Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain. OBJECTIVES: To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief. METHODS: We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and µ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and µ-receptor availabilities were assessed with PET radiotracers [11 C]raclopride and [11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans. RESULTS: µ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS. CONCLUSIONS: rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS. SIGNIFICANCE: Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition but not change the sensory discrimination of painful stimuli.

[18F]FDG-PET reveals temporal hypometabolism in patients with temporal lobe epilepsy even when quantitative MRI and histopathological analysis show only mild hippocampal damage.

BACKGROUND: The relationship between reduced glucose metabolism in positron emission tomography with fludeoxyglucose F 18 ([(18)F]FDG-PET) and hippocampal damage (HD) in patients with temporal lobe epilepsy is still unclear. OBJECTIVE: To determine whether the presence and severity of HD verified by quantitative magnetic resonance imaging (QMRI) and histopathological analysis affect the degree of hypometabolism. PATIENTS AND METHODS: Sixteen patients with drug-resistant temporal lobe epilepsy underwent [(18)F]FDG-PET and QMRI (hippocampal volumetry and T2 relaxometry) before surgery. Histopathological analysis of the hippocampus included measurements of neuronal loss, proliferation of glial cells, and mossy fiber sprouting. The asymmetry in glucose metabolism described the degree of hypometabolism. RESULTS: Temporal hypometabolism was not related to severity of HD as measured by QMRI or histopathological analysis. The degree of hypometabolism did not differ in patients with mild, moderate, or severe HD. In addition, [(18)F]FDG-PET revealed significant temporal hypometabolism even though hippocampal QMRI findings were normal or showed only mild HD. Thus, glucose consumption was reduced over and above the histopathological changes. CONCLUSIONS: [(18)F]FDG-PET is sensitive for localizing the epileptogenic region in patients with temporal lobe epilepsy. However, it is insensitive to reflect the severity of HD.

[11 C]Flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology.

OBJECTIVE: To detect reduced [11C]flumazenil in patients with temporal lobe epilepsy (TLE) and to relate binding to histopathology. METHODS: The authors studied 16 patients who underwent epilepsy surgery because of drug-resistant TLE using [11C]flumazenil PET and quantitative MRI. In 12 patients, resected hippocampus was available for histologic analysis. [11C]Flumazenil binding potential (fitted BP) was assessed with the simplified reference tissue model. RESULTS: [11C]Flumazenil fitted BP in the medial temporal lobe was reduced in all patients with abnormal hippocampal volumetry or T2 relaxometry on MRI. Fitted BP was also reduced in 46% of the patients with hippocampal volume within the normal range and in 38% of patients with less than 2 SD T2 prolongation. In all MRI-negative/PET-positive patients, the histologic analysis verified hippocampal damage. Also, [11C]flumazenil fitted BP correlated with the severity of reduced hippocampal volume, T2 prolongation, and histologically assessed neuronal loss and astrogliosis. CONCLUSION: [11C]Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI.

[18F]FDG-PET and whole-scalp MEG localization of epileptogenic cortex.

PURPOSE: To evaluate combined [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 122-channel whole-scalp magnetoencephalography (MEG) in lateralizing the epileptogenic cortex in patients whose routine presurgical evaluations gave discordant results about the location of the epileptic focus. METHODS: Nine patients (five women, four men) aged 13-40 years were studied. Subdural EEG (SEEG) was recorded from eight patients. Six patients were operated on. RESULTS: In seven of nine patients, PET and MEG agreed in localizing the epileptogenic cortex. When PET and MEG were in congruence, SEEG agreed with the findings. In five of six operated-on patients, PET and MEG results were congruent, and the outcome of the operation was successful. Two patients had discordant PET and MEG results. In one patient, PET showed bitemporal hypometabolism, whereas MEG showed epileptiform activity in the right parietal lobe. The surgical outcome of the palliative temporal lobectomy was poor. Another patient had unilateral temporal hypometabolism in PET and bitemporal activity in MEG. She was not operated on. CONCLUSIONS: In most patients, PET and MEG were congruent in locating the epileptogenic cortex. Thus the combination of these techniques may provide useful support for the localization of the seizure onset and reduce the need for invasive procedures.

Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo.

OBJECTIVE: To compare the efficacy, tolerability, and safety of three daily dosage regimens of oral piracetam in patients with progressive myoclonus epilepsy. METHODS: Twenty patients (12 men, eight women), aged 17-43 years, with classical Unverricht-Lundborg disease were enrolled in a multicentre, randomised, double blind trial of crossover design in which the effects of daily doses of 9.6 g, 16.8 g, and 24 g piracetam, given in two divided doses, were compared with placebo. The crossover design was such that patients received placebo and two of the three dosage regimens of piracetam, each for two weeks, for a total treatment period of six weeks and thus without wash out between each treatment phase. The primary outcome measure was a sum score representing the adjusted total of the ratings of six components of a myoclonus rating scale in which stimulus sensitivity, motor impairment, functional disability, handwriting, and global assessments by investigators and patients were scored. Sequential clinical assessments were made by the same neurologist in the same environment at the same time of day. RESULTS: Treatment with 24 g/day piracetam produced significant and clinically relevant improvement in the primary outcome measure of mean sum score (p=0.005) and in the means of its subtests of motor impairment (p=0.02), functional disability (p=0.003), and in global assessments by both investigator (p=0.002) and patient (p=0.01). Significant improvement in functional disability was also found with daily doses of 9.6 g and 16.8 g. The dose-effect relation was linear and significant. More patients showed clinically relevant improvement with the highest dosage and, in individual patients, increasing the dose improved response. Piracetam was well tolerated and adverse effects were few, mild, and transient. CONCLUSIONS: This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage.

Comparison of [18F]FDG-PET, [99mTc]-HMPAO-SPECT, and [123I]-iomazenil-SPECT in localising the epileptogenic cortex.

OBJECTIVES: Firstly, to compare the findings of interictal 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and of single photon emission computed tomography (SPECT) using 99mTc-hexamethyl propylene-amine-oxime (HMPAO) and 123I-iomazenil in localising the epileptogenic cortex in patients who were candidates for epilepsy surgery, but in whom clinical findings, video EEG monitoring (V-EEG), MRI, and neuropsychological evaluations did not give any definite localisation of the seizure onset. Secondly, to assess the ability of these functional methods to help in the decision about the epilepsy surgery. METHODS: Eighteen epileptic patients were studied with FDG-PET and iomazenil-SPECT. HMPAO-SPECT was performed in 11 of these 18 patients. Two references for localisation was used--ictal subdural EEG recordings (S-EEG) and the operated region. RESULTS: Fifteen of 18 patients had localising findings in S-EEG. FDG-PET findings were in accordance with the references in 13 patients and iomazenil-SPECT in nine patients. HMPAO-SPECT visualised the focus less accurately than the two other methods. In three patients S-EEG showed independent bitemporal seizure onset. In these patients FDG-PET showed no lateralisation. However, iomazenil-SPECT showed temporal lobe lateralisation in two of them. CONCLUSION: FDG-PET seemed to localise the epileptogenic cortex more accurately than interictal iomazenil-SPECT in patients with complicated focal epilepsy.