Latent variable analysis of negative affect and its contributions to neural responses during shock anticipation

Abstract

Negative affect is considered an important factor in the etiology of depression and anxiety, and is highly related to pain. However, negative affect is not a unitary construct. To identify specific targets for treatment development, we aimed to derive latent variables of negative affect and test their unique contributions to affective processing during anticipation of unpredictable, painful shock. Eighty-three subjects (43 with depression and anxiety spectrum disorders and 40 healthy controls) completed self-report measures of negative valence and underwent neuroimaging while exploring computer-simulated contexts with and without the threat of a painful, but tolerable, shock. Principal component analysis (PCA) extracted distinct components of general negative affect (GNA) and pain-related negative affect (PNA). While elevated GNA and PNA were both indicative of depression and anxiety disorders, greater PNA was more strongly related to task-specific anxious reactivity during shock anticipation. GNA was associated with increased precuneus and middle frontal gyrus activity, whereas PNA was related to increased bilateral anterior insula activity. Anterior insula activity mediated the relationship between PNA and task-specific anxious reactivity. In conclusion, GNA and PNA have distinct neural signatures and uniquely contribute to anxious anticipation. PNA, via insula activity, may relate to arousal in ways that could contribute to affective dysregulation, and thus may be an important treatment target.

Fig. 1

Anticipation of unpredictable, painful shock task [40]. a During the task, subjects explored two contexts, one in which there was a threat (T) of receiving a painful electric shock stimulation at any time, and one in which they were safe (S) from receiving any shock. The acronyms colored in red denote contextual epochs in which unsignaled shocks were administered. b Static pictures of the computer-simulated rooms that served as threat and safe contexts. c Following each threat context in which an electric shock was administered, subjects rated the intensity of the shock received. d Following each scan, subjects also retrospectively rated how fearful they were in the threat and safe contexts using a 0–100 scale

Fig. 2

During anticipation of unpredictable, painful shock, general negative affect (GNA) was related to increased hemodynamic activity in the left precuneus (lPRE) and right middle frontal gyrus (rMFG), while pain-related negative affect was related to increased hemodynamic activity in the bilateral dorsal anterior insula (dAI). Greater hemodynamic responses to anticipation of unpredictable shock in the left and right dAI were related to greater SA and SCRs across all participants. Left is left

Fig. 3

The pathways from pain-related negative affect (PNA) to the left and right dorsal anterior insula (dAI; path a), and then from dAI to subjective anxiety (SA) and skin conductance responses (SCRs; path b) represent indirect effects of PNA on anxious reactivity through dAI activity, respectively (quantified as the product of paths a and b). Pathway c represents the direct effect of PNA on anxious reactivity. Model coefficients are reported in an unstandardized form, thus they map directly onto the measurement scales used. A 95% confidence interval (CI) for the indirect effect (ab) does not contain and is entirely above zero providing evidence that dAI serves as a mediator of the effect of pain-related negative affect on anxious reactivity