The crossroads of anxiety: distinct neurophysiological maps for different symptomatic groups

Abstract

Background: Despite the devastating impact of anxiety disorders (ADs) worldwide, long-lasting debates on causes and remedies have not solved the clinician's puzzle: who should be treated and how? Psychiatric classifications conceptualize ADs as distinct entities, with strong support from neuroscience fields. Yet, comorbidity and pharmacological response suggest a single "serotonin dysfunction" dimension. Whether AD is one or several disorders goes beyond academic quarrels, and the distinction has therapeutic relevance. Addressing the underlying dysfunctions should improve treatment response. By its own nature, neurophysiology can be the best tool to address dysfunctional processes.

Purpose: To search for neurophysiological dysfunctions and differences among panic disorder (PD), agoraphobia-social-specific phobia, obsessive-compulsive disorder (OCD) and generalized anxiety disorder.

Methods: A sample population of 192 unmedicated patients and 30 aged-matched controls partook in this study. Hypothesis-related neurophysiological variables were combined into ten independent factors: 1) dysrhythmic patterns, 2) delta, 3) theta, 4) alpha, 5) beta (whole-head absolute power z-scores), 6) event-related potential (ERP) combined latency, 7) ERP combined amplitude (z-scores), 8) magnitude, 9) site, and 10) site of hyperactive networks. Combining single variables into representative factors was necessary because, as in all real-life phenomena, the complexity of interactive processes cannot be addressed through single variables and the multiplicity of potentially implicated variables would demand an extremely large sample size for statistical analysis.

Results: The nonparametric analysis correctly classified 81% of the sample. Dysrhythmic patterns, decreased delta, and increased beta differentiated AD from controls. Shorter ERP latencies were found in several individual patients, mostly from the OCD group. Hyperactivities were found at the right frontorbital-striatal network in OCD and at the panic circuit in PD.

Conclusions: Our findings support diffuse cortical instability in AD in general, with individual differences in information processing deficits and regional hyperactivities in OCD and PD. Study limitations and the rationale behind the variable selection and combination strategy will be discussed before addressing the therapeutic implications of our findings.

Keywords: EEG; ERP; LORETA; anxiety disorders; dysrhythmic; epileptiform.

Figure 1

Multiple correspondence analysis. Notes: Mosaic plots of the three categorical factors: dysrhythmic patterns (EPI) are shown in the box on the left, network (nROI) in the middle box, and side in the box on the right. Dysrhythmic patterns (EPI, left plot) were more frequent in the PD and OCD groups; hyperactive nROIs (middle plot) from the frontostriatal network were more frequent in the OCD group, predominantly on the right side (right plot). Abbreviations: CNTRL, control; dn, dorsal attention; EPI, epileptiform patterns at visual inspection; fn, extended orbito-fronto-striatal; GAD, generalized anxiety; OCD, obsessive–compulsive disorder; PD, panic disorder; pn, extended panic; nROI, network representative combination of ROIs; ROI, region of interest; SP, agoraphobia-social-specific phobia.

Figure 2

Probabilistic neural network classifier. Notes: Scatterplot of the individual scores on the three measurements with highest discriminant weight: nbzLORETA, ERPa and WHBP. Segregation is clearer for the CNTRL (green), GAD (yellow), and SP (purple), with some overlap between the OCD (gray) and PD (red). These two groups showed more differences in nROI location and side, which are not plotted in this graph. Notice that each of these factors relates to one of the three hypothetical dysfunctions. Abbreviations: CNTRL, control; ERPa, amplitude of the event-related-potentials; GAD, generalized anxiety disorder; nbzLORETA, highest network-broadband z values of current source density; nROI, network representative combination of ROIs; OCD, obsessive–compulsive disorder; PD, panic disorder; SP, agoraphobia-social-specific phobia; WHBP, whole-head beta power.

Figure 3

Group-mean maps of absolute power z-scores in the four conventional bands, and bzLORETA of the generalized anxiety disorder (GAD), obsessive–compulsive disorder (OCD), panic disorder (PD), and agoraphobia-social-specific phobia (SP) groups. Notes: Decreased delta and increased beta were found in all groups. Focal changes in several bands were seen in the right frontal region of the OCD group and temporal regions in the PD group. bzLORETA was significantly increased at anterior cingulate in GAD, orbital and right extranuclear regions in OCD, bilateral amygdala and hippocampus and right insula in PD. Power z-scores on the right-side scale, bzLORETA scores on the left-side scale. Abbreviations: bzLORETA, broadband z-transformed low-resolution electromagnetic topography; CNTRL, control.

Figure 4

Individual examples of EEG trace (C), ERP, P300 response (B), absolute power (A), and bzLORETA maps (lower panels) of two patients with obsessive–compulsive disorder. Notes: Epileptiform activity was seen in the EEG of one patient (A) but not in the other (C). Both showed power increases at more than two bands, earlier P300 response, and increased bzLORETA at orbital and right extranuclear regions. Abbreviations: bzLORETA, broadband z-transformed low-resolution electromagnetic topography; EEG, electroencephalogram; ERP, event-related potential.

Figure 5

Scatterplot of vectors for the discriminant functions. Note: The first derived function (Function 1) separates the PD and OCD groups from all others while the second (Function 2) contributes to the definition among all. Abbreviations: CNTRL, control; GAD, generalized anxiety disorder; OCD, obsessive–compulsive disorder; PD, panic disorder; SP, agoraphobia-social-specific phobia.