Clinical trial NCT03739645: Human Behaviors Related to the Expectation of Pain
Official title: Physiological Studies in Healthy Subjects, Chronic Pain Patients and in Patients Undergoing Neurosurgical Procedures of Human Forebrain Mechanisms Mediating Somatic Sensation, Motor Control and Neurological Disorders
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Fear Pain
Keywords: fear
pain
conditioning
skin conductance response
Ratings of Pain and Conditioning
Eye position metrics
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: University of Maryland
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2018-11-14
Enrollment: 32
Sex: ALL
Minimum age (years): 16
Maximum age (years): 88
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Analysis of eye position and skin conductance levels will be examined to identify attentional and anxiety related processes for the fear of pain during the conditioned stage. Correlation of skin conductance levels versus slopes during the conditioning stage with state versus trait anxiety will be taken as confirmatory evidence. Power analysis for a two-way ANOVA was conducted to determine a sufficient sample size using an alpha of 0.05, power 0.80, a high effect size (pilot data indicate η2 values for main effects \> 0.5). Based on these assumptions, we conservatively use a sample size of 40.
Primary purpose: BASIC_SCIENCE

Brief summary: The conditioned expectation of pain is an important aspect of pain-related disability produced by environments and stimuli associated with a painful injury on the job, although the neuroscience of this expectation is unclear. We will develop and use novel objective methods for measurement of expectation and threat related attention. The results of this study may lead to testable hypotheses regarding the psychological basis of the fear of pain, threat and task related attention. We will also use these results, and development of novel autonomic and ratings metrics for state and trait anxiety as well as threat and task related attention which could be used as an instrumented test for diagnosis and management of PTSD and anxiety disorders. .

Detailed description: The conditioned expectation or fear of pain often results in disability produced by stimuli related to a painful injury on the job, although there are questions about attentional and anxiety related expectation. Conditioned expectation in humans can be produced by a protocol that consists of a train of two visual conditioning stimuli, one of which is paired (CS+) with a painful laser pulse unconditioned stimulus (US), while the other is not. This protocol will be used to study the expectation of pain in this study, and its relationship to task and threat related attention measured by eye position and to anxiety, task directed sustained attention, and scalp EEG metrics. These results may also be used in an instrumented test for the diagnosis and management of PTSD and anxiety disorders.

EEG studies may clarify the relationship of unpleasantness (valence) and the ability of stimuli to command attention (salience) of the conditioned and unconditioned stimuli which which are significant but under studied aspects of the fear of the pain. Studies of scalp EEG activation and functional connectivity will be used to estimate global properties of the forebrain networks involved in the fear of pain, as well as the valence and the salience) of the conditioned and unconditioned stimuli.

Activations are measured by the proportion of electrodes over a quadrant or lobe of the scalp a significant ratio of electrical power following an event over baseline (event related spectral perturbation, ERSP). Functional connectivity will be measured by causal interactions following an event over baseline. The approach of this protocol is that causal interactions are based upon causal influences by an approach based upon the concept of linear predictability. Briefly, a signal Y is said to exert an influence upon signal X when the predication error of the X is reduced by adding the past information of Y (causal interaction). The signals from any two quadrants or lobes will be analyzed by event related causality to determine the magnitude and direction of causal interactions between the two to determine fear and pain related directed interactions related to aversive conditioning.

Our Preliminary Data shows EEG activations in global distributed forebrain networks for the expectation of pain are consistent with the evidence of studies of anatomic projections and functional MRI (fMRI) signals. These models including our Preliminary Data from intracranial recordings identify structures in the medial temporal lobe (amygdala and hippocampus) which are involved in expectation of pain, while EEG suggests global activations related to valence and salience of conditioned and unconditioned stimuli. The premise of this study is that novel autonomic and eye position metrics will measure state and trait anxiety as well as threat and task related attention to parse out the experience and anticipation of pain.

Eligibility criteria: Inclusion Criteria:

* Man or woman between 18 and 80 years of age.
* Fluent speaker of English.
* Undergoing seizure monitoring at Hopkins Hospital through intracranial electrodes.
* Possess ability to understand study procedures and comply with them for the entire length of the study;
* Women of childbearing age must use pharmacological contraception (oral or patch) for the duration of the study follow-up.

Exclusion Criteria:

* Inability or unwillingness of individual to give written informed consent. Presence of any neurological disease other than epilepsy which is unstable or is not optimally treated.
* Presence of a significant abnormality on routine neuropsychological testing.
* Presence of any medical or psychiatric disease which is unstable or is not optimally treated.

Presence of an abnormal MRI scan except for Normal variants or Medial Temporal Sclerosis (altered pathology and MRI signal in temporal lobe).

* Women who are pregnant or women of childbearing capacity who may become pregnant (i.e. not using contraception).
* Presence of generalized seizures, or reflex seizures i.e. triggered by a sensory stimulus.
* Presence of a language or hearing impairment.
* Non-English speakers.

Primary outcomes:
measure: Skin Conductance Response
timeFrame: 5 seconds post conditioned stimulus
measure: State Anxiety as Assessed by the Spielberger State-Trait Anxiety Inventory
timeFrame: Baseline, post conditioning up to 6 minutes
measure: Experimental Pain as Assessed by a Pain Rating Scale
timeFrame: Post conditioning approximately 6 minutes
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Hopkins Epilepsy Monitoring Unit, Zayhed 12.
state: Maryland
Study officials:
affiliation: Dept of Neurosurgery, Hopkins University.
name: Fred A Lenz, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Liu CC, Shi CQ, Franaszczuk PJ, Crone NE, Schretlen D, Ohara S, Lenz FA. Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus. Neuroscience. 2011 Mar 31;178:208-17. doi: 10.1016/j.neuroscience.2011.01.029. Epub 2011 Jan 20.
citation: Liu CC, Chien JH, Kim JH, Chuang YF, Cheng DT, Anderson WS, Lenz FA. Cross-frequency coupling in deep brain structures upon processing the painful sensory inputs. Neuroscience. 2015 Sep 10;303:412-21. doi: 10.1016/j.neuroscience.2015.07.010. Epub 2015 Jul 10.
citation: Chien JH, Colloca L, Korzeniewska A, Cheng JJ, Campbell CM, Hillis AE, Lenz FA. Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than Expectancy. Neuroscience. 2017 Mar 27;346:81-93. doi: 10.1016/j.neuroscience.2016.12.047. Epub 2017 Jan 8.
citation: Liu CC, Crone NE, Franaszczuk PJ, Cheng DT, Schretlen DS, Lenz FA. Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe. Neuroscience. 2011 Aug 25;189:359-69. doi: 10.1016/j.neuroscience.2011.05.067. Epub 2011 Jun 12.
citation: Liu CC, Ohara S, Franaszczuk P, Zagzoog N, Gallagher M, Lenz FA. Painful stimuli evoke potentials recorded from the medial temporal lobe in humans. Neuroscience. 2010 Feb 17;165(4):1402-11. doi: 10.1016/j.neuroscience.2009.11.026. Epub 2009 Nov 17.