H2O Positron Emission Tomography Research Articles

Transfer of the sFLT-1 Gene in Morris Hepatoma Results in Decreased Growth and Perfusion and Induction of Genes Associated with Stress Response

Inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometrical analyses are desirable to evaluate the biological effects caused by this treatment modality. Using a bicistronic retroviral vector for transfer of the soluble receptor for the vascular endothelial growth factor (sFLT) hepatoma (MH3924A) cell lines with sFLT expression were generated. In human umbilical vein endothelial cells cultured with conditioned medium of sFLT-expressing hepatoma cells, the inhibitory action of secreted sFLT was determined using a Coulter counter and a thymidine incorporation assay. Furthermore, in vivo experiments were done to measure the effects on tumor growth and perfusion. Finally, the tumors were examined by immunohistochemistry (including computer-assisted morphometry) and DNA chip analysis. Stable sFLT-expressing hepatoma cells inhibited endothelial cell proliferation in vitro. In vivo, growth and perfusion, as measured by H(2)(15)O positron emission tomography, were reduced in genetically modified tumors. However, the immunohistochemically quantified microvascularization and macrovascularization, as indicated by CD31- and alpha-actin-positive area, revealed no significant changes, whereas the number of apoptotic cells was increased in sFLT-expressing tumors, although not significantly. DNA chip analysis of tumors with gene transfer showed an increase of genes related to apoptosis, signal transduction, and oxidative stress. Our results suggest that sFLT expression inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes in this model. Enhanced expression of genes for signal transduction, stress, and metabolism indicates tumor defense reactions.

Functional disconnection of the semantic networks in schizophrenia

Patients with schizophrenia exhibit deficits in semantic processing, which can form the basis of thought disorders. The objective of this study was to explore functional connectivity between the activated areas during semantic processing in schizophrenia. Twelve patients with schizophrenia and 12 healthy controls were studied with [15O]H2O positron-emission tomography during semantic judgment. The expected activation in the left inferior occipitotemporal cortex significantly correlated with several other regional activations in normal study participants, but with no other regional activations in patients with schizophrenia. This finding suggests that schizophrenia involves a disconnection of semantic networks. The resultant distortion in semantic processing may have an impact on thought disorders.

Changes in Cerebral Blood Flow and Cerebral Oxygen Metabolism during Neural Activation Measured by Positron Emission Tomography: Comparison with Blood Oxygenation Level-Dependent Contrast Measured by Functional Magnetic Resonance Imaging

The discrepancy between the increases in cerebral blood flow (CBF) and CMRO2 during neural activation causes an increase in venous blood oxygenation and, therefore, a decrease in paramagnetic deoxyhemoglobin concentration in venous blood. This can be detected by functional magnetic resonance imaging (fMRI) as blood oxygenation level-dependent (BOLD) contrast. In the present study, changes in the cerebral oxygen extraction fraction (OEF) that corresponds to the ratio of CMRO2 to CBF, and in the BOLD signal during neural activation, were measured by both positron emission tomography (PET) and fMRI in the same human subjects. C15O, 15O2, and H2(15)O PET studies were performed in each subject at rest (baseline) and during performance of a right-hand motor task. Functional magnetic resonance imaging studies were then performed to measure the BOLD signal under the two conditions. During performance of the motor task, a significant increase in CBF and a significant decrease in OEF were observed in the left precentral gyrus, left superior frontal gyrus, right precentral gyrus, right cingulate gyrus, and right cerebellum. A significant positive correlation was observed between changes in the CBF and the BOLD signal, and a significant negative correlation was observed between changes in the OEF and the BOLD signal. This supports the assumption on which BOLD contrast studies during neural activation are based.

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.

Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the 4 Allele)

Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

The neural basis of altruistic punishment.

Many people voluntarily incur costs to punish violations of social norms. Evolutionary models and empirical evidence indicate that such altruistic punishment has been a decisive force in the evolution of human cooperation. We used H2 15O positron emission tomography to examine the neural basis for altruistic punishment of defectors in an economic exchange. Subjects could punish defection either symbolically or effectively. Symbolic punishment did not reduce the defector's economic payoff, whereas effective punishment did reduce the payoff. We scanned the subjects' brains while they learned about the defector's abuse of trust and determined the punishment. Effective punishment, as compared with symbolic punishment, activated the dorsal striatum, which has been implicated in the processing of rewards that accrue as a result of goal-directed actions. Moreover, subjects with stronger activations in the dorsal striatum were willing to incur greater costs in order to punish. Our findings support the hypothesis that people derive satisfaction from punishing norm violations and that the activation in the dorsal striatum reflects the anticipated satisfaction from punishing defectors.

Cerebellar Involvement in Visual On-Line Adaptation of Vertical Stroke Size: A PET Activation Study

Introduction: Behavioral data suggest that visual feedback can be effectively used for on-line adjustment of letter size during open-loop automated handwriting (Mai et Marquart Exp Brain Res 1999; 128: 224–228). Objective: Our intent was to pinpoint the involvement of the cerebellum in visual on-line adaptation of letter size. Methods: In eight male right-handed subjects (age: 25–39 years), we used H2 15O positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) during a handwriting task and a control condition (holding the pen). The written trace was recorded using a graphics tablet. Visual feedback of handwriting was continuously provided on a computer screen. In each trial, participants wrote four pairs of „l„ („ll ll ll ll“) every six seconds. Subjects were asked to match the letter size to the distance between two horizontal lines (˜ 9mm) using the feedback on the screen. The critical manipulation was an unpredictable change in the gain of vertical feedback during each trial. After the subject had written the first pair of „l“, the gain of vertical feedback was either reduced to 66% (1/3 of the trials), enlarged to 133% (1/3 of the trials) or remained the same (1/3 of the trials). Subjects were asked to maintain stroke size as specified by the horizontal lines. Kinematics of handwriting were analyzed using CS software (MedCom, Munich, Germany). The mean number of inversions in velocity (NIV) was calculated for each scan to quantify the degree of automation. Three scans per condition were acquired in each subject. PET data were analyzed with SPM99 (Wellcome Dept. of Neuroscience, ION, UCL, UK). Using a general linear model, the NIV were treated as a regressor to model the changes in rCBF associated with the mean NIV per scan (p<0.001, uncorrected). Results: Regression analysis revealed a positive linear relationship between the rCBF in several cerebellar clusters and the degree of automation during handwriting (i.e., as indexed by the NIV). These cerebellar areas were located bilaterally in the medial and paramedian aspects of the superior cerebellum. Conclusion: Our findings demonstrate that a high degree of open-loop performance is associated with an increased cerebellar activity during a task requiring rapid integration of visual feedback. This activity pattern points to a significant role of the cerebellum in on-line adjustments of movement amplitude during skilled hand movements.

The neural correlates of cue-induced craving in cocaine-dependent women.

Drug use reminders are associated with localized changes in brain activity related to intense drug wanting or craving in cocaine-dependent men. While cocaine dependence is prevalent and disabling in women, and certain clinically relevant sex differences exist, there is an absence of knowledge related to the neural correlates of cocaine craving in cocaine-dependent women. The differential neural response to imagery depicting cocaine use and neutral imagery was defined by using [15O]H2O positron emission tomography (PET) imaging in eight cocaine-dependent women. Results were compared with a matched group of eight cocaine-dependent men. Cocaine-related imagery was associated with relative increases in cocaine craving and increases in regional cerebral blood flow in the superior temporal gyrus, dorsal anterior and posterior cingulate cortex, nucleus accumbens area, and the central sulcus. Compared with the results of an identical PET study in matched cocaine-dependent men, conditioned cocaine craving in women was associated with less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex and greater activation of the central sulcus and widely distributed frontal cortical areas. These findings suggest the presence of sex differences in the functional anatomy of cue-induced cocaine craving associated with drug dependence. Such differences may reflect sex differences in conditioned associations to cocaine use, in affective and other corollaries of cocaine craving, or in their volitional regulation and may underlie apparent sex differences in the effects of cocaine abstinence and the expectations of treatment outcome. Some support for the need for sex-specific strategies for treatment of cocaine dependence is also furnished by the findings of this study.

Cerebral and cerebellar activation in power and precision grip movements: an H2 15O positron emission tomography study.

Most human manual grip movements can be divided into power gripping and precision gripping, but central neural control during these tasks remains unclear. We investigated activation of the whole brain to analyze how simple hand movements are performed. The cerebral blood flow of seven healthy right-handed volunteers was measured by H2 15O positron emission tomography during right grip tasks without gripping a target object. Auditory-cued, repetitive power grips (i.e., fist making) and repetitive precision grips (i.e., opposition of the tip of the index finger and the tip of the thumb) were performed at 1.26 Hz. The areas activated during both tasks were the left primary sensorimotor cortex, caudal portion of the dorsal premotor, caudal portion of the supplementary motor area, cingulate motor area, and the right spinocerebellum and intermediate region of the cerebrocerebellum in comparison with the rest state. The analysis of power grip-precision grip tasks showed the activated peaks in the upper portion of the left sensorimotor area and right cerebellar vermis, but these areas were activated in both the tasks [(power grip-rest) and (precision grip-rest)] with uncorrected P < 0.001 as the statistical criterion. With P < 0.05 corrected as the statistical criterion, the results showed no significant activated peaks in regional cerebral blood flow. Our findings indicate no difference in brain activation between the acts of power grip and precision grip without a target object.

Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia.

Symptoms of irritable bowel syndrome (IBS) and fibromyalgia (FM) commonly coexist. We hypothesized that one of the mechanisms underlying this comorbidity is increased activation of brain regions concerned with the processing and modulation of visceral and somatic afferent information, in particular subregions of the anterior cingulate cortex (ACC). Regional cerebral blood flow (rCBF) was assessed in age-matched female IBS (n = 10) and IBS + FM (n = 10) subjects using H(2)(15)O positron emission tomography during noxious visceral (rectal) and somatic pressure stimuli. GI symptom severity was significantly higher in the IBS patients compared with the IBS + FM patients (p < 0.05). In addition, IBS + FM patients rated somatic pain as more intense than their abdominal pain (p < 0.05). Whereas the somatic stimulus was less unpleasant than the visceral stimulus for IBS patients without FM, the somatic and visceral stimuli were equally unpleasant in the IBS + FM group. Group differences in regional brain activation were entirely within the middle subregion of the ACC. There was a greater rCBF increase in response to noxious visceral stimuli in IBS patients and to somatic stimuli in IBS + FM patients. Chronic stimulus-specific enhancement of ACC responses to sensory stimuli in both syndromes may be associated with cognitive enhancement of either visceral (IBS) or somatic (IBS + FM) sensory input and may play a key pathophysiologic role in these chronic pain syndromes.

A H215O Positron Emission Tomography Study on Mental Imagery of Movement Sequences—The Effect of Modulating Sequence Length and Direction

A H215O Positron Emission Tomography Study on Mental Imagery of Movement Sequences—The Effect of Modulating Sequence Length and Direction

Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron

Background & Aims: The 5-HT3 receptor (5-HT3R) antagonist Alosetron (Alos) reduces the symptoms of female patients with diarrhea-predominant irritable bowel syndrome (IBS); yet, the mechanism(s) underlying this effect remains incompletely understood. We determined the effect of Alos on regional cerebral blood flow (rCBF) in the absence and presence of rectal or sigmoid stimulation to evaluate 2 hypothesized mechanisms of therapeutic action: peripheral antinociception and inhibition of emotional motor system (EMS) regions in the brain. Methods: Forty-nine nonconstipated irritable bowel syndrome (IBS) patients (26 female) received H215O positron emission tomography (PET) brain scans before a randomized, placebo-controlled, 3-week trial with Alos (1–4 mg twice daily). PET scans were repeated after treatment in 37 completers. We assessed rCBF during baseline, rectal distention, and anticipation of undelivered rectal distention. The 3 conditions were repeated after a series of noxious sigmoid distentions. Rectal (45 mm Hg) and sigmoid (60 mm Hg) distentions were performed with a computer-controlled barostat device. Results: Alos treatment, as compared with placebo, improved IBS symptoms and reduced rCBF in 5-HT3R containing regions of the EMS, but not in areas activated by pain. Reduction of rCBF appeared greatest in the absence of visceral stimulation, and was partially reversed by rectal or sigmoid distention. Symptom improvement across sessions was significantly correlated with rCBF decreases in the 5-HT3R-rich amygdala, ventral striatum, and dorsal pons. Conclusions: Reduction in IBS symptoms correlated with a drug-induced reduction in the activity of central autonomic networks mediating emotional expression that was maximal in the absence of nociceptive input.GASTROENTEROLOGY 2002;123:969-977

BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger.

Air hunger (uncomfortable urge to breathe) is a component of dyspnea (shortness of breath). Three human H(2)(15)O positron emission tomography (PET) studies have identified activation of phylogenetically ancient structures in limbic and paralimbic regions during dyspnea. Other studies have shown activation of these structures during other sensations that alert the organism to urgent homeostatic imbalance: pain, thirst, and hunger for food. We employed blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine activation during air hunger. fMRI conferred several advantages over PET: enhanced signal-to-noise, greater spatial resolution, and lack of ionizing radiation, enabling a greater number of trials in each subject. Six healthy men and women were mechanically ventilated at 12-14 breaths/min. The primary experiment was conducted at mean end-tidal PCO(2) of 41 Torr. Moderate to severe air hunger was evoked during 42-s epochs of lower tidal volume (mean = 0.75 L). Subjects described the sensation as "like breath-hold," "urge to breathe," and "starved for air." In the baseline condition, air hunger was consistently relieved by epochs of higher tidal volume (mean = 1.47 L). A control experiment in the same subjects under a background of mild hypocapnia (mean end-tidal PCO(2) = 33 Torr) employed similar tidal volumes but did not evoke air hunger, controlling for stimulus variables not related to dyspnea. During each experiment, we maintained constant end-tidal PCO(2) and PO(2) to avoid systematic changes in global cerebral blood flow. Whole-brain images were acquired every 5 s (T2*, 56 slices, voxel resolution 3 x 3 x 3 mm). Activations associated with air hunger were determined using voxel-based interaction analysis of covariance that compared data between primary and control experiments (SPM99). We detected activations not seen in the earlier PET study using a similar air hunger stimulus (Banzett et al. 2000). Limbic and paralimbic loci activated in the present study were within anterior insula (seen in all 3 published studies of dyspnea), anterior cingulate, operculum, cerebellum, amygdala, thalamus, and basal ganglia. Elements of frontoparietal attentional networks were also identified. The consistency of anterior insular activation across subjects in this study and across published studies suggests that the insula is essential to dyspnea perception, although present data suggest that the insula acts in concert with a larger neural network.

Assessment of acetazolamide reactivity in cerebral blood flow using spectral analysis and technetium-99m hexamethylpropylene amine oxime.

Cerebral blood flow (CBF) can be quantified noninvasively using the brain perfusion index (BPI), determined from radionuclide angiographic data generated with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO). Previously, the BPI has been calculated using graphical analysis (GA); however, the GA method is greatly affected by the first-pass extraction fraction and retention fraction, which are not only variable, but lower in cases with an increased CBF, such as after the administration of acetazolamide. Thus, GA-calculated BPI values (BPIG) may not reflect the absolute CBF. The objective of this study was to use the spectral analysis of radionuclide angiographic data collected using 99mTc-HMPAO to examine changes in the BPI after the administration of acetazolamide. We studied the CBF of both cerebral hemispheres in six healthy male volunteers; the BPI was measured at rest and after the intravenous administration of 1 g of acetazolamide. In all participants, an H215O positron emission tomography (PET) examination was also performed, and the spectral analysis-calculated BPI values (BPIS) and BPIG values were compared with the actual CBF measured using H215O PET (mCBFPET). The BPIS was 1.070 +/- 0.051 (mean +/- SD) at rest and 1.497 +/- 0.098 after acetazolamide; the corresponding BPIG values were 0.646 +/- 0.073 and 0.721 +/- 0.107. The BPIS values were significantly correlated with the mCBFPET values, whereas the BPIG values were not. According to the BPIS values, the increase in BPI after the intravenous administration of acetazolamide was 40.1 +/- 8.4%, as opposed to an increase of only 11.3 +/- 6.5% according to the BPIG values. These results suggest that the spectral analysis of 99mTc-HMPAO-generated data yields a more reliable BPI than GA for the quantification of CBF after acetazolamide administration.

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

Covert auditory attention generates activation in the rostral/dorsal anterior cingulate cortex.

The anterior cingulate cortex (ACC) is believed to mediate conscious information processing or high-capacity attention. However, previous functional imaging studies have largely relied on tasks that involve motor function as well as attention. The work from our group utilizing an auditory continuous performance task demonstrated increased activity in a caudal division of the ACC that borders the supplementary motor area (SMA). Activity in this region was attributed to motor responding as well as attention. In the present study, we used (15)O H(2)O positron emission tomography (PET) to map brain activation during nonmotor, covert auditory attention. Our hypothesis was that a different region within the ACC, anterior to the SMA, would be active during covert attention (CA). Six men and six women were asked to monitor aurally presented syllables presented at a 1-sec interstimulus interval. During the CA condition, subjects were asked to continuously discriminate target (.19 probability) from nontarget stimuli. Simultaneous recording of event-related potentials (ERPs) confirmed the discrimination of target and nontarget stimuli and the allocation of attention capacity. Comparison of the monitored versus nonmonitored presentation of stimuli demonstrated significant activity in a rostral/dorsal division of the right ACC, anterior to SMA. Other regions of activation included the lateral prefrontal cortex and posterior superior temporal gyrus in the left hemisphere, consistent with neurocognitive models of language and vigilance. We conclude that a rostral/dorsal subdivision of the right ACC is specific for conscious attention during auditory processing, in contrast to premotor response formation.

Dissociation of Working Memory Processing Associated with Native and Second Languages: PET Investigation

Verbal working memory plays a significant role in language comprehension and problem-solving. The prefrontal cortex has been suggested as a critical area in working memory. Given that domain-specific dissociations of working memory may exist within the prefrontal cortex, it is possible that there may also be further functional divisions within the verbal working memory processing. While differences in the areas of the brain engaged in native and second languages have been demonstrated, little is known about the dissociation of verbal working memory associated with native and second languages. We have used H215O positron emission tomography in 14 normal subjects in order to identify the neural correlates selectively involved in working memory of native (Korean) and second (English) languages. All subjects were highly proficient in the native language but poorly proficient in the second language. Cognitive tasks were a two-back task for three kinds of visually presented objects: simple pictures, English words, and Korean words. The anterior portion of the right dorsolateral prefrontal cortex and the left superior temporal gyrus were activated in working memory for the native language, whereas the posterior portion of the right dorsolateral prefrontal cortex and the left inferior temporal gyrus were activated in working memory for the second language. The results suggest that the right dorsolateral prefrontal cortex and left temporal lobe may be organized into two discrete, language-related functional systems. Internal phonological processing seems to play a predominant role in working memory processing for the native language with a high proficiency, whereas visual higher order control does so for the second language with a low proficiency.

Long-Term Consequences of Switching Handedness: A Positron Emission Tomography Study on Handwriting in “Converted” Left-Handers

Until some decades ago, left-handed children who attended German schools were forced to learn to write with their right hand. To explore the long-term consequences of switching handedness, we studied the functional neuroanatomy of handwriting in 11 adult “converted” left-handers and 11 age-matched right-handers. All participants had used exclusively their right hand for writing since early childhood. Using [15O]H2O positron emission tomography, changes in normalized regional cerebral blood flow (rCBF) were assessed while participants repetitively wrote a stereotyped word with their right hand. The kinematics of handwriting did not differ between converted left-handers and right-handers. In innate right-handers, handwriting caused a preponderant left-hemispheric activation of parietal and premotor association areas. In contrast, converted left-handers demonstrated a more bilateral activation pattern with distinct activation foci in the right lateral premotor, parietal, and temporal cortex. Moreover, foci in the right rostral supplementary motor area and the right inferior parietal lobule demonstrated a positive linear relationship between the degree of “left-handedness” and normalized rCBF during right-hand writing. Functional activity in the primary sensorimotor cortex was not affected by handedness. Our findings provide evidence for persisting differences in the functional neuroanatomy of handwriting between right-handers and converted left-handers, despite decades of right-hand writing. Right-hemispheric activation in converted left-handers may reflect suppression of unwanted left-hand movements. Alternatively, this activity may represent persistent left-handedness and, as such, demonstrate a hemispheric asymmetry of hand movement representations in cortical motor association areas in relation to the direction and degree of handedness.

Long-term consequences of switching handedness: a positron emission tomography study on handwriting in "converted" left-handers.

Until some decades ago, left-handed children who attended German schools were forced to learn to write with their right hand. To explore the long-term consequences of switching handedness, we studied the functional neuroanatomy of handwriting in 11 adult "converted" left-handers and 11 age-matched right-handers. All participants had used exclusively their right hand for writing since early childhood. Using [15O]H2O positron emission tomography, changes in normalized regional cerebral blood flow (rCBF) were assessed while participants repetitively wrote a stereotyped word with their right hand. The kinematics of handwriting did not differ between converted left-handers and right-handers. In innate right-handers, handwriting caused a preponderant left-hemispheric activation of parietal and premotor association areas. In contrast, converted left-handers demonstrated a more bilateral activation pattern with distinct activation foci in the right lateral premotor, parietal, and temporal cortex. Moreover, foci in the right rostral supplementary motor area and the right inferior parietal lobule demonstrated a positive linear relationship between the degree of "left-handedness" and normalized rCBF during right-hand writing. Functional activity in the primary sensorimotor cortex was not affected by handedness. Our findings provide evidence for persisting differences in the functional neuroanatomy of handwriting between right-handers and converted left-handers, despite decades of right-hand writing. Right-hemispheric activation in converted left-handers may reflect suppression of unwanted left-hand movements. Alternatively, this activity may represent persistent left-handedness and, as such, demonstrate a hemispheric asymmetry of hand movement representations in cortical motor association areas in relation to the direction and degree of handedness.

Continuous Transcranial Magnetic Stimulation during Positron Emission Tomography: A Suitable Tool for Imaging Regional Excitability of the Human Cortex

In six healthy volunteers, H215O positron emission tomography (PET) was employed to evaluate rate-dependent functional activation of the left primary sensorimotor hand area (SM1HAND) during subthreshold repetitive transcranial magnetic stimulation (rTMS). Using an eight-shaped coil, continuous trains of rTMS were delivered during nine 50-s H215O PET scans. Nine different stimulation frequencies were used, ranging from 1 to 5 Hz. Stimulus intensity was set at 10% below active motor threshold. During three additional PET scans, an ineffective rTMS was applied via another eight-shaped coil, which was held 10 cm above the vertex. Statistical parametric mapping was employed to assess relative differences in normalized regional cerebral blood flow (rCBF) across conditions. Compared with ineffective rTMS, subthreshold rTMS increased normalized rCBF in the stimulated SM1HAND. Moreover, the increase in rCBF in the left SM1HAND showed a linear positive relationship with the rate of rTMS, indicating a rate-dependent functional activation of the stimulated SM1HAND. These data demonstrate that, by varying the variables of rTMS across scans, continuous rTMS during H215O PET provides a noninvasive tool to study the regional excitability profile of a distinct cortical area.