Neurofilament-light in former athletes: a potential biomarker of neurodegeneration and progression.

BACKGROUND/OBJECTIVE: This study aimed to evaluate serum neurofilament light chain (NF-L) levels in former professional contact sports athletes with multiple concussions (ExPro) as a potential biomarker of neurodegeneration and predictor of white-matter (WM) abnormality progression. METHODS: Concentrations of NF-L in the serum of fifty-two cognitively normal ExPro and twenty-one healthy controls (HC) with no history of concussions were measured using single molecule array (Simoa) technology. Both groups underwent neuroimaging at the time of serum collection. Eighteen of the participants in the ExPro underwent follow-up imaging after 2 years. RESULTS: Levels of serum NF-L were not significantly different between the ExPro and HC. However, in the ExPro group, NF-L levels were positively correlated with the mean diffusivity (MD) of corpus callosum (CC) and fornix, and total ventricular volume. Moreover, NF-L levels in the ExPro group at the first visit were positively correlated with the amount of increase in CC MD at the 2-year follow-up. CONCLUSIONS: NF-L levels reflect neuronal changes in the ExPro group and predict the extent of decrease in white matter integrity over time. Serum NF-L might be a biomarker of neurodegeneration and WM abnormality progression in ExPro.

Slow-5 dynamic functional connectivity reflects the capacity to sustain cognitive performance during pain.

Some individuals are more distracted by pain during a cognitive task than others, representing poor pain coping. We have characterized individuals as A-type (attention dominates) or P-type (pain dominates) based on how pain interferes with task speed. The ability to optimize behavior during pain may relate to the flexibility in communication at rest between the dorsolateral prefrontal cortex (DLPFC) of the executive control network, and the anterior mid-cingulate cortex (aMCC) of the salience network (SN) - regions involved in cognitive-interference. The aMCC and aIns (SN hub) also signify pain salience; flexible communication at rest between them possibly allowing prioritizing task performance during pain. We tested the hypotheses that pain-induced changes in task performance are related to resting-state dynamic functional connectivity (dFC) between these region pairs (DLPFC-aMCC; aMCC-aIns). We found that 1) pain reduces task consistency/speed in P-type individuals, but enhances performance in A-type individuals, 2) task consistency is related to the FC dynamics within DLPFC-aMCC and aMCC-aIns pairs, 3) brain-behavior relationships are driven by dFC within the slow-5 (0.01-0.027Hz) frequency band, and 4) dFC across the brain decreases at higher frequencies. Our findings point to neural communication dynamics at rest as being associated with prioritizing task performance over pain.

Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms.

Studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in monkeys suggest that excessive inhibitory outflow from the internal segment of the globus pallidus (GPi) suppresses the motor thalamus, which reduces activation of the cerebral cortex motor system, resulting in the slowness and poverty of movement of Parkinson's disease (PD). This hypothesis is supported by reports of high rates of spontaneous neuronal discharges and hypermetabolism in GPi (ref. 4-7) and impaired activation of the supplementary motor area (SMA) and dorsolateral prefrontal regions in PD patients. Furthermore, lesion or chronic high-frequency electrical (likely inactivating) stimulation of GPi (ref. 10-14) is associated with marked improvements in akinesia and rigidity, and the impaired activation of SMA is reversed when the akinesia is treated with dopamine agonists. To test whether improvement in motor function with pallidal surgery can be attributed to increased activity in premotor cortical regions, we assessed the changes in regional cerebral blood flow (rCBF) and parkinsonian symptoms during disruption of GPi activity with high-frequency stimulation delivered through implanted brain electrodes. Positron emission tomography (PET) revealed an increase in rCBF in ipsilateral premotor cortical areas during GPi stimulation, which improved rigidity and bradykinesia. These results suggest that disrupting the excessive inhibitory output of the basal ganglia reverses parkinsonism, via a thalamic relay, by activation of brain areas involved in the initiation of movement.

Stability of phantom limb phenomena after upper limb amputation: a longitudinal study.

Amputees may experience stump pain (SP), phantom limb (PL) sensations, pain, and/or a general awareness of the missing limb. The mechanisms underlying these perceptions could involve nervous system neuroplasticity and be reflected in altered sensory function of the residual limb. Since little is known about the progression of post-amputation sensory phenomena over time, we longitudinally evaluated the stability of, and relationships among: 1) subjective reports of PL sensations, pain, awareness, and SP, 2) stump tactile and tactile spatial acuity thresholds, and 3) use of a functional vs. a cosmetic prosthesis in 11 otherwise healthy individuals with recent unilateral, traumatic upper-extremity amputation. Subjects were evaluated within 6 months and at 1-3 years after amputation. Processing of tactile sensory information from the stump remained stable over the study time period. PL awareness was frequent, stable over time, intense, and occurred with or without PL sensations. Functional prosthetic use correlated with stable vividness of PL awareness whereas subjects who used a cosmetic prosthesis had less vivid PL awareness at follow-up. Initial SP correlated with follow-up SP, the initial PL pain correlated with follow-up PL pain but neither initial nor follow-up SP appear to be related to follow-up PL pain after accounting for initial PL pain intensity. Neither limb temperature nor prosthesis-use correlated with the initial vs. follow-up change in PL pain intensity. These data provide evidence that PL pain described 1-3 years after an amputation is not related in any simple way to peripheral sensory function, SP, or limb temperature; and PL awareness but not PL pain may be influenced by the frequent use of a functional prosthesis.

Neural correlates of prickle sensation: a percept-related fMRI study.

The painful sensations produced by a laceration, freeze, burn, muscle strain or internal injury are readily distinguishable because each is characterized by a particular sensory quality such as sharp, aching, burning or prickling. We propose that there are specific neural correlates of each pain quality, and here we used a new functional magnetic resonance imaging (fMRI) method to identify time-locked responses to prickle sensations that were evoked by noxious cold stimuli. With percept-related fMRI, we identified prickle-related brain activations in the anterior cingulate cortex (ACC), insula, secondary somatosensory cortex (S2), prefrontal cortex (PFC), premotor cortex (PMC), caudate nucleus and dorsomedial thalamus, indicating that multiple pain, sensory and motor areas act together to produce the prickle sensation.

A multimodal cortical network for the detection of changes in the sensory environment.

Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.

Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Retinoids regulate gene transcription by interacting with both retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs). Since unliganded RXRs can act as heterodimerization partners for RARs and other nuclear hormone receptors, it is unclear whether ligand binding by RXRs actually regulates the expression of naturally occurring genes. To address this issue, we synthesized the RXR-selective retinoid SR11237 and confirmed its specificity in transient transfection and proteolytic susceptibility assays before using it to assess the contribution of ligand-activated RXRs to retinoid action. Unlike RAR ligands, SR11237 did not increase endogenous RAR beta mRNA levels in F9 embryonal carcinoma cells, even though it activated transcription of an RXR-responsive reporter gene in these cells. Thus, it is likely that RARs mediate the induction of RAR beta gene expression by RA. In contrast, the RXR-specific ligand induced rat growth hormone mRNA in GH3 pituitary cells, indicating that the effects of RA on growth hormone gene expression at least in part involve ligand binding to endogenous RXRs in vivo. Our results indicate that in addition to serving as cofactors for other nuclear hormone receptors, endogenous RXRs can function as ligand-dependent regulators of gene expression, i.e., classical nuclear hormone receptors.

Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities.

BACKGROUND: The combination of fenfluramine and phentermine was a widely used obesity treatment before the withdrawal of fenfluramine for an association with heart valve regurgitation. The prevalence and clinical significance of regurgitation among patients treated with these medications has yet to be fully established. METHODS AND RESULTS: To evaluate the potential association between the duration of treatment and the prevalence of heart valve abnormalities, we examined 1163 patients who had taken fenfluramine-phentermine and 672 control patients who had not taken the drug combination within 5 years. Mild or greater aortic regurgitation was present in 8.8% of treated patients and 3.6% of control patients (P<0.001). Moderate or greater mitral regurgitation was present in 2.6% of treated patients and 1.5% of control patients (P=0.18). The adjusted odds ratio compared with controls of aortic regurgitation of mild or greater severity increased according to duration of treatment: 90 to 180 days, 1.5 (P=0.23); 181 to 360 days, 2.4 (P=0.002); 361 to 720 days, 4.6 (P<0.001); >720 days, 6.2 (P<0.001). CONCLUSIONS: This is the largest study to demonstrate a relation between the length of treatment with fenfluramine-phentermine and the prevalence of valvular abnormalities. These findings suggest that valvular abnormalities in patients who took fenfluramine-phentermine primarily involve those who had taken these medications for >6 months and predominantly results in mild aortic regurgitation. The valve regurgitation identified by this study was not accompanied by significant differences in cardiovascular symptoms nor physical findings other than a higher prevalence of heart murmurs.

Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fenfluramine hydrochloride was withdrawn from the market in September 1997 after reports of heart valve abnormalities in patients who used it. The prevalence of echocardiographic abnormalities and the clinical cardiovascular status of patients who received fenfluramine monotherapy remains uncertain. METHODS: A long-term, follow-up evaluation was undertaken in subjects who were randomly assigned to receive either fenfluramine hydrochloride (60 mg daily) or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular status was evaluated by echocardiography, medical history, and physical examination. RESULTS: From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable. No statistically significant differences were identified in the prevalence of aortic or mitral regurgitation by Food and Drug Administration criteria or by grade, aortic or mitral valve leaflet mobility restriction or thickening, elevated pulmonary artery systolic pressure, or abnormal left ventricular ejection fraction. No significant differences were demonstrated in cardiovascular status by physical examination, and no serious cardiac events were noted among fenfluramine-treated subjects. CONCLUSION: There was no evidence of drug-related heart disease up to 4.9 years after anorexigen therapy in subjects who were randomly assigned to receive fenfluramine at the recommended dose for up to 3 months.

Induction of retinoic acid receptor-beta by retinoic acid is cell specific.

The retinoic acid (RA) receptor-beta (RAR beta) gene is dramatically up-regulated by RA in F9 teratocarcinoma cells due to the presence of an RA-responsive element (RARE) in its promoter. Remarkably, however, RAR beta mRNA was essentially unaffected by RA in rat pituitary GH3 cells, even though the GH gene was induced by RA, and these cells express mRNAs specific for multiple RAR subtypes and for the potential RAR coactivators, retinoid X-receptors. The absence of RA induction of RAR beta was also observed in GH1 cells as well as in murine AtT-20 pituitary cells and rat H35 hepatocarcinoma cells. The RA unresponsiveness of the RAR beta gene in GH3 and AtT-20 cells was not due to a mutation in the RARE, which was identical to that in RA-responsive F9 cells. Furthermore, while AtT-20 and F9 cells both expressed multiple RAR beta isoforms, including RAR beta 2, which was profoundly induced by RA in F9 cells, none of these was highly regulated by RA in AtT-20 cells. The failure of RA to induce RAR beta mRNA in certain murine and rat pituitary and nonpituitary cell lines indicates that target gene responsiveness to RA is cell type specific in some cases.

Immunocytochemical delineation of thyroid hormone receptor beta 2-like immunoreactivity in the rat central nervous system.

The thyroid hormone receptors (TR) are nuclear proteins that include TR alpha and TR beta subtypes, each encoded by a separate gene. Both TR alpha and TR beta give rise to several isoforms of which three, TR alpha 1, TR beta 1, and TR beta 2 bind T3 and mediate the action of thyroid hormone. Although TR beta 2 was initially thought to be confined to the anterior pituitary, we recently observed small quantities of TR beta 2 messenger RNA (mRNA) by polymerase chain reaction analysis of discrete hypothalamic regions. To further examine the distribution of TR beta 2 in the brain, we performed immunocytochemical studies using a highly specific antiserum to TR beta 2, raised against a unique amino acid sequence (TR beta 2[131-145]) that is not present in the other known TRs. This antiserum immunoprecipitated TR beta 2 but not TR alpha 1 or TR beta 1. Immunoreactive TR beta 2 was widely distributed throughout the brain and primarily localized to the cell nucleus. Particularly intense immunostaining was present in the cerebral cortex, cerebellum, and hypothalamus, including regions where TR beta 2 mRNA had not previously been identified. In addition, immunoprecipitation of nuclear extracts with anti-TR beta 2 reduced total T3 binding capacity by approximately 20%, suggesting that immunoreactive TR beta 2 comprises a substantial portion of the total content of nuclear thyroid hormone binding proteins. These studies demonstrate that immunoreactive TR beta 2 is more widely represented in the central nervous system than previously suspected and may play an important role in mediating the action of T3 in many different regions of the brain. The finding of TR beta 2-like material could be due to a disproportionately high ratio of the TR beta 2 translation product and its mRNA in certain regions of the brain, or could indicate the existence of a novel TR beta 2-related protein that is important for T3 binding.

Decreased follistatin gene expression in gonadotroph adenomas.

What growth factors are involved in the pathogenesis of gonadotroph adenomas is not yet known. Activin is one possible candidate because it stimulates growth and differentiation in many cells, including the gonadotroph cell, and it stimulates FSH secretion, characteristic of gonadotroph adenomas. As activin beta B-subunit is expressed in gonadotroph adenomas, we sought to determine whether activin receptor II and follistatin are also expressed. Total ribonucleic acid (RNA) was extracted from 10 gonadotroph adenomas that did not express pit-1 and was reverse transcribed. The resulting complementary DNAs for human activin receptor II and follistatin were amplified by PCR. All 10 adenomas expressed activin receptor II messenger RNA (mRNA), as did nonadenomatous pituitary tissue. Only 2 of the 10 gonadotroph adenomas expressed detectable follistatin mRNA, although all 4 nonadenomatous pituitaries did. Quantitation of follistatin mRNA by competitive reverse transcription-PCR showed that none of the 10 gonadotroph adenomas expressed as much follistatin mRNA as did the 4 nonadenomatous pituitaries, and 8 of the 10 expressed less than 10% as much. Immunospecific staining showed follistatin in the cytoplasm of the gonadotroph cells of all 5 nonadenomatous pituitaries studied, but only faintly in 1 gonadotroph adenoma and not at all in the other 9. These results suggest that pit-1-negative gonadotroph adenomas express less follistatin mRNA and follistatin peptide than do nonadenomatous gonadotroph cells. A consequence could be less binding, and thereby enhanced effectiveness, of activin, contributing to adenoma growth.

Cold-evoked pain varies with skin type and cooling rate: a psychophysical study in humans.

The psychophysical responses to noxious cold stimulation of the skin in normal human subjects are not well understood. Continuous pain ratings with the visual analogue scale is an important method to assess these responses. In this study, we addressed several important issues about the parameters with which stimuli are delivered: the type of skin stimulated, the rate with which the stimulus temperature decreases, and the dimension of the pain rated by subjects. Cold stimuli were delivered to the thenar eminence (glabrous skin) and the dorso-lateral hand (hairy skin) via a 4 cm(2) Peltier-type stimulator. Cold and pain thresholds were determined by the method of limits (MOL). A computerized visual analogue scale (VAS) was used to obtain continuous ratings of pain intensity and affect. The McGill Pain Questionnaire (MPQ) was used to assess the quality of cold-evoked pain. Supra-threshold stimuli (34 degrees C base) were delivered at 0.5, 1 or 2 degrees C/s to 2 degrees C, held for 20s and returned to baseline at 9 degrees C/s. These studies revealed: (1) Cold thresholds, measured with MOL, were lower (i.e. occurred at higher absolute temperatures) for the hairy skin of the dorso-lateral hand compared to the glabrous skin of the thenar eminence. (2) A similar pattern was evident for cold induced pain thresholds with MOL at 1.5 degrees C/s and with intensity and affect VAS scales at 0.5 and 1 degrees C/s. (3) Exponents for supra-threshold ratings fit to power functions were larger for the glabrous skin site than the hairy skin site regardless of cooling rate or dimension of pain measured. (4) All pain indices were higher for slower cooling rates. (5) No significant differences were found in the pain indices for pain ratings of intensity and affect. (6) A substantial proportion of subjects chose words representing paradoxical heat with the MPQ. (7) Painful paradoxical heat sensations occurred most often during cooling, while innocuous warm sensations mainly occurred during the rewarming phase.

Cognitive modulation of pain-related brain responses depends on behavioral strategy.

Interactions of pain and cognition have been studied in humans and animals previously, but the relationship between such behavioral interactions and brain activity is unknown. We aimed to show using functional MRI (fMRI) how a cognitively demanding task (Stroop) modulates pain-related brain activations and conversely, how pain modulates attention-related activity. Reaction time data indicated two types of pain responders: subjects in the A group had a faster Stroop reaction time when pain was concomitant to the attention task, while those in the P group had a slower Stroop performance during painful stimulation. fMRI data obtained during Stroop performance with and without noxious stimulation were subjected to region of interest analyses. We first tested whether brain activity during painful median nerve stimulation was modulated by cognitive load. We next tested whether brain activity during the high conflict cognitive task was modulated by pain. Pain-related activity in three regions, primary (S1), and secondary (S2) somatosensory cortices, and anterior insula, was attenuated by cognitive engagement, but this effect was specific to the A group. Pain-related activations in the caudal and rostral anterior cingulate cortex (ACC) and ventroposterior thalamus were not modulated by cognitive load. None of the areas showing attention-related responses, including bilateral dorsolateral prefrontal and posterior parietal cortices, were modulated by pain. These findings suggest that cortical regions associated with pain can be modulated by cognitive strategies. Furthermore, the distinction of behavioral subgroups may relate to cognitive coping strategies taken by patients with chronic pain.

A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients.

Thalamic neurons are known to switch their firing from a tonic pattern during wakefulness to a bursting pattern during sleep. Several studies have described the existence of bursting activity in awake chronic pain patients and have suggested that this activity is abnormal and may be related to their pain. However, we have frequently observed bursting activity in awake non-pain patients suggesting that there may not be a causal relationship between thalamic bursting activity and chronic pain. To examine this issue more rigorously we compared the incidence and pattern of bursting activity of lateral thalamic neurons of both pain and non-pain patients in a state of wakefulness. Recordings were obtained from lateral thalamic areas of different groups of patients (n = 91) suffering from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal neuralgia, post-stroke pain) and motor disorders (e.g. Parkinson's disease, essential tremor) during stereotactic surgical procedures for the treatment of pain and movement disorders. Burst indices (the number of bursting cells per electrode track) were computed for all the explorations in the two groups. The burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16, respectively) were not significantly different from each other. The bursts were analyzed to see if they fulfilled the criteria of low-threshold calcium spike (LTS)-evoked bursts characterized by (i) a shortening of the first interspike interval with an increase in the number of interspike intervals in the burst and also (ii) a progressive prolongation of successive interspike intervals. LTS-evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and 15/32 (47%) cells in non-pain patients. These data demonstrate that the occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is prevalent in both pain and non-pain patients. This suggests that the bursting activity of thalamic neurons in pain patients is not necessarily related to the occurrence of their pain.

Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.

Human platelet acetylcholinesterase: the effects of anticholinesterases on platelet function.

Platelet acetylcholinesterase (AChE) activity was measured in gel-filtered platelet preparations. Three different anticholinesteratic agents (eserine, neostigmine, and diisopropylphosphorofluoridate) at final concentrations of 10 muM caused complete inhibition of AChE activity after 30 min incubation at room temperature with either platelet-rich plasma or gel-filtered platelets. Complete inhibition of platelet AChE had no effect on platelet aggregation, factor-3 availability, and plasma clot retraction. We conclude that platelet membrane AChE activity is not required for normal platelet function as measured by these in vitro parameters.

Visceral pain evoked by thalamic microstimulation in humans.

Microstimulation within and below the ventrocaudal nucleus (Vc) in the human thalamus typically evokes non-painful, paraesthetic cutaneous sensations. We now describe cases in which thalamic microstimulation evoked visceral pains. Data were obtained during stereotactic thalamotomy procedures. Patient 211 had a history of essential tremor. At a site 0.5 mm ventroposterior to Vc, microstimulation elicited pain described as 'deep, internal, in a straight line like my appendix pain years ago'. Patient 153 had a history of post-stroke hemibody pain. In each of two trajectories, at sites approximately 2 mm ventroposterior to Vc, microstimulation evoked pain in the groin. At one of these sites, the pain was described as 'like having a baby'. These and additional observations suggest that stimulation ventroposterior to Vc can evoke visceral pain and may trigger pain 'memories'.

Event-related fMRI of pain: entering a new era in imaging pain.

Previous imaging studies of pain used a block design of prolonged (up to 1 min) noxious stimulation that are not well tolerated and subject to temporal interactions. We describe an adaptation of event-related fMRI to study pain with short duration stimuli. Functional images were acquired with a spiral sequence on a 1.5T GE echospeed MRI system of the thalamus, anterior cingulate, insula and second somatosensory cortex during brief (1-3 s) noxious thermal stimulation of the hand of normal volunteers. An MRI-compatible computerized rating system continuously monitored subjects' pain. Brief pain-related activations were clearly identified in the cortex and thalamus with a hemodynamic delay of 3-6 s. These findings demonstrate that brief stimuli combined with on-line pain ratings can be used to study pain with fMRI.

fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation.

Functional MRI (fMRI) can detect changes from resting levels of blood flow and oxygenation during task performance (i.e. activation). We used a simple electrical nerve stimulation technique together with fMRI to study pain process in the human cortex. Images of the primary somatosensory (SI) and cingulate cortex (Cg) were obtained from subjects during stimulation at painful and non-painful intensities. Stimuli that evoked non-painful tingling sensations activated the contralateral SI but not Cg. Stimuli that evoked painful sensations activated both the contralateral SI and Cg. These data indicate that fMRI can detect pain-related changes in SI and Cg evoked by electrical stimulation of peripheral nerves. These findings add to the evidence for a role of SI and Cg in human pain processes and provide a simple method of stimulus delivery for its study.