Robert Doll

Computational modeling of Adelta-fiber-mediated nociceptive detection of electrocutaneous stimulation

Sensitization is an example of malfunctioning of the nociceptive pathway in either the peripheral or central nervous system. Using quantitative sensory testing, one can only infer sensitization, but not determine the defective subsystem. The states of the subsystems may be characterized using computational modeling together with experimental data. Here, we develop a neurophysiologically plausible model replicating experimental observations from a psychophysical human subject study. We study the effects of single temporal stimulus parameters on detection thresholds corresponding to a 0.5 detection probability. To model peripheral activation and central processing, we adapt a stochastic drift-diffusion model and a probabilistic hazard model to our experimental setting without reaction times. We retain six lumped parameters in both models characterizing peripheral and central mechanisms. Both models have similar psychophysical functions, but the hazard model is computationally more efficient. The model-based effects of temporal stimulus parameters on detection thresholds are consistent with those from human subject data.

Observation of time-dependent psychophysical functions and accounting for threshold drifts

Methods to obtain estimates of psychophysical functions are used in numerous fields, such as audiology, vision, and pain. Neurophysiological and psychological processes underlying this function are assumed to remain stationary throughout a psychophysical experiment. However, violation of this assumption (e.g., due to habituation or changing decisional factors) likely affects the estimates of psychophysical parameters. We used computer simulations to study how non-stationary processes, resulting in a time-dependent psychophysical function, affect threshold and slope estimates. Moreover, we propose methods to improve the estimation quality when stationarity is violated. A psychophysical detection experiment was modeled as a stochastic process ruled by a logistic psychophysical function. The threshold was modeled to drift over time and was defined as either a linear or nonlinear function. Threshold and slope estimates were obtained by using three estimation procedures: a static procedure assuming stationarity, a relaxed procedure accounting for linear effects of time, and a threshold tracking paradigm. For illustrative purposes, data acquired from two human subjects were used to estimate their thresholds and slopes using all estimation procedures. Threshold estimates obtained by all estimations procedures were similar to the mean true threshold. However, due to threshold drift, the slope was underestimated by the static procedure. The relaxed procedure only underestimated the slope when the threshold drifted nonlinearly over time. The tracking paradigm performed best and therefore, we recommend using the tracking paradigm in human psychophysical detection experiments to obtain estimates of the threshold and slope and to identify the mode of non-stationarity.

Dependence of Nociceptive Detection Thresholds on Physiological Parameters and Capsaicin-Induced Neuroplasticity: A Computational Study

Physiological properties of peripheral and central nociceptive subsystems can be altered over time due to medical interventions. The effective change for the whole nociceptive system can be reflected in changes of psychophysical characteristics, e.g., detection thresholds. However, it is challenging to separate contributions of distinct altered mechanisms with measurements of thresholds only. Here, we aim to understand how these alterations affect Aδ-fiber-mediated nociceptive detection of electrocutaneous stimuli. First, with a neurophysiology-based model, we study the effects of single-model parameters on detection thresholds. Second, we derive an expression of model parameters determining the functional relationship between detection thresholds and the interpulse interval for double-pulse stimuli. Third, in a case study with topical capsaicin treatment, we translate neuroplasticity into plausible changes of model parameters. Model simulations qualitatively agree with changes in experimental detection thresholds. The simulations with individual forms of neuroplasticity confirm that nerve degeneration is the dominant mechanism for capsaicin-induced increases in detection thresholds. In addition, our study suggests that capsaicin-induced central plasticity may last at least 1 month.

Pharmacodynamic Evaluation: Pain Methodologies

Despite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds with fewer side effects is therefore essential. With an increased demand to demonstrate pharmacodynamic effects of new analgesic compounds, the importance of human evoked pain models is now higher than ever. Pharmacodynamic evaluation with human evoked pain models offers the possibility to determine the dose ranges at which new analgesics exert their pharmacological effect. Pain models may also aid in the choice of target population, determine which modality of pain a new drug is expected to be most suitable, help to differentiate between a central or more peripheral mode of action of new drugs, and help determine which other effects contribute to its mode of action, e.g., sedation. Human evoked pain models are conducted in standardized laboratories where factors like P. Siebenga · P. Okkerse · G. van Amerongen · R.J. Doll · A. Mentink · J. Hay · G.J. Groeneveld (*) Centre for Human Drug Research, Leiden, The Netherlands e-mail: psiebenga@chdr.nl; pokkerse@chdr.nl; gvamerongen@chdr.nl; rjdoll@chdr.nl; amentink@chdr. nl; jhay@chdr.nl; ggroeneveld@chdr.nl # Springer International Publishing AG 2018 F.J. Hock, M.R. Gralinski (eds.), Drug Discovery and Evaluation: Methods in Clinical Pharmacology, https://doi.org/10.1007/978-3-319-56637-5_56-1 1 stimulus intensity, frequency, duration, and location can be controlled. Using pain models in healthy volunteers has important advantages over assessing the effects of new drugs in patients with pain; the pain elicited in human pain models is predictable in its intensity while clinical pain will naturally fluctuate. Analgesic properties can be investigated with pain models without the influence of accompanying symptoms that are often seen in patients with pain. General Introduction Pain is intended as a warning to the body that a noxious stimulus can (potentially) harm the body. The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (Bonica 1979). Prevalence studies show that in Western countries 19–31% of the adult population suffers from a form of chronic pain (Macfarlane et al. 2013; Moore et al. 2015). Despite the availability of potent analgesics such as opioids, chronic pain remains a high unmet medical need as many effective analgesics have important side effects and chronic treatment with opioids leads to tolerance and addiction. The development of better and more specific analgesic compounds therefore remains essential. With an increased demand to demonstrate pharmacodynamic effects of new compounds as early as possible in clinical drug studies, the importance of human evoked pain models is now more than ever. In a pure neurophysiological sense, nociceptive pain occurs when nociceptors are stimulated by noxious stimuli (e.g., mechanical, thermal, electrical, or chemical stimuli). After a threshold has been reached, the nociceptive nerve fiber transmits the pain signal to the spinal cord. The signal is modulated at several locations along ascending pathways through the dorsal horn and spinal cord. From the spinal cord, the pain signal is projected to supraspinal centers where the brain can modulate the excitatory activity via descending control (Olesen et al. 2012). Perception of pain is even more complex where more than one sensory system is responsible for transmission of the painful stimulus (Aguggia 2003). From a more neuropsychosocial point of view, pain is a complex experience influenced by many factors such as emotion, fear, anxiety, but also cultural background, sex, genetics, and educational background. Due to its complexity, it can be difficult to assess the effects of analgesic drugs on pain in patients, and animal pain models demonstrate low predictability for clinical efficacy in humans. Several explanations are receptor dissimilarity between species, differences in pharmacokinetics, and morphological and functional differences between the brains of animals and humans (Olesen et al. 2012). Human evoked pain models can control some of these influencing factors. Therefore, these models are an important step in the translation of animal research to pain patients. Pharmacodynamic evaluation through human evoked pain models offers the possibility to differentiate between a centrally or peripherally acting drug, for which modality of pain a new drug will be most suitable (nociceptive, neuropathic, or inflammatory), and which other effects contribute to its mode of action (e.g., sedation, tolerance) (Oertel and Lötsch 2013; Okkerse et al. 2017; Olesen et al. 2012; Staahl et al. 2009a). This can be done in early clinical trials with healthy volunteers, which is not only cost-reducing but also time saving. Other advantages of using human evoked pain models are (1) stimulus intensity, duration, and modality are controlled and do not vary over time; (2) differentiated responses to different standardized stimulus modalities; (3) the response can be assessed quantitatively and compared over time; (4) pain sensitivity can be compared quantitatively between various normal/ affected/treated regions; (5) models of pathological conditions can be studied and the effects of drugs on such mechanisms quantified; and (6) pain models can be easily performed in healthy subjects, who are easier to recruit into clinical studies (Arendt-Nielsen et al. 2007a). Evoked pain is mostly short-lasting, with most stimuli being applied exogenously and are 2 P. Siebenga et al.