Jonas Zaman

Associative fear learning and perceptual discrimination: a perceptual pathway in the development of chronic pain.

Recent neuropsychological theories emphasize the influence of maladaptive learning and memory processes on pain perception. However, the precise relationship between these processes as well as the underlying mechanisms remain poorly understood; especially the role of perceptual discrimination and its modulation by associative fear learning has received little attention so far. Experimental work with exteroceptive stimuli consistently points to effects of fear learning on perceptual discrimination acuity. In addition, clinical observations have revealed that in individuals with chronic pain perceptual discrimination is impaired, and that tactile discrimination training reduces pain. Based on these findings, we present a theoretical model of which the central tenet is that associative fear learning contributes to the development of chronic pain through impaired interoceptive and proprioceptive discrimination acuity.

Influence of prior information on pain involves biased perceptual decision-making.

Summary Prior information about features of a stimulus is a strong modulator of perception. For instance, the prospect of more intense pain leads to an increased perception of pain, whereas the expectation of analgesia reduces pain, as shown in placebo analgesia and expectancy modulations during drug administration [1]. This influence is commonly assumed to be rooted in altered sensory processing and expectancy-related modulations in the spinal cord [2], are often taken as evidence for this notion. Contemporary models of perception, however, suggest that prior information can also modulate perception by biasing perceptual decision-making — the inferential process underlying perception in which prior information is used to interpret sensory information. In this type of bias, the information is already present in the system before the stimulus is observed [3]. Computational models can distinguish between changes in sensory processing and altered decision-making as they result in different response times for incorrect choices in a perceptual decision-making task (Figure S1A,B) [4]. Using a drift-diffusion model, we investigated the influence of both processes in two independent experiments. The results of both experiments strongly suggest that these changes in pain perception are predominantly based on altered perceptual decision-making.

Perceptual discrimination in fear generalization: Mechanistic and clinical implications

For almost a century, Pavlovian conditioning is the imperative experimental paradigm to investigate the development and generalization of fear. However, despite the rich research tradition, the conceptualization of fear generalization has remained somewhat ambiguous. In this selective review, we focus explicitly on some challenges with the current operationalization of fear generalization and their impact on the ability to make inferences on its clinical potential and underlying processes. The main conclusion is that, despite the strong evidence that learning influences perception, current research has largely neglected the role of perceptual discriminability and its plasticity in fear generalization. We propose an alternative operationalization of generalization, where the essence is that Pavlovian conditioning itself influences the breadth of fear generalization via learning-related changes in perceptual discriminability. Hence a conceptualization of fear generalization is incomplete without an in-depth analysis of processes of perceptual discriminability. Furthermore, this highlights perceptual learning and discriminability as important future targets for pre-clinical and clinical research.

Influence of Interoceptive Fear Learning on Visceral Perception.

Objectives Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. Methods In a novel fear learning–generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. Results Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). Conclusions These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity.

Learning to breathe? Feedforward regulation of the inspiratory motor drive

Claims have been made that breathing is in part controlled by feedforward regulation. In a classical conditioning paradigm, we investigated anticipatory increases in the inspiratory motor drive as measured by inspiratory occlusion pressure (P100). In an acquisition phase, an experimental group (N=13) received a low-intensity resistive load (5 cmH2O/l/s) for three consecutive inspirations as Conditioned Stimulus (CS), preceding a load of a stronger intensity (20 cmH2O/l/s) for three subsequent inspirations as unconditioned stimulus (US). The control group (N=11) received the low-intensity load for six consecutive inspirations. In a post-acquisition phase both groups received the low-intensity load for six consecutive inspirations. Responses to the CS-load only differed between groups during the first acquisition trials and a strong increase in P100 during the US-loads was observed, which habituated across the experiment. Our results suggest that the disruption caused by adding low to moderate resistive loads to three consecutive inspirations results in a short-lasting anticipatory increase in inspiratory motor drive.

Anxiety, pCO2 and cerebral blood flow.

This study examined the effect of anxiety on cerebral blood flow at different levels of pCO2 in healthy participants (N=29). Three types of breathing were used to manipulate pCO2 in a within-subject threat-of-shock paradigm: spontaneous breathing, CO2-inhalation and hyperventilation resulting in normo-, hyper- and hypocapnia. Transcranial Doppler ultrasonography was used to measure CBF velocity (CBFv) in the right middle cerebral artery, while breathing behavior and end-tidal pCO2 were monitored. During normocapnia, elevated anxiety was clearly associated with increased CBFv. Consistent with the cerebral vasoconstrictive and vasodilating effects of, respectively, hypo- and hypercapnia, we observed a positive linear association between CBFv and pCO2. The slope of this association became steeper with increasing anxiety, indicating that anxiety enhances the sensitivity of CBFv to changes in pCO2. The findings may elucidate conflicting findings in the literature and are relevant for brain imaging relying on regional cerebral blood flow.

Gradients of fear: How perception influences fear generalization☆☆☆

The current experiment investigated whether overgeneralization of fear could be due to an inability to perceptually discriminate the initial fear-evoking stimulus from similar stimuli, as fear learning-induced perceptual impairments have been reported but their influence on generalization gradients remain to be elucidated. Three hundred and sixty-eight healthy volunteers participated in a differential fear conditioning paradigm with circles of different sizes as conditioned stimuli (CS), of which one was paired to an aversive IAPS picture. During generalization, each subject was presented with one of 10 different sized circles including the CSs, and were asked to categorize the stimulus as either a CS or as novel after fear responses were recorded. Linear mixed models were used to investigate differences in fear generalization gradients depending on the participants perception of the test stimulus. We found that the incorrect perception of a novel stimulus as the initial fear-evoking stimulus strongly boosted fear responses. The current findings demonstrate that a significant number of novel stimuli used to assess generalization are incorrectly identified as the initial fear-evoking stimulus, providing a perceptual account for the observed overgeneralization in panic and anxiety disorders. Accordingly, enhancing perceptual processing may be a promising treatment for targeting excessive fear generalization.

Interoceptive cues predicting exteroceptive events

The growing body of research on interoceptive conditioning has predominantly focused on associative learning paradigms that investigated the formation of intero-interoceptive or extero-interoceptive associations. Yet, little research has explored whether interoceptive sensations can enter an intero-exteroceptive association. Therefore, in an interoceptive conditioning paradigm, healthy participants experienced a respiratory resistance for 8s, causing mild dyspnea (interoceptive conditioned stimulus, CS), that was either paired to an aversive electrocutaneous stimulus (unconditioned stimulus, US) (experimental condition, n=25), or presented in an unpaired fashion (control condition, n=25) during the acquisition phase. In a subsequent extinction phase, the US was not delivered anymore. US-expectancy, skin conductance responses (SCR), and eyeblink startle EMG were used as indices of associative learning. During acquisition, we observed stronger US expectancies during the CS as compared to the intertrial interval in the experimental group, but not in the control group, nor during extinction. In line, only in the experimental group did skin conductance responses to the CS increase across acquisition. The pattern of the eyeblink startle data did not reach statistical significance. In sum, interoceptive sensations can become associated with exteroceptive events.

Effect of seated trunk posture on eye blink startle and subjective experience: comparing flexion, neutral upright posture, and extension of spine

Postures are known to be able to affect emotion and motivation. Much less is known about whether (affective) modulation of eye blink startle occurs following specific postures. The objective of the current study was to explore this. Participants in the present study were requested to assume three different sitting postures: with the spine flexed (slouched), neutral upright, and extended. Each posture was assumed for four minutes, and was followed by the administration of brief self-report questionnaires before proceeding to the next posture. The same series of postures and measures were repeated prior to ending the experiment. Results indicate that, relative to the other postures, the extended sitting posture was associated with an increased startle, was more unpleasant, arousing, had smaller levels of dominance, induced more discomfort, and was perceived as more difficult. The upright and flexed sitting postures differed in the level of self-reported positive affect, but not in eye blink startle amplitudes.

Cortico-brainstem mechanisms of biased perceptual decision-making in the context of pain

Perceptual decision-making is commonly studied using stimuli with different physical properties but of comparable affective value. Here, we investigate neural processes underlying human perceptual decisions in the affectively rich domain of pain using a drift-diffusion model in combination with a probabilistic cueing paradigm. This allowed us to characterize a novel role for the dorsolateral prefrontal cortex (DLPFC), whose anticipatory responses reflecting a decision bias were dependent on the affective value of the stimulus. During intense noxious stimulation, these model-based anticipatory DLPFC responses were linked to an engagement of the periaqueductal gray (PAG), a midbrain region implicated in defensive responses including analgesia. Complementing these findings on biased decision-making, the model parameter reflecting sensory processing predicted subcortical responses (in amygdala and PAG) when expectations were violated. Our findings highlight the importance of taking a broader perspective on perceptual decisions and link decisions about pain with subcortical circuitry implicated in endogenous pain modulation.