Frode Willoch

Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis.

&NA; Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color‐word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain‐related activation in multiple brain areas, particularly in the so‐called ‘medial pain system’. Distraction significantly increased the activation of the cingulo‐frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo‐frontal cortex may exert top–down influences on the PAG and posterior thalamus to gate pain modulation during distraction.

Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study

A high percentage of patients with mild cognitive impairment (MCI) develop clinical dementia of the Alzheimer type (AD) within 1 year. The aim of this longitudinal study was to identify characteristic patterns of cerebral metabolism at baseline in patients converting from MCI to AD, and to evaluate the changes in these patterns over time. Baseline and follow-up examinations after 1 year were performed in 22 MCI patients (12 males, 10 females, aged 69.8±5.8 years); these examinations included neuropsychological testing, structural cranial magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography (PET) evaluation of relative cerebral glucose metabolic rate (rCMRglc). Individual PET scans were stereotactically normalised with NEUROSTAT software (Univ. of Michigan, Ann Arbor, USA). Subsequently, statistical comparison of PET data with an age-matched healthy control population and between patient subgroups was performed using SPM 99 (Wellcome Dept. of Neuroimaging Sciences, London, UK). After 1 year, eight patients (36%) had developed probable AD (referred to as MCIAD), whereas 12 (55%) were still classified as having stable MCI (referred to as MCIMCI). Compared with the healthy control group, a reduced rCMRglc in AD-typical regions, including the temporoparietal and posterior cingulate cortex, was detected at baseline in patients with MCIAD. Abnormalities in the posterior cingulate cortex reached significance even in comparison with the MCIMCI group. After 1 year, MCIAD patients demonstrated an additional bilateral reduction of rCMRglc in prefrontal areas, along with a further progression of the abnormalities in the parietal and posterior cingulate cortex. No such changes were observed in the MCIMCI group. In patients with MCI, characteristic cerebral metabolic differences can be delineated at the time of initial presentation, which helps to define prognostic subgroups. A newly emerging reduction of rCMRglc in prefrontal cortical areas is associated with the transition from MCI to AD.

Region-specific encoding of sensory and affective components of pain in the human brain: A positron emission tomography correlation analysis.

Brain imaging with positron emission tomography has identified some of the principal cerebral structures of a central network activated by pain. To discover whether the different cortical and subcortical areas process different components of the multidimensional nature of pain, we performed a regression analysis between noxious heat‐related regional blood flow increases and experimental pain parameters reflecting detection of pain, encoding of pain intensity, as well as pain unpleasantness. The results of our activation study indicate that different functions in pain processing can be attributed to different brain regions; ie, the gating function reflected by the pain threshold appeared to be related to anterior cingulate cortex, the frontal inferior cortex, and the thalamus, the coding of pain intensity to the periventricular gray as well as to the posterior cingulate cortex, and the encoding of pain unpleasantness to the posterior sector of the anterior cingulate cortex. Ann Neurol 1999;45:40–47

Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study.

&NA; Based on concepts that endogenous opioids participate in neural transmission of pain, the present study in central poststroke pain (CPSP) patients investigated changes in opioid receptor (OR) binding in neural structures centrally involved in the processing of pain. Five patients with central pain after lesions in the brain stem, thalamus or parietal cortex and twelve healthy volunteers underwent a [11C]diprenorphine positron emission tomography study. Binding potentials were calculated using a reference region model in all subjects. Statistical parametric mapping was applied for t‐statistical analysis on voxel‐basis. Binding potential values for each individual were extracted from a volume of interest at each identified significant peak. Spectral analysis was applied for quantification of global values. Significant regional reduced 11C‐diprenorphine binding (corrected for multiple tests) was detected in contralateral thalamus, parietal, secondary somatosensory, insular and lateral prefrontal cortices, and along the midline in anterior cingulate, posterior cingulate and midbrain gray matter. Individual extracted binding values disclosed a reduced binding in these regions in all patients independent from the particular lesion site. The poststroke pain syndrome is associated with a characteristic pattern of reduced OR binding within the neural circuitry processing pain. It is suggested that an imbalance of excitatory‐inhibitory mechanisms in certain brain structures, as evidenced in decreased [11C]diprenorphine binding, is one of the causes or the consequences of poststroke pain.

Imaging of opioid receptors in the central nervous system.

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.

Phantom limb pain in the human brain: unraveling neural circuitries of phantom limb sensations using positron emission tomography.

Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain‐processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network. Ann Neurol 2000;48:842–849

Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study.

Background The current study investigated dose-dependent effects of the &mgr;-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET). Methods Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 &mgr;g · kg−1 · min−1), and moderate remifentanil (0.15 &mgr;g · kg−1 · min−1). The remaining three participated in the low and moderate conditions. A semi-randomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping. Results Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis. Conclusion Remifentanil induced dose-dependent changes in relative rCBF in areas involved in pain processing. At moderate doses, rCBF responses were additionally detected in structures known to participate in modulation of vigilance and alertness. Insight into the mechanisms of opioid analgesia within the pain-processing neural network may lead to a better understanding of antinociception and opioid treatment.

Opioidergic activation in the medial pain system after heat pain

Abstract Opioids modulate the affective component of pain and in vivo data indicate that opioids induce activation changes in the rostral ACC, insula and other brain areas. Hence, opioidergic release is to be expected in these brain regions following experimental pain stimulation. We examined healthy volunteers during heat pain and control subjects during rest using [18F]fluorodiprenorphine‐PET. Pain stimulation led to significant reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula. The finding of altered opioidergic receptor availability in the rostral ACC after experimental nociceptive pain is novel and provides direct evidence for the involvement of this region in endogenous opioidergic inhibition of pain.

Imaging brain activation induced by long trains of repetitive transcranial magnetic stimulation

USING Positron emission tomography (PET), we measured the relative changes in regional cerebral metabolic rate of glucose (rCMRglc) during 2Hz repetitive transcranial magnetic stimulation (rTMS) of the left sensorimotor cortex (SM1) and during imitation of rTMS-induced arm movements. Such stimulation caused an rCMRglc increase of about 8% within the SM1. The relative rCMRglc increase within SM1 was significantly greater in magnitude and larger in area during voluntary imitation of rTMS-induced arm movements. Moreover, the rostral part of the SMA was significantly more activated by voluntary movements than during rTMS. Combining rTMS and PET has the potential to visualize rTMS-related net brain activation, and may open up new possibilities for functional network analysis by comparing willed brain activation with electromagnetic brain activation.

Tau protein in cerebrospinal fluid is significantly increased at the earliest clinical stage of Alzheimer disease.

Summary:The concentration of tau protein in cerebrospinal fluid (CSF) was determined in 40 patients with clinically diagnosed probable Alzheimer disease (AD) and in 36 cognitively healthy controls. A significant increase of CSF tau was found in the AD patients, even in 19 subjects with very mild dementia as defined by a Mini-Mental State Examination score of 25 and above. Using a cutoff value of 260 pg/mL the sensitivity of elevated tau was 0.89, the specificity was 0.97, and the proportion of correctly allocated cases was 95%. In the AD groups there were no significant associations between CSF tau level and age, age at onset, duration of illness, apolipoprotein E genotype, severity of cognitive impairment, or deficit in regional cerebral blood flow as measured using 99Tm-ethyl cystein dimer single photon emission computed tomography. The findings demonstrate that CSF tau is significantly increased at the earliest clinical stage of AD and shows only minimal overlap with age-matched cognitively healthy controls. This finding suggests that CSF tau could be a biological marker of AD even before dementia has developed.