Erich Talamoni Fonoff

Repetitive Transcranial Magnetic Stimulation Is Efficacious as an Add-On to Pharmacological Therapy in Complex Regional Pain Syndrome (CRPS) Type I

UNLABELLED Single-session repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) is effective in the treatment of chronic pain patients, but the analgesic effect of repeated sessions is still unknown. We evaluated the effects of rTMS in patients with refractory pain due to complex regional pain syndrome (CRPS) type I. Twenty-three patients presenting CRPS type I of 1 upper limb were treated with the best medical treatment (analgesics and adjuvant medications, physical therapy) plus 10 daily sessions of either real (r-) or sham (s-) 10 Hz rTMS to the motor cortex (M1). Patients were assessed daily and after 1 week and 3 months after the last session using the Visual Analogical Scale (VAS), the McGill Pain Questionnaire (MPQ), the Health Survey-36 (SF-36), and the Hamilton Depression (HDRS). During treatment there was a significant reduction in the VAS scores favoring the r-rTMS group, mean reduction of 4.65 cm (50.9%) against 2.18 cm (24.7%) in the s-rTMS group. The highest reduction occurred at the tenth session and correlated to improvement in the affective and emotional subscores of the MPQ and SF-36. Real rTMS to the M1 produced analgesic effects and positive changes in affective aspects of pain in CRPS patients during the period of stimulation. PERSPECTIVE This study shows an efficacy of repetitive sessions of high-frequency rTMS as an add-on therapy to refractory CRPS type I patients. It had a positive effect in different aspects of pain (sensory-discriminative and emotional-affective). It opens the perspective for the clinical use of this technique.

Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception.

TOC summary Motor cortex stimulation‐induced analgesia occurs, at least in part, through the inhibition of the thalamic sensory neurons and the neuronal disinhibition in the periaqueductal gray. ABSTRACT Motor cortex stimulation is generally suggested as a therapy for patients with chronic and refractory neuropathic pain. However, the mechanisms underlying its analgesic effects are still unknown. In a previous study, we demonstrated that cortical stimulation increases the nociceptive threshold of naive conscious rats with opioid participation. In the present study, we investigated the neurocircuitry involved during the antinociception induced by transdural stimulation of motor cortex in naive rats considering that little is known about the relation between motor cortex and analgesia. The neuronal activation patterns were evaluated in the thalamic nuclei and midbrain periaqueductal gray. Neuronal inactivation in response to motor cortex stimulation was detected in thalamic sites both in terms of immunolabeling (Zif268/Fos) and in the neuronal firing rates in ventral posterolateral nuclei and centromedian‐parafascicular thalamic complex. This effect was particularly visible for neurons responsive to nociceptive peripheral stimulation. Furthermore, motor cortex stimulation enhanced neuronal firing rate and Fos immunoreactivity in the ipsilateral periaqueductal gray. We have also observed a decreased Zif268, δ‐aminobutyric acid (GABA), and glutamic acid decarboxylase expression within the same region, suggesting an inhibition of GABAergic interneurons of the midbrain periaqueductal gray, consequently activating neurons responsible for the descending pain inhibitory control system. Taken together, the present findings suggest that inhibition of thalamic sensory neurons and disinhibition of the neurons in periaqueductal gray are at least in part responsible for the motor cortex stimulation‐induced antinociception.

Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system.

Epidural motor cortex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches. Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying mechanisms of pain control have not been clarified yet. The aim of this study was to investigate the effects of epidural electrical MCS on the nociceptive threshold of naive rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated cortex, but no changes were noticed in the ipsilateral paw. When the nociceptive test was repeated 15 min after cessation of electrical stimulation, the nociceptive threshold returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally, no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished the increase in nociceptive threshold induced by MCS. Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective antinociceptive effect, which is mediated by opioids.

Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease

Objective: To prospectively evaluate the effect of subthalamic nucleus deep brain stimulation (STN-DBS) on the different characteristics of pain and other nonmotor symptoms (NMS) in patients with Parkinson disease (PD). Methods: Forty-four patients with PD and refractory motor symptoms were screened for STN-DBS. Patients were evaluated before and 1 year after surgery. The primary outcome was change in pain prevalence after surgery. Secondary outcome measures were changes in motor function (Unified Parkinsons Disease Rating Scale), characteristics of pain and other NMS using specific scales and questionnaires, and quality of life. Results: Forty-one patients completed the study. The prevalence of pain changed from 70% to 21% after surgery (p < 0.001). There were also significant improvements in pain intensity, NMS, and quality of life after STN-DBS (p < 0.05). Dystonic and musculoskeletal pain responded well to DBS, while central pain and neuropathic pain were not influenced by surgery. There was a strong correlation between the change in pain intensity and the improvement in quality of life (r = 0.708, p < 0.005). No correlation was found between pain improvement and preoperative response to levodopa or motor improvement during stimulation (r = 0.247, p = 0.197 and r = 0.249, p = 0.193, respectively) or with changes in other NMS. Conclusions: STN-DBS decreased pain after surgery, but had different effects in different types of PD-related pain. Motor and nonmotor symptom improvements after STN-DBS did not correlate with pain relief. Classification of evidence: This study provides Class IV evidence that in patients with idiopathic PD with refractory motor fluctuations, STN-DBS decreases the prevalence of pain and improves quality of life.

Subthalamic deep brain stimulation modulates small fiber–dependent sensory thresholds in Parkinson’s disease

TOC summary Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with Parkinson’s disease and specifically modulates small fiber–mediated sensations. ABSTRACT The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson’s disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off‐medication condition with the stimulator turned on or off (on‐ and off‐stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age‐matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P = .019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off‐stimulation condition. In the on‐stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber–mediated sensations.

Functional mapping of the motor cortex of the rat using transdural electrical stimulation

Motor cortex stimulation oriented by functional cortical mapping is used mainly for treating otherwise intractable neurological disorders, however, its mechanism of action remains elusive. Herein, we present a new method for functional mapping of the rat motor cortex using non-invasive transdural electrical stimulation. This method allows a non-invasive mapping of the surface of the neocortex providing a differentiation of representative motor areas. This study may facilitate further investigation about the mechanisms mediating the effects of electrical stimulation, possibly benefiting patients who do not respond to this neuromodulation therapy.

Transdural motor cortex stimulation reverses neuropathic pain in rats: a profile of neuronal activation.

Motor cortex stimulation (MCS) has been used to treat patients with neuropathic pain resistant to other therapeutic approaches; however, the mechanisms of pain control by MCS are still not clearly understood. We have demonstrated that MCS increases the nociceptive threshold of naive conscious rats, with opioid participation. In the present study, the effect of transdural MCS on neuropathic pain in rats subjected to chronic constriction injury of the sciatic nerve was investigated. In addition, the pattern of neuronal activation, evaluated by Fos and Zif268 immunolabel, was performed in the spinal cord and brain sites associated with the modulation of persistent pain. MCS reversed the mechanical hyperalgesia and allodynia induced by peripheral neuropathy. After stimulation, Fos immunoreactivity (Fos-IR) decreased in the dorsal horn of the spinal cord and in the ventral posterior lateral and medial nuclei of the thalamus, when compared to animals with neuropathic pain. Furthermore, the MCS increased the Fos-IR in the periaqueductal gray, the anterior cingulate cortex and the central and basolateral amygdaloid nuclei. Zif268 results were similar to those obtained for Fos, although no changes were observed for Zif268 in the anterior cingulate cortex and the central amygdaloid nucleus after MCS. The present findings suggest that MCS reverts neuropathic pain phenomena in rats, mimicking the effect observed in humans, through activation of the limbic and descending pain inhibitory systems. Further investigation of the mechanisms involved in this effect may contribute to the improvement of the clinical treatment of persistent pain.Motor cortex stimulation (MCS) has been used to treat patients with neuropathic pain resistant to other therapeutic approaches; however, the mechanisms of pain control by MCS are still not clearly understood. We have demonstrated that MCS increases the nociceptive threshold of naive conscious rats, with opioid participation. In the present study, the effect of transdural MCS on neuropathic pain in rats subjected to chronic constriction injury of the sciatic nerve was investigated. In addition, the pattern of neuronal activation, evaluated by Fos and Zif268 immunolabel, was performed in the spinal cord and brain sites associated with the modulation of persistent pain. MCS reversed the mechanical hyperalgesia and allodynia induced by peripheral neuropathy. After stimulation, Fos immunoreactivity (Fos‐IR) decreased in the dorsal horn of the spinal cord and in the ventral posterior lateral and medial nuclei of the thalamus, when compared to animals with neuropathic pain. Furthermore, the MCS increased the Fos‐IR in the periaqueductal gray, the anterior cingulate cortex and the central and basolateral amygdaloid nuclei. Zif268 results were similar to those obtained for Fos, although no changes were observed for Zif268 in the anterior cingulate cortex and the central amygdaloid nucleus after MCS. The present findings suggest that MCS reverts neuropathic pain phenomena in rats, mimicking the effect observed in humans, through activation of the limbic and descending pain inhibitory systems. Further investigation of the mechanisms involved in this effect may contribute to the improvement of the clinical treatment of persistent pain.

Cerebral hemodynamics: concepts of clinical importance

Cerebral hemodynamics and metabolism are frequently impaired in a wide range of neurological diseases, including traumatic brain injury and stroke, with several pathophysiological mechanisms of injury. The resultant uncoupling of cerebral blood flow and metabolism can trigger secondary brain lesions, particularly in early phases, consequently worsening the patients outcome. Cerebral blood flow regulation is influenced by blood gas content, blood viscosity, body temperature, cardiac output, altitude, cerebrovascular autoregulation, and neurovascular coupling, mediated by chemical agents such as nitric oxide (NO), carbon monoxide (CO), eicosanoid products, oxygen-derived free radicals, endothelins, K+, H+, and adenosine. A better understanding of these factors is valuable for the management of neurocritical care patients. The assessment of both cerebral hemodynamics and metabolism in the acute phase of neurocritical care conditions may contribute to a more effective planning of therapeutic strategies for reducing secondary brain lesions. In this review, the authors have discussed concepts of cerebral hemodynamics, considering aspects of clinical importance.

Decompressive craniectomy and head injury: brain morphometry, ICP, cerebral hemodynamics, cerebral microvascular reactivity, and neurochemistry

There has been renewed interest in decompressive craniectomy as a surgical treatment for elevated intracranial pressure (ICP), although evidence-based clinical data are still lacking and some experimental results are conflicting. Ongoing clinical trials on the use of this operation after traumatic brain injury (TBI) may clarify the clinical application of this technique, however, some pathophysiological issues, such as the timing of this operation, its effect on brain edema formation, and its role for secondary brain damage, are still controversial. This review addresses recent clinical data on the influence of decompressive craniectomy on the brain pathophysiology in TBI. Decompressive craniectomy with dural augmentation enlarges intracranial space so that the swollen cerebral hemisphere could expand out of normal cranial limits, avoiding progression of brain herniation. The gain in intracranial volume results in both the improvement of cerebral compliance and a decrease in ICP; the latter favors a rise in both cerebral blood flow and cerebral microvascular perfusion, which can be accompanied by elevation in brain tissue oxygen tension (PbtO2) as well as the return of abnormal metabolic parameters to normal values in cases of cerebral ischemia. Enhancement of edema formation, impairment of cerebrovascular pressure reactivity, and non-restoration of brain aerobic metabolism due to metabolic crisis may occur after craniectomy and require further investigations. This review suggests that decompressive craniectomy as the sole treatment is likely to be insufficient; efforts must be made to maintain adequate brain hemodynamics, preferably coupled with brain metabolism, in addition to treating brain metabolic abnormalities, during postoperative stages.

Cerebral Microdialysis in Traumatic Brain Injury and Subarachnoid Hemorrhage: State of the Art

Cerebral microdialysis (CMD) is a laboratory tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is inserted into the interstitium of the brain. A solute is slowly infused into the catheter at a constant velocity. The fenestrated membranes at the tip of the catheter permit free diffusion of molecules between the brain interstitium and the perfusate, which is subsequently collected for laboratory analysis. The major molecules studied using this method are glucose, lactate, pyruvate, glutamate, and glycerol. The collected substances provide insight into the neurochemical features of secondary injury following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and valuable information about changes in brain metabolism within a short time frame. In this review, the authors detail the CMD technique and its associated markers and then describe pertinent findings from the literature about the clinical application of CMD in TBI and SAH.