Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study.

This study was designed to evaluate whether subjects with amyloid beta (Aß) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aß pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aß+) or negative (Aß-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aß+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aß+ MCI subjects demonstrated greater worsening compared with Aß- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aß+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aß+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aß+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aß+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aß+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aß- subjects do.

Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease.

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.

Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

OBJECTIVE: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. METHODS: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. RESULTS: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. CONCLUSION: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB: a case-control study.

OBJECTIVES: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20). METHODS: In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42. RESULTS: Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions. CONCLUSIONS: Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.

[11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.

BACKGROUND: Beta-amyloid (Abeta) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to Abeta plaques in vivo, N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]PIB for "Pittsburgh Compound-B"), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes. METHODS: Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [(11)C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [(11)C]PIB-Abeta binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue. RESULTS: Patients with DAT had elevated BP values vs nondemented subjects (p < 0.0001). Four of the 41 nondemented subjects had elevated cortical BP values and their BP values as a group were not significantly different from the DAT subjects' BP values. Two of these four nondemented subjects had [(11)C]PIB uptake, both visually and quantitatively, that was indistinguishable from the DAT subjects. CONCLUSIONS: Elevated [(11)C]PIB binding in nondemented subjects suggests that [(11)C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer disease state. Longitudinal studies will be required to determine the association of elevated [(11)C]PIB binding and risk of developing dementia of the Alzheimer type.

The hippocampus and depression.

The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT(2A) receptors in the hippocampus using positron emission tomography (PET) to detect regional changes in [18F]altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.

Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.

BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces. METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.

Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane.

BACKGROUND: Abundant in vitro and animal model data suggest the postsynaptic gamma-aminobutyric acid receptor type A (GABA(A)-R) is an important target for volatile general anesthetics, but the relevance of these models is untested in humans. Because benzodiazepines have also been shown to act via a specific GABA(A)-R site, they provide sensitive probes for the GABA(A)-R. Availability of the 11C-labeled benzodiazepine ligand, flumazenil, allowed us to quantitatively test in humans whether the volatile anesthetic isoflurane affects GABA(A)-Rs in vivo in a dose-dependent manner. METHODS: 11C-flumazenil positron emission tomography scans were obtained in 12 healthy subjects while awake (control condition) and anesthetized with either 1.0 or 1.5 minimum alveolar concentration isoflurane (n = 7 and 5, respectively; isoflurane conditions). Regions of interest included areas of high, intermediate, and low GABA(A)-benzodiazepine site density. For each subject and experimental condition, the binding of 11C-flumazenil, expressed as distribution volume (which linearly correlates to maximal binding site density and apparent ligand affinity), was obtained by curve fitting using a two-compartment model. RESULTS: The ratio of distribution volume increased significantly in each examined region during the isoflurane conditions compared with control conditions (P < 0.01, one-tailed t test). Furthermore, the increases in ratio of distribution volume during the 1.5-minimum alveolar concentration isoflurane condition were significantly greater than those measured during 1.0 minimum alveolar concentration isoflurane inhalation (P < 0.002, one-tailed t test). CONCLUSIONS: Isoflurane exposure appeared to enhance receptor-specific 11C-flumazenil binding in a dose-dependent manner. The results suggest the possibility that a conformational change of the GABA(A)-R is involved in the mechanism of action of isoflurane in the living human brain.

Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data.

Coupling of cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO(2)) in physiologically activated brain states remains the subject of debates. Recently it was suggested that CBF is tightly coupled to oxidative metabolism in a nonlinear fashion. As part of this hypothesis, mathematical models of oxygen delivery to the brain have been described in which disproportionately large increases in CBF are necessary to sustain even small increases in CMRO(2) during activation. We have explored the coupling of CBF and oxygen delivery by using two complementary methods. First, a more complex mathematical model was tested that differs from those recently described in that no assumptions were made regarding tissue oxygen level. Second, [(15)O] water CBF positron emission tomography (PET) studies in nine healthy subjects were conducted during states of visual activation and hypoxia to examine the relationship of CBF and oxygen delivery. In contrast to previous reports, our model showed adequate tissue levels of oxygen could be maintained without the need for increased CBF or oxygen delivery. Similarly, the PET studies demonstrated that the regional increase in CBF during visual activation was not affected by hypoxia. These findings strongly indicate that the increase in CBF associated with physiological activation is regulated by factors other than local requirements in oxygen.

A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy.

PURPOSE: Locoregional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is in part associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been difficult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-based hypoxia measurement technique which employs a Cu(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) tracer is of great interest. Oxygen electrode measurements in animal experiments have demonstrated a strong correlation between low tumor pO(2) and excess (60)Cu-ATSM accumulation. Intensity-modulated radiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In this study, we examined the feasibility of combining these novel technologies to develop hypoxia imaging (Cu-ATSM)-guided IMRT, which may potentially deliver higher dose of radiation to the hypoxic tumor subvolume to overcome inherent hypoxia-induced radioresistance without compromising normal tissue sparing. METHODS AND MATERIALS: A custom-designed anthropomorphic head phantom containing computed tomography (CT) and positron emitting tomography (PET) visible targets consisting of plastic balls and rods distributed throughout the "cranium" was fabricated to assess the spatial accuracy of target volume mapping after multimodality image coregistration. For head-and-neck cancer patients, a CT and PET imaging fiducial marker coregistration system was integrated into the thermoplastic immobilization head mask with four CT and PET compatible markers to assist image fusion on a Voxel-Q treatment-planning computer. This system was implemented on head-and-neck cancer patients, and the gross tumor volume (GTV) was delineated based on physical and radiologic findings. Within GTV, regions with a (60)Cu-ATSM uptake twice that of contralateral normal neck muscle were operationally designated as ATSM-avid or hypoxic tumor volume (hGTV) for this feasibility study. These target volumes along with other normal organs contours were defined and transferred to an inverse planning computer (Corvus, NOMOS) to create a hypoxia imaging-guided IMRT treatment plan. RESULTS: A study of the accuracy of target volume mapping showed that the spatial fidelity and imaging distortion after CT and PET image coregistration and fusion were within 2 mm in phantom study. Using fiducial markers to assist CT/PET imaging fusion in patients with carcinoma of the head-and-neck area, a heterogeneous distribution of (60)Cu-ATSM within the GTV illustrated the success of (60)Cu-ATSM PET to select an ATSM-avid or hypoxic tumor subvolume (hGTV). We further demonstrated the feasibility of Cu-ATSM-guided IMRT by showing an example in which radiation dose to the hGTV could be escalated without compromising normal tissue (parotid glands and spinal cord) sparing. The plan delivers 80 Gy in 35 fractions to the ATSM-avid tumor subvolume and the GTV simultaneously receives 70 Gy in 35 fractions while more than one-half of the parotid glands are spared to less than 30 Gy. CONCLUSION: We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through coregistering hypoxia (60)Cu-ATSM PET to the corresponding CT images for IMRT planning. Future investigation is needed to establish a clinical-pathologic correlation between (60)Cu-ATSM retention and radiation curability, to understand tumor re-oxygenation kinetics, and tumor target uncertainty during a course of radiation therapy before implementing this therapeutic approach to patients with locally advanced tumor.

Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.

Patterns of relative cerebral blood flow in minor cognitive motor disorder in human immunodeficiency virus infection.

Individuals infected with HIV are at risk to develop cognitive impairment during the course of their disease. Although many patients develop an HIV-associated dementia, others may develop the less severe minor cognitive motor disorder (MCMD). In this study, relative cerebral blood flow was measured with PET imaging in HIV+ MCMD patients, HIV+ control subjects, and HIV- control subjects; analyses were performed by using statistical parametric mapping. Comparing a short-term memory task versus a rest state yielded activation in superior temporal cortex, postcentral gyrus, and cerebellum in all three subject groups. Comparing long- and short-term memory tasks yielded activation throughout the frontal cortex, including BA46. Activation in this area was reduced in the HIV+ control subjects and further reduced in the MCMD+ patients. Thus, brain activation associated with lower-level, automatic processing appears normal in HIV+ MCMD+ subjects, but activation associated with effortful retrieval and organizational processes is abnormal.

Functional neuroanatomy of semantic memory: recognition of semantic associations.

In an effort to examine the functional neuroanatomy of semantic memory, we studied the relative cerebral blood flow of eight healthy young subjects using 15O-water positron emission tomography (PET). Relative to a visual baseline control condition, each of four visual matching-to-sample tasks activated components of the ventral visual processing stream, including the inferior occipital and temporal cortices. Contrasting the task with the highest semantic component, a variation on the Pyramids and Palm Trees paradigm, with a size discrimination task resulted in focal activation in the anterior inferior temporal lobe, focused in the parahippocampal gyrus. There was additional activation in BA47 of the inferior frontal cortex. These data replicate and extend previously reported results using similar paradigms, and are consistent with cognitive neuropsychological models that stress the executive role of BA47 in semantic processing tasks.

Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction.

The serotonin (5-HT) neurotransmitter system, which has a widespread distribution in the central nervous system, has been implicated in regulating mood and many human behaviors. There is evidence from postmortem human studies and limited information from prior in vivo studies to support a decline in 5-HT2A receptor density with aging. We examined nine elderly (ages 61-76) and nine young (ages 18-29) healthy individuals with positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT2A binding site. The PET data were corrected for differences in brain tissue volume between the young and elderly subjects using a magnetic resonance (MR) imaging-based partial volume correction method. Highly significant and widespread cortical reductions in 5-HT2A specific binding were demonstrated in the elderly group relative to young controls. Regional losses averaged 61% before and 57% following correction for effects of cerebral atrophy. This finding, which is consistent with prior postmortem and in vivo studies, has both etiological and potential therapeutic implications for behavioral changes commonly observed in the elderly, including geriatric depression.

Cerebral blood flow in hypertensive patients: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks.

We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [(15)O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicated hypertensive patients and control subjects differed in rCBF response during both memory tasks. Hypertensives showed relatively diminished rCBF responses in right hemisphere areas combined with compensatory activation of homologous areas in the left cerebral cortex. Essential hypertension appears to selectively influence the circulatory reserve of portions of cerebral cortex and secondarily induce recruitment of other cortical areas to process certain tasks.

A method for the assessment of the functional neuroanatomy of human sleep using FDG PET.

Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assessment of brain function in humans (related to cognitive operations) during sleep has been limited, until recently, to surface electrophysiologic recordings that limit analysis of regional function, particularly in deep structures. The current report describes one method of assessing human forebrain activation during sleep using the [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) method and positron emission tomography (PET) measures of regional cerebral glucose utilization. In comparison with other functional brain imaging techniques (e.g., assessment of blood flow or functional magnetic resonance imaging), this method offers the advantage of a more naturalistic study of sleep since subjects do not have to sleep in a scanning device. This leads to a higher rate of successful completion of studies. The primary disadvantage of this method is the decreased temporal resolution necessitating assessments of global sleep states (e.g., REM or NREM) as opposed to assessing events within a sleep state (e.g., sleep spindles or rapid eye movements).

An examination of regional cerebral blood flow during object naming tasks.

The purpose of this study was to examine regional cerebral blood flow using positron emission tomography (PET) during the performance of tasks related to visual confrontation naming. Ten healthy, young participants were scanned twice in each of 5 conditions; blood flow was measured using standard PET [15O]-water technology. Two major findings have replicated previous studies. First, the naming of visually presented objects, whether covert or overt, requires a region of the left inferior cortex including the fusiform gyrus. Second, during overt naming, there is an increase in activity in the inferior or frontal cortex and insula as a consequence of generating speech code. These data are consistent with other studies demonstrating the importance of the inferior temporal regions for semantic processing, and the frontal cortex for word form generation.

Brain regions responsive to novelty in the absence of awareness.

Brain regions responsive to novelty, without awareness, were mapped in humans by positron emission tomography. Participants performed a simple reaction-time task in which all stimuli were equally likely but, unknown to them, followed a complex sequence. Measures of behavioral performance indicated that participants learned the sequences even though they were unaware of the existence of any order. Once the participants were trained, a subtle and unperceived change in the nature of the sequence resulted in increased blood flow in a network comprising the left premotor area, left anterior cingulate, and right ventral striatum. Blood flow decreases were observed in the right dorsolateral prefrontal and parietal areas. The time course of these changes suggests that the ventral striatum is responsive to novel information, and the right prefrontal area is associated with the maintenance of contextual information, and both processes can occur without awareness.

In vivo imaging of nitrous oxide-induced changes in cerebral activation during noxious heat stimuli.

BACKGROUND: Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Position emission tomography was used in nine volunteers to identify the loci of nitrous oxide-modulated cerebral responses to a peripheral noxious stimulus. METHODS: Nitrous oxide-pain interactions were studied by comparing regional cerebral blood flow responses to a 48 degrees C tonic heat stimulus, applied to each volunteer's left forearm, during room air inhalation with those obtained while 20% nitrous oxide was administered. Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. Locations of specific regional activation related to pain, and nitrous oxide, were identified using the statistical parametric mapping method, with a significance level of P < 0.01. Pain was rated by visual analog scale and the values were compared using Wilcoxon rank sum analysis. RESULTS: Pain produced cerebral activation in the contralateral thalamus, anterior cingulate, and supplementary motor area. Adding nitrous oxide during pain stimulation abolished activation in these areas but was associated with activation in the contralateral infralimbic and orbitofrontal cortices. In parallel, mean visual analog scale scores decreased significantly from 67 +/- 4 (SEM) to 54 +/- 5 (P < 0.05). CONCLUSIONS: Nitrous oxide, at 20% concentration, appears to modulate pain processing in the brain's medial pain system, and also activates the infralimbic and orbitofrontal cortices. The potential contribution of the affected brain areas to nitrous oxide analgesia is discussed.

Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography.

Recent positron emission tomography (PET) studies have demonstrated areas of pain processing in the human brain. Given the inhibitory effects of opioids on neuronal activity, we predicted that fentanyl's analgesic effects would be associated with suppression of pain-evoked responses in these distinct brain areas. To test this, PET was used to measure cerebral blood flow responses, as reflections of regional neuronal activity, to painful and nonpainful thermal stimuli both in the absence and presence of fentanyl in humans. During each PET scan in nine healthy volunteers a tonic heat source was placed against the subject's left forearm, delivering a preset temperature of either 40 degrees C (nonpainful) or 47-48 degrees C (painful). Subjects underwent eight blood flow studies, each consisting of 50 mCi [15O]water injection and a PET scan. The first four studies were performed during placebo administration in the stimulus sequence: nonpainful, painful, painful, nonpainful. This sequence was then repeated during intravenous (i.v.) administration of fentanyl 1.5 micrograms/kg [corrected]. Significant differences in regional cerebral blood flow (rCBF) between the placebo and the fentanyl conditions during nonpainful and painful stimuli were identified using statistical parametric mapping. It was found that pain increased rCBF in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, and contralateral supplementary motor area. Fentanyl increased rCBF in the anterior cingulate and contralateral motor cortices, and decreased rCBF in the thalamus (bilaterally) and posterior cingulate during both stimuli. During combined pain stimulation and fentanyl administration, fentanyl significantly augmented pain-related rCBF increases in the supplementary motor area and prefrontal cortex. This activation pattern was associated with decreased pain perception, as measured on a visual analog scale. In contrast to our hypothesis, these data indicate that fentanyl analgesia involves augmentation of pain-evoked cerebral responses in certain areas, as well as both activation and inhibition in other brain regions unresponsive to pain stimulation alone.