Katarina Forkmann

The effect of treatment history on therapeutic outcome: an experimental approach.

Therapeutic context can critically determine treatment outcome.1 Prior experience with a treatment is an important contextual factor that has been shown to modulate treatment efficacy.2,3 To date, this influence of prior treatment experience has been studied only within the same treatment approach. However, in clinical practice, treatments are often changed, particularly in case of failure. The aim of this study was therefore to investigate whether the effects of treatment history carry over from one treatment approach to another.

Pain-specific modulation of hippocampal activity and functional connectivity during visual encoding.

Acute and chronic pain automatically attract attention and thus interfere with cognitive functioning. Impaired memory is a prominent complaint of patients with chronic pain that substantially contributes to pain-related disability. In this fMRI study, we investigated the specific influence of pain on neural processes of memory encoding in healthy human volunteers using a visual task. To investigate the specificity of the interruptive effect of pain on the encoding of visual objects, objects were presented (1) alone, (2) with painful heat stimuli, or (3) with auditory stimuli that were matched for unpleasantness to the heat stimuli. The interruptive effect of concomitant aversive stimulation on behavioral measures and neural processing was assessed in a categorization task during encoding and in a subsequent recognition task. Pain interfered with object processing and encoding of visual stimuli. On the behavioral level, this resulted in slower reaction times during the categorization task for pain compared with auditory stimuli and in a lower recognition rate in the pain condition but not in the tone condition. Pain catastrophizing amplified this interruptive effect of pain. On the neural level, this pain-related disruption of encoding was associated with reduced activity in the right anterior hippocampus during encoding. Moreover, the hippocampus exhibited reduced functional connectivity with extrastriate regions during painful stimulation relative to auditory stimulation. In summary, our results show a pain-related disruption of visual encoding over and above the unpleasantness of a stimulus, suggesting a pain-specific interruptive mechanism that interferes with an early stage of memory formation.

Age-dependent decline of endogenous pain control: exploring the effect of expectation and depression.

Although chronic pain affects all age ranges, it is particularly common in the elderly. One potential explanation for the high prevalence of chronic pain in the older population is impaired functioning of the descending pain inhibitory system which can be studied in humans using conditioned pain modulation (CPM) paradigms. In this study we investigated (i) the influence of age on CPM and (ii) the role of expectations, depression and gender as potential modulating variables of an age-related change in CPM. 64 healthy volunteers of three different age groups (young = 20–40 years, middle-aged = 41–60 years, old = 61–80 years) were studied using a classical CPM paradigm that combined moderate heat pain stimuli to the right forearm as test stimuli (TS) and immersion of the contralateral foot into ice water as the conditioning stimulus (CS). The CPM response showed an age-dependent decline with strong CPM responses in young adults but no significant CPM responses in middle-aged and older adults. These age-related changes in CPM responses could not be explained by expectations of pain relief or depression. Furthermore, changes in CPM responses did not differ between men and women. Our results strongly support the notion of a genuine deterioration of descending pain inhibitory mechanisms with age.

The Effect of Treatment History on Therapeutic Outcome: Psychological and Neurobiological Underpinnings

It is increasingly recognized that the efficacy of medical treatments is determined in critical part by the therapeutic context in which it is delivered. An important characteristic of that context is treatment history. We recently reported first evidence for a carry-over of treatment experience to subsequent treatment response across different treatment approaches. Here we expand on these findings by exploring the psychological and neurobiological underpinnings of the effect of treatment experience on future treatment response in an experimental model of placebo analgesia with a conditioning procedure. In a combined behavioral and neuroimaging study we experimentally induced positive or negative experiences with an analgesic treatment in two groups of healthy human subjects. Subsequently we compared responses to a second, different analgesic treatment between both groups. We found that participants with an experimentally induced negative experience with the first treatment showed a substantially reduced response to a second analgesic treatment. Intriguingly, several psychological trait variables including anxiety, depression and locus of control modulate the susceptibility for the effects of prior treatment experiences on future treatment outcome. These behavioral effects were supported by neuroimaging data which showed significant differences in brain regions encoding pain and analgesia between groups. These differences in activation patterns were present not only during the pain phase, but also already prior to painful stimulation and scaled with the individual treatment response. Our data provide behavioral and neurobiological evidence showing that the influence of treatment history transfers over time and over therapeutic approaches. Our experimental findings emphasize the careful consideration of treatment history and a strictly systematic treatment approach to avoid negative carry-over effects.

Phasic and Tonic Pain Differentially Impact the Interruptive Function of Pain

The interruptive effect of painful experimental stimulation on cognitive processes is a well-known phenomenon. This study investigated the influence of pain duration on the negative effects of pain on cognition. Thirty-four healthy volunteers performed a rapid serial visual presentation task (RSVP) in which subjects had to detect (visual detection task) and count the occurrence of a target letter (working memory task) in two separate sessions while being stimulated on the left volar forearm with either short (2 sec) or long (18 sec) painful heat stimuli of equal subjective intensity. The results show that subjects performed significantly worse in the long pain session as indexed by decreased detection and counting performance. Interestingly, this effect on performance was also observed during control trials of the long pain session in which participants did not receive any painful stimulation. Moreover, subjects expected long painful stimulation to have a greater impact on their performance and individual expectation correlated with working memory performance. These findings suggest that not only the length of painful stimulation but also its expected ability to impair cognitive functioning might influence the interruptive function of pain. The exact relevance of expectation for the detrimental effects of pain on cognitive processes needs to be explored in more detail in future studies.

Greater fear of visceral pain contributes to differences between visceral and somatic pain in healthy women

Abstract This functional magnetic resonance imaging study addressed similarities and differences in behavioral and neural responses to experimental visceral compared with somatic pain stimuli and explored the contribution of fear of pain to differences between pain modalities. In N = 22 healthy women, we assessed blood oxygen level–dependent responses to rectal distensions and cutaneous heat stimuli matched for perceived pain intensity. Fear of pain and pain unpleasantness were assessed before and after scanning. Visceral pain was more fear evoking and more unpleasant, and trial-by-trial intensity ratings failed to habituate across trials (all interactions modality × time: P < 0.01). Differences in fear of pain and pain intensity independently contributed to greater visceral pain unpleasantness (combined regression model: R2 = 0.59). We observed joint neural activations in somatosensory cortex and frontoparietal attention network (conjunction analysis: all pFWE <0.05), but distensions induced greater activation in somatosensory cortex, dorsal and ventral anterior insula, dorsal anterior and midcingulate cortices, and brainstem, whereas cutaneous heat pain led to enhanced activation in posterior insula and hippocampus (all pFWE <0.05). Fear of visceral pain correlated with prefrontal activation, but did not consistently contribute to neural differences between modalities. These findings in healthy women support marked differences between phasic pain induced by rectal distensions vs cutaneous heat, likely reflecting the higher salience of visceral pain. More studies with clinically relevant pain models are needed to discern the role of fear in normal interindividual differences in the response to different types of pain and as a putative risk factor in the transition from acute to chronic pain.

Expectations impact short-term memory through changes in connectivity between attention- and task-related brain regions

Over the recent years, neuroimaging studies have investigated the neural mechanisms underlying the influence of expectations on perception. However, it seems equally reasonable to assume that expectations impact cognitive functions. Here we used fMRI to explore the role of expectations on task performance and its underlying neural mechanisms. 43 healthy participants were randomly assigned to two groups. Using verbal instructions, group 1 was led to believe that pain enhances task performance while group 2 was instructed that pain hampers their performance. All participants performed a Rapid-Serial-Visual-Presentation (RSVP) Task (target detection and short-term memory component) with or without concomitant painful heat stimulation during 3T fMRI scanning. As hypothesized, short-term memory performance showed an interaction between painful stimulation and expectation. Positive expectations induced stronger neural activation in the right inferior parietal cortex (IPC) during painful stimulation than negative expectation. Moreover, IPC displayed differential functional coupling with the left inferior occipital cortex under pain as a function of expectancy. Our data show that an individuals expectation can influence cognitive performance in a visual short-term memory task which is associated with activity and connectivity changes in brain areas implicated in attentional processing and task performance.

Quantitative Sensory Testing in adults with Autism Spectrum Disorders

Altered sensory perception has been found in patients with autism spectrum disorders (ASD) and might be related to aberrant sensory perception thresholds. We used the well-established, standardized Quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain to investigate 13 somatosensory parameters including thermal and tactile detection and pain thresholds in 13 ASD adults and 13 matched healthy controls with normal IQ values. There were no group differences between somatosensory detection and pain thresholds. Two ASD patients showed paradoxical heat sensations and another two ASD subjects presented dynamic mechanical allodynia; somatosensory features that were absent in controls. These findings suggest that central mechanisms during complex stimulus integration rather than peripheral dysfunctions probably determine somatosensory alterations in ASD.

Reinstatement of pain-related brain activation during the recognition of neutral images previously paired with nociceptive stimuli.

Abstract Remembering an event partially reactivates cortical and subcortical brain regions that were engaged during its experience and encoding. Such reinstatement of neuronal activation has been observed in different sensory systems, including the visual, auditory, olfactory, and somatosensory domain. However, so far, this phenomenon of incidental memory has not been explored in the context of pain. In this functional magnetic resonance imaging study, we investigated the neural reinstatement of pain-related and tone-related activations during the recognition of neutral images that had been encoded during (1) painful stimulation, (2) auditory stimulation of comparable unpleasantness, or (3) no additional stimulation. Stimulus-specific reinstatement was tested in 24 healthy male and female participants who performed a visual categorization task (encoding) that was immediately followed by a surprise recognition task. Neural responses were acquired in both sessions. Our data show a partial reinstatement of brain regions frequently associated with pain processing, including the left posterior insula, bilateral putamen, and right operculum, during the presentation of images previously paired with painful heat. This effect was specific to painful stimuli. Moreover, the bilateral ventral striatum showed stronger responses for remembered pain-associated images as compared with tone-associated images, suggesting a higher behavioral relevance of remembering neutral pictures previously paired with pain. Our results support the biological relevance of pain in that only painful but not equally unpleasant auditory stimuli were able to “tag” neutral images during their simultaneous presentation and reactivate pain-related brain regions. Such mechanisms might contribute to the development or maintenance of chronic pain and deserve further investigation in clinical populations.

Pain Affects Visual Orientation: an Eye-Tracking Study

Because of its unique evolutionary relevance, it is understood that pain automatically attracts attention. So far, such attentional bias has mainly been shown for pain-related stimuli whereas little is known about shifts in attentional focus after actual painful stimulation. This study investigated attentional shifts by assessing eye movements into the direction of painful stimulation. Healthy participants were presented either a blank screen or a picture showing a natural scene while painful electrical stimuli were applied to the left or right hand. In general, painful stimulation reduced exploratory behavior as reflected by less and slower saccades as well as fewer and longer fixations. Painful stimulation on the right hand induced a rightward bias (ie, increased initial saccades, total number and duration of fixations to the right hemifield of the screen). Pain applied to the left hand as well as no pain induced a leftward bias that was largest for the direction of first saccades. These findings are in line with previous observations of attentional biases toward pain-related information and highlight eye tracking as a valuable tool to assess involuntary attentional consequences of pain. Future studies are needed to investigate how the observed changes in eye movements relate to pain-induced changes in perception and cognition. PERSPECTIVE The study investigated pain-induced attentional shifts in terms of reflexive eye movements. This attention-capturing quality of pain should be examined in chronic pain conditions because it might contribute to the cognitive impairments often observed in chronic pain patients.