional Brain Mapping Laboratory, Department of Neurology, University Hospital Geneva, 24, Rue Micheli du Crest, CH-1211 Geneva 14, Switzerland.
- 2
Present address: Department of Psychiatry and Psychotherapy, University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.