Efficacy of repetitive dual-site paired associative Transcranial magnetic stimulation in the treatment of generalized anxiety disorder

Abstract

Up to 50% of patients with generalized anxiety disorder (GAD) respond poorly to drug treatment and cognitive behavioral therapy. Transcranial magnetic stimulation (TMS) has been widely used in the treatment of psychiatric diseases. The research on TMS treatment of GAD has mainly focused on the right dorsolateral prefrontal cortex (DLPFC), which is considered a key structure for processing and responding to positive and negative emotion-related information [[1]Davidson R.J. Irwin W. The functional neuroanatomy of emotion and affective style.Trends Cognit Sci. 1999; 3: 11-21https://10.1016/s1364-6613(98)01265-0Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar]. Low-frequency stimulation over the right DLPFC may relieve anxiety symptoms by downregulating reactions to negative emotional stimuli [[2]De Raedt R. Leyman L. Baeken C. Van Schuerbeek P. Luypaert R. Vanderhasselt M.A. et al.Neurocognitive effects of HF-rTMS over the dorsolateral prefrontal cortex on the attentional processing of emotional information in healthy women: an event-related fMRI study.Biol Psychol. 2010; 85: 487-495https://10.1016/j.biopsycho.2010.09.015Crossref PubMed Scopus (87) Google Scholar]. Patients with GAD have a bias toward negative stimuli, and it is difficult to divert their attention from negative stimuli [[3]Bishop S.J. Neurocognitive mechanisms of anxiety: an integrative account.Trends Cognit Sci. 2007; 11: 307-316https://10.1016/j.tics.2007.05.008Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar]. The posterior parietal cortex (PPC) is involved in the mechanisms of attentional bias [[4]Mevorach C. Humphreys G.W. Shalev L. Opposite biases in salience-based selection for the left and right posterior parietal cortex.Nat Neurosci. 2006; 9: 740-742https://10.1038/nn1709Crossref PubMed Scopus (133) Google Scholar]; therefore, the neuromodulation of the right PPC PPC may reduce attentional biases for threat (ABT) and treat symptoms. The DLPFC and parietal cortex are anatomically and functionally connected and are involved in the top-down attentional control network [[5]Marois R. Chun M.M. Gore J.C. A common parieto-frontal network is recruited under both low visibility and high perceptual interference conditions.J Neurophysiol. 2004; 92: 2985-2992https://10.1152/jn.01061.2003Crossref PubMed Scopus (30) Google Scholar]. A functional magnetic resonance imaging study in GAD patients showed an intra-amygdalar abnormality and engagement of a frontoparietal executive control network that included the DLPFC and PPC PPC [[6]Etkin A. Prater K.E. Schatzberg A.F. Menon V. Greicius M.D. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder.Arch Gen Psychiatr. 2009; 66: 1361-1372https://10.1001/archgenpsychiatry.2009.104Crossref PubMed Scopus (425) Google Scholar]. Therefore, we designed a novel stimulation pattern, repetitive dual-site paired associative stimulation (rDS-PAS), which sequentially and repetitively delivers rTMS over the right DLPFC and right inferior parietal lobe (IPL) at a fixed interstimulus interval (ISI). Hypothesizing that timing-dependent plasticity was operative in rDS-PAS, we designed three different ISIs for testing. We hypothesized that rDS-PAS at these three different ISIs may produce different therapeutic effects on the behaviour of GAD patients as indexed by clinical scales. Twenty-nine patients were enrolled and met diagnostic criteria for GAD according to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV-TR. Patients were included if they (1) had scores > 14 on the HRSA; and (2) had scores < 20 on the 24-item Hamilton Rating Scale for Depression (HRSD); and (3) were right-handed. Patients were excluded if they (1) had psychiatric diseases other than GAD; (2) had neurological or organic diseases; (3) had implanted metals in the body; (4) had substance or alcohol abuse or dependence. Patients who had been taking serotonin reuptake inhibitor medications were required to keep the type and dosage of medication unchanged four weeks prior to enrollment and throughout the study. All subjects provided written informed consent, and all procedures were approved by the Xuanwu Hospital Ethics Committee. All subjects received measurements of HRSA, HRSD and Pittsburgh Sleep Quality Index (PSQI) at baseline, posttreatment, two weeks of follow-up, and one month of follow-up. TMS was sequentially and repetitively delivered over the right DLPFC and right IPL. The site of the DLPFC was localized 5 cm directly anterior to the left abductor pollicis brevis (APB) representation in the primary motor cortex. The site of the right IPL was localized at P4, referring to the international standardized 10–20 system of electrode placement. The rTMS was delivered via two figure-of-eight coils. Coil A targeted the right DLPFC with the handle pointing posterior and lateral and oriented approximately 45° from the sagittal plane. Coil B targeted the right IPL with the handle pointing posterior medial and oriented approximately 45° from the sagittal plane. All subjects were randomly divided into three groups. IPL stimulation followed DLPFC stimulation by 10 ms (Group A, n = 9), 20 ms (Group B, n = 8) and 50 ms (Group C, n = 12). All subjects received rDS-PAS with a frequency of 1 Hz and an intensity of 90% of the resting motor threshold (RMT) of the left APB. The stimulation consisted of 15 trains of 100 pulses with an intertrain interval of 30 seconds, which were administered daily for 10 consecutive days. The statistical analysis was performed using R software (R foundation for Statistical Computing, Austria, version 3.6.1). At baseline, age, duration of disease, and clinical scores were analyzed among the three groups by one-way analysis of variance. Gender and medication exposure were analyzed by the chi-square test. A mixed model analysis, which refers to the mixture of random (intercept) and fixed effects, was performed for comparing the three groups at the four time points [[7]Belle G.V. Fisher L.D. Heagerty P.J. Lumley T. Longitudinal data analysis.in: Belle G.V. Fisher L.D. Heagerty P.J. Lumley T. Biostatistics: a methodology for the health Sciences. Wiley, Hoboken, New Jersey2004: 728-765Crossref Google Scholar]. All the data were initially tested for normality. All analyses were 2-tailed. The Bonferroni method was used to correct for multiple comparison. In each group, the clinical scores at posttreatment, two-week follow-up and one-month follow-up were compared with scores at baseline. Therefore, a total of 18 comparisons were made. The adjusted α was 0.05/18 = 0.0028; that is, p < 0.0028 indicated significance. Regarding the time trends, there were three groups to compare, and thus, the adjusted α was 0.05/3 = 0.0167. All subjects completed the entire study without adverse side effects. There were no significant differences in age, gender, medication exposures, disease duration, and baseline clinical scores among the three groups. For HRSA score, there was no interaction of time with group. In Group B and Group C, the HRSA scores significantly decreased at posttreatment, two-week follow-up, and one-month follow-up compared to baseline. There was a significant difference between Group C and Group A (p = 0.0093) (see Fig. 1). For HRSD and PSQI scores, there was no interaction of time with group. In all groups, the HRSD and PSQI scores did not significantly decrease at any posttreatment time points when compared to the baseline. There were no significant differences among the groups. This study suggests that 1 Hz rDS-PAS (with an ISI of 20 ms and 50 ms) over the right DLPFC and IPL can improve symptoms in patients with GAD. We speculate that the low-frequency rDS-PAS inhibits the hyperactivity of both the right DLPFC and IPL. The DPLFC and PPC PPC are important components of the executive control network which participates in the top-down regulation of the amygdala, the key brain region in emotional control [[8]Ochsner K.N. Gross J.J. The cognitive control of emotion.Trends Cognit Sci. 2005; 9: 242-249https://10.1016/j.tics.2005.03.010Abstract Full Text Full Text PDF PubMed Scopus (2776) Google Scholar,[9]Larson C.L. Baskin-Sommers A.R. Stout D.M. Balderston N.L. Curtin J.J. Schultz D.H. et al.The interplay of attention and emotion: top-down attention modulates amygdala activation in psychopathy.Cognit Affect Behav Neurosci. 2013; 13: 757-770https://10.3758/s13415-013-0172-8Crossref PubMed Scopus (71) Google Scholar], which shows an enhanced connection to the PPC PPC and DLPFC [[7]Belle G.V. Fisher L.D. Heagerty P.J. Lumley T. Longitudinal data analysis.in: Belle G.V. Fisher L.D. Heagerty P.J. Lumley T. Biostatistics: a methodology for the health Sciences. Wiley, Hoboken, New Jersey2004: 728-765Crossref Google Scholar]. GAD can be considered a disturbed network connectivity-based disorder, therefore, it is reasonable to modulate multiple targets in core brain regions to bring the brain network back to a balanced state. The results also suggested that the therapeutic effects of rDS-PAS depended on the stimulation intervals of the two targets. We speculate that at intervals of 10 ms, the stimulation over the right DLPFC produced an inhibition of the subsequent stimulation over the right IPL and therefore eliminated the original regulatory effect of TMS over the right IPL. The TMS study in bistable perception conducted by Vernet also showed similar frontoparietal interactions at intervals of 10 ms [[10]Vernet M. Brem A.K. Farzan F. Pascual-Leone A. Synchronous and opposite roles of the parietal and prefrontal cortices in bistable perception: a double-coil TMS-EEG study.Cortex. 2015; 64: 78-88https://10.1016/j.cortex.2014.09.021Crossref PubMed Scopus (19) Google Scholar]. We hypothesize that 10 ms probably reflects the propagation distance from the DLPFC to the IPL. rDS-PAS is a novel stimulation mode. By pairing two stimuli targeting at two brain regions that are associated with each other, the stimulation effect can be enhanced or weakened. This work was partially supported by National Key Research and Development Program of China (No. 2016YFF0201002 ), Beijing Key Clinical Specialty Excellence Project and Chinese Academy of Sciences - Austrian International Cooperation Project (No. Y8662911ZX).

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