Laboratory of Clinical Neurophysiology

Haifa, Israel

Laboratory of Clinical Neurophysiology

Haifa, Israel
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Kisler L.-B.,Haifa University | Granovsky Y.,Laboratory of Clinical Neurophysiology | Granovsky Y.,Rambam Health Care Campus | Sinai A.,Rambam Health Care Campus | And 3 more authors.
Experimental Brain Research | Year: 2016

Behavioral studies found greater pain sensitivity in females that vanishes fully or partially when controlling for the emotional state. Furthermore, pain-related brain activation hints at the role of limbic structures in sex differences in pain processing. We aimed to investigate the role of pain-related limbic structures in mediating the relation between subjects’ affective state (i.e., anxiety) and pain. Contact heat-evoked potentials (CHEPs) were recorded in 26 healthy subjects (13 males) simultaneously with innocuous (42 °C) baseline and target noxious (52 °C) series of stimuli administered to the left non-dominant volar forearm. The N2 and P2 components were analyzed, and their generators’ activity was estimated using standardized low-resolution brain electromagnetic tomography. Thereafter, structural equation modeling (SEM) was applied separately for females and males, examining the mediatory role of the CHEPs’ limbic structures generators [posterior midcingulate cortex (pMCC), insula, amygdala, and hippocampus] in the anxiety–pain sensitivity association. Females exhibited greater P2 amplitudes that were highly associated with larger pMCC activity (r = 0.910, p < 0.001). This correlation was also evident in males, though with less strength (r = 0.578, p = 0.039). Moreover, the P2 amplitudes were associated both in females (r = 0.645, p = 0.017) and males (r = 0.608, p = 0.028) with the activity of the amygdala\hippocampus\insula. SEM revealed that the relationship between state anxiety and pain ratings was only in females fully mediated via the effect of the pMCC on the P2 amplitude. These findings suggest that sexual dimorphism in anxiety-related brain activity may explain the differences found in CHEPs and the sex-related association between anxiety and pain. © 2016, Springer-Verlag Berlin Heidelberg.


Honigman L.,Laboratory of Clinical Neurophysiology | Yarnitsky D.,Laboratory of Clinical Neurophysiology | Yarnitsky D.,Rambam Health Care Campus | Sprecher E.,Laboratory of Clinical Neurophysiology | And 2 more authors.
Experimental Brain Research | Year: 2013

The endogenous analgesia (EA) system is psychophysically evaluated using various paradigms, including conditioned pain modulation (CPM) and offset analgesia (OA) testing, respectively, the spatial and temporal filtering processes of noxious information. Though both paradigms assess the function of the EA system, it is still unknown whether they reflect the same aspects of EA and consequently whether they provide additive or equivalent data. Twenty-nine healthy volunteers (15 males) underwent 5 trials of different stimulation conditions in random order including: (1) the classic OA three-temperature stimulus train ('OA'); (2) a three-temperature stimulus train as control for the OA ('OAcon'); (3) a constant temperature stimulus ('constant'); (4) the classic parallel CPM ('CPM'); and (5) a combination of OA and CPM ('OA + CPM'). We found that in males, the pain reduction during the OA + CPM condition was greater than during the OA (P = 0.003) and CPM (P = 0.07) conditions. Furthermore, a correlation was found between OA and CPM (r = 0.62, P = 0.01) at the time of maximum OA effect. The additive effect found suggests that the two paradigms represent at least partially different aspects of EA. The moderate association between the CPM and OA magnitudes indicates, on the other hand, some commonality of their underlying mechanisms. © Springer-Verlag Berlin Heidelberg 2013.


Gois J.,University of Sao Paulo | Valente K.,Laboratory of Clinical Neurophysiology | Vicentiis S.,Laboratory of Clinical Neurophysiology | Moschetta S.,Laboratory of Clinical Neurophysiology | And 3 more authors.
Epilepsy and Behavior | Year: 2011

Despite the growing evidence of poor psychosocial adjustment, at present there is no formal method of assessment of social adjustment in patients with temporal lobe epilepsy (TLE). First, we assessed social adjustment in patients with TLE using a self-report questionnaire and compared the results with those from quality-of-life (QOL) scales. Second, we verified the influence of cognitive performance and clinical variables of epilepsy on social adjustment and QOL. We evaluated 35 people with TLE and 38 healthy controls. Patients had worse social adjustment, and it was correlated with worse perception of cognitive function. Attention and verbal memory dysfunctions were negatively correlated with social adjustment. However, there was no significant correlation between cognitive performance and QOL. Regarding clinical variables, persons with left TLE showed worse social adjustment and patients with frequent seizures showed worse QOL. These findings indicate the relevance of evaluating social adjustment and emphasize the importance of cognitive rehabilitation to improved social adjustment. © 2010 Elsevier Inc.


Yarnitsky D.,Rambam Medical Center | Yarnitsky D.,Laboratory of Clinical Neurophysiology
Current Opinion in Anaesthesiology | Year: 2010

Purpose of review: There is a growing body of knowledge on pain modulation in various disease states. This article reviews the state of the art regarding the clinical relevance of pain inhibition as revealed by 'pain inhibits pain' test paradigms, trying to organize the clinically relevant data, and emphasizing the pathophysiology of pain. In line with recent experts' recommendations, the term conditioned pain modulation (CPM) will be used, replacing the previous terms 'diffuse noxious inhibitory control (DNIC)' or 'DNIC-like' effects. Recent findings: Most of the work in this context was done on the idiopathic pain syndromes, such as irritable bowel syndrome, temporomandibular disorders, fibromyalgia, and tension type headache. The pattern of reduced CPM efficiency seems common to these syndromes and an assertion is made that low CPM efficiency, reflecting low pain inhibitory capacity, is a pathogenetic factor in the development of the idiopathic pain syndromes. Low CPM efficiency was shown to be predictive of acute and chronic postoperative pain, and, in some reports, to be associated with neuropathic pain levels. SUMMARY: Low CPM efficiency is associated with higher pain morbidity and vice versa. Further work is awaited on clarifying plasticity of CPM and its relevance to selection and efficacy of pain therapy. © 2010 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Yarnitsky D.,Rambam Health Care Campus | Yarnitsky D.,Laboratory of Clinical Neurophysiology | Granot M.,Haifa University | Nahman-Averbuch H.,Laboratory of Clinical Neurophysiology | And 3 more authors.
Pain | Year: 2012

This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r = 0.628, P <.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R2 = 0.673; P =.012) showed that drug efficacy was predicted only by CPM (P =.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r = -0.411, P =.033). However, this improvement occurred only in patients with less efficient CPM (16.8 ± 16.0 to -1.1 ± 15.5, P <.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Nahman-Averbuch H.,Laboratory of Clinical Neurophysiology | Granovsky Y.,Laboratory of Clinical Neurophysiology | Granovsky Y.,Rambam Health Care Campus | Coghill R.C.,Wake forest University | And 4 more authors.
Headache | Year: 2013

Objective To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine. Background One of the most explored mechanisms underlying the pain modulation system is "diffuse noxious inhibitory controls," which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation. Methods Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) "test-stimulus" (Ts) alone that was given first followed by (2) parallel CPM application (CPM-parallel), and (3) sequential CPM application (CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition "0" consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application. Results Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs (P =.005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P =.028). Conclusions Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine. © 2013 American Headache Society.


Nahman-Averbuch H.,Laboratory of Clinical Neurophysiology | Martucci K.T.,Wake forest University | Granovsky Y.,Laboratory of Clinical Neurophysiology | Granovsky Y.,Rambam Health Care Campus | And 4 more authors.
Pain | Year: 2014

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intrapa-rietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Emerson N.M.,Wake forest University | Zeidan F.,Wake forest University | Lobanov O.V.,Wake forest University | Hadsel M.S.,Wake forest University | And 10 more authors.
Pain | Year: 2014

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity, we used voxel-based morphometry to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49 C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions showed a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


PubMed | Wake forest University, Laboratory of Clinical Neurophysiology and Haifa University
Type: Journal Article | Journal: Pain | Year: 2014

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity, we used voxel-based morphometry to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions showed a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure.


Nir R.-R.,Laboratory of Clinical Neurophysiology | Yarnitsky D.,Laboratory of Clinical Neurophysiology
Current Opinion in Supportive and Palliative Care | Year: 2015

Purpose of review Conditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM. Recent findings The main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction. Summary The reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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