Evolution of functional reorganization in hemiplegic stroke: a serial positron emission tomographic activation study

We used serial positron emission tomography (PET) to study the evolution of functional brain activity within 12 weeks after a first subcortical stroke. Six hemiplegic stroke patients and three normal subjects were scanned twice (PET 1 and PET 2) by using passive elbow movements as an activation paradigm. Increases of regional cerebral blood flow comparing passive movements and rest and differences of regional cerebral blood flow between PET 1 and PET 2 in patients and normal subjects were assessed by using statistical parametric mapping. In controls, activation was found in the contralateral sensorimotor cortex, supplementary motor area, and bilaterally in the inferior parietal cortex with no differences between PET 1 and PET 2. In stroke patients, at PET 1, activation was observed in the bilateral inferior parietal cortex, contralateral sensorimotor cortex, and ipsilateral dorsolateral prefrontal cortex, supplementary motor area, and cingulate cortex. At PET 2, significant increases of regional cerebral blood flow were found in the contralateral sensorimotor cortex and bilateral inferior parietal cortex. A region that was activated at PET 2 only was found in the ipsilateral premotor area. Recovery from hemiplegia is accompanied by changes of brain activation in sensory and motor systems. These alterations of cerebral activity may be critical for the restoration of motor function.     

Impaired mesial frontal and putamen activation in Parkinson's disease: a positron emission tomography study.

Selection of movement in normal subjects has been shown to involve the premotor, supplementary motor, anterior cingulate, posterior parietal, and dorsolateral prefrontal areas. In Parkinson's disease (PD), the primary pathological change is degeneration of the nigrostriatal dopaminergic projections, and this is associated with difficulty in initiating actions. We wished to investigate the effect of the nigral abnormality in PD on cortical activation during movement. Using C15O2 and positron emission tomography (PET), we studied regional cerebral blood flow in 6 patients with PD and 6 control subjects while they performed motor tasks. Subjects were scanned while at rest, while repeatedly moving a joystick forward, and while freely choosing which of four possible directions to move the joystick. Significant increases in regional cerebral blood flow were determined with covariance analysis. In normal subjects, compared to the rest condition, the free-choice task activated the left primary sensorimotor cortex, left premotor cortex, left putamen, right dorsolateral prefrontal cortex and supplementary motor area, anterior cingulate area, and parietal association areas bilaterally. In the patients with PD, for the free-choice task, compared with the rest condition, there was significant activation in the left sensorimotor and premotor cortices but there was impaired activation of the contralateral putamen, the anterior cingulate, supplementary motor area, and dorsolateral prefrontal cortex. Impaired activation of the medial frontal areas may account for the difficulties PD patients have in initiating movements.     

The effects of pharmacological doses of 2-deoxyglucose on cerebral blood flow in healthy volunteers

The effects of glucose deprivation on cerebral blood flow (CBF) have been extensively investigated during insulin-induced hypoglycemia in laboratory animals. Pharmacological doses of glucose analog, 2-deoxyglucose (2DG), is an alternative glucoprivic agent that in contrast to insulin, directly inhibits glycolysis and glucose utilization. Both glucoprivic conditions markedly increase CBF in laboratory animals. How 2DG affects CBF in humans is still undetermined. In the present study we have employed H₂¹⁵O positron emission tomography (PET) to examine the effects of pharmacological doses of 2DG (40 mg/kg) on regional and global cerebral blood flow in 10 brain areas in 13 healthy volunteers. 2DG administration significantly raised regional CBF (rCBF) in the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus. 2DG produced a trend towards elevated CBF in whole brain and frontal cortex, while no changes were observed in the corpus callosum and thalamus. In addition, 2DG significantly decreased body temperature and mean arterial pressure (MAP). Maximal percent changes in hypothalamic rCBF were significantly correlated with maximal changes in body temperature but not with MAP. These results indicate that cerebral glucoprivation produced by pharmacological doses of 2DG is accompanied by widespread activation of cortical and subcortical blood flow and that the blood flow changes in the hypothalamus may be related to 2DG-induced hypothermia.     

Regional cerebral blood flow changes in motor cortical areas after transient anesthesia of the forearm

To study the effect of deafferentation on cortical areas activated by movement of the proximal muscles, we measured regional cerebral blood flow with positron emission tomography and ¹⁵O-labeled water. Flexion-extension movements of the right elbow before deafferentation were associated with an increase of regional cerebral blood flow in the primary sensorimotor area bilaterally, posterior supplementary motor area bilaterally, ipsilateral cerebellum, contralateral putamen, premotor area, anterior cingulate area, and posterior parietal region. Transient anesthesia of the right forearm induced by ischemic block caused an increase of regional cerebral blood flow in the primary sensorimotor area bilaterally at rest, but there was no change of regional cerebral blood flow with movement, indicating that the movement-related change in cerebral blood flow was reduced. These findings are consistent with increased excitability of neurons as a result of deafferentation. In the supplementary motor area, anesthesia did not induce any change in regional cerebral blood flow at rest, but there was a decline with movement, again indicating a reduction of the change in cerebral blood flow related to movement. This might be due to a reduction in sensory feedback because of the anesthesia.     

Functional correlates of pallidal stimulation for Parkinson's disease

We measured regional cerebral blood flow with H2 15O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinson's disease. Six right-handed patients with Parkinson's disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication-free state. Internal globus pallidus deep brain stimulation improved off-state United Parkinson's Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention.     

The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography

We have studied regional cerebral blood flow changes in 6 patients after their recovery from a first hemiplegic stroke. All had a single well-defined hemispheric lesion and at least a brachial monoparesis that subsequently recovered. Each patient had 6 measurements of cerebral blood flow by positron tomography with 2 scans at rest, 2 during movement of fingers of the recovered hand, and 2 during movement of fingers of the normal hand. When the normal fingers were moved, regional cerebral blood flow increased significantly in contralateral primary sensorimotor cortex and in the ipsilateral cerebellar hemisphere. When the fingers of the recovered hand were moved, significant regional cerebral blood flow increases were observed in both contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres. Other regions, namely, insula, inferior parietal, and premotor cortex, were also bilaterally activated with movement of the recovered hand. We have also demonstrated, by using a new technique of image analysis, different functional connections between the thalamic nuclei and specific cortical and cerebellar regions during these movements. Our results suggest that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.     

Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus

Acute bouts of exercise have been shown to produce transient increases in regional cerebral glucose utilization, oxygen uptake, and cerebral blood flow in motor cortex, striatum, and hippocampus. The purpose of this study was to determine whether or not chronic exercise will cause long-term metabolic plasticity in brain structures activated during physical activity. The activity of cytochrome oxidase (COX), is coupled to the production of ATP, and reflects long-term plasticity in metabolic capacity. The present study examined whether or not 6 months of voluntary exercise would increase COX activity in the striatum, sensorimotor cortex, and three hippocampal subfields. Five-month-old, female Long-Evans hooded rats were randomly assigned to a control or exercise condition. Exercising rats had running wheels attached to their home cages. After the training period, fresh brains were rapidly frozen and sectioned with a cryostat. COX activity was measured using COX histochemical methods and optical densitometry. Rats in the exercise condition had significantly higher optical density in the hindlimb and forelimb motor cortices (18%, P<0.01) and dorsolateral caudate putamen (17%, P<0.01), but not in the ventrolateral caudate putamen or any subfield of the hippocampus. Although exercise is believed to increase neuronal activity in the hippocampus, motor cortex and striatum, only limb representations in the motor cortex and striatum increase bioenergetic capacity after regular exercise.     

Cerebellar and frontal hypometabolism in alcoholic cerebellar degeneration studied with positron emission tomography

Local cerebral metabolic rate for glucose was studied utilizing 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 14 chronically alcohol-dependent patients and 8 normal control subjects of similar age and sex. Nine of the 14 patients (Group A) had clinical signs of alcoholic cerebellar degeneration, and the remaining 5 (Group B) did not have signs of alcoholic cerebellar degeneration. PET studies of Group A revealed significantly decreased local cerebral metabolic rates for glucose in the superior cerebellar vermis in comparison with the normal control subjects. Group B did not show decreased rates in the cerebellum. Both Groups A and B showed decreased local cerebral metabolic rates for glucose bilaterally in the medial frontal area of the cerebral cortex in comparison with the normal control subjects. The severity of the clinical neurological impairment was significantly correlated with the degree of hypometabolism in both the superior cerebellar vermis and the medial frontal region of the cerebral cortex. The degree of atrophy detected in computed tomography scans was significantly correlated with local cerebral metabolic rates in the medial frontal area of the cerebral cortex, but not in the cerebellum. The data indicate that hypometabolism in the superior cerebellar vermis closely follows clinical symptomatology in patients with alcoholic cerebellar degeneration, and does not occur in alcohol-dependent patients without clinical evidence of cerebellar dysfunction. Hypometabolism in the medial frontal region of the cerebral cortex is a prominent finding in alcohol-dependent patients with or without alcoholic cerebellar degeneration.     

Anterior thalamic nucleus stimulation modulates regional cerebral metabolism: An FDG-MicroPET study in rats

The mechanism underlying the antiepileptic function of deep brain stimulation (DBS) of the anterior thalamic nucleus (ATN) remains unknown, presumably related to functional lesioning of target. We measured the regional normalized cerebral metabolic rate of glucose (nCMRglc) with ¹⁸F-fluorodeoxyglucose (FDG)-MicroPET in animals receiving either ATN stimulation or lesioning. Bilateral ATN stimulation reversibly increased glucose uptake in the target region, the thalamus and hippocampus, and decreased glucose uptake in the cingulate cortex and frontal cortex. However, bilateral ATN lesioning decreased glucose uptake only in the target region. Animals with bilateral ATN lesions showed no metabolic changes after ATN stimulation. Thus, bilateral DBS of the ATN reversibly induces metabolic activation of the target area and modulates energy metabolism in remote brain regions via efferent or afferent fibers in non-epileptic rats. DBS of the ATN may work by a different mechanism than ATN lesioning.     

Subthalamic nucleus stimulation reduces abnormal motor cortical overactivity in Parkinson disease

BACKGROUND: Based on the basal ganglia model, it has been hypothesized that the efficacy of high-frequency stimulation of the subthalamic nucleus (STN) against parkinsonian symptoms relies on the activation of cortical premotor regions. In previous positron emission tomography activation studies, STN high-frequency stimulation was associated with selective activation of midline premotor areas during hand movements but mainly reduced the regional cerebral blood flow in movement-related areas, peculiarly at rest. OBJECTIVE: To investigate with positron emission tomography the role of regional cerebral blood flow reduction in the clinical improvement provided by STN high-frequency stimulation. METHODS: Seven patients with advanced Parkinson disease, who were markedly improved by bilateral STN high-frequency stimulation, underwent positron emission tomography with H2(15)O while the right STN electrode was turned off. The patients were studied at rest and during right-hand movements in 3 electrode conditions: no stimulation, inefficient low-frequency stimulation, and efficient high-frequency stimulation. RESULTS: The main effect of high-frequency stimulation was to reduce regional cerebral blood flow in the left primary sensorimotor cortex, the lateral premotor cortex, the right cerebellum, and the midline premotor areas. The selective activation of the anterior cingulate cortex and the left primary sensorimotor cortex during hand movement under STN high-frequency stimulation was attributed to decreased regional cerebral blood flow at rest, rather than increased activation induced by STN high-frequency stimulation. Akinesia was correlated with the abnormal overactivity in the contralateral primary sensorimotor cortex and the ipsilateral cerebellum. CONCLUSION: High-frequency stimulation of the STN acts through the reduction of abnormal resting overactivity in the motor system, allowing selective cortical activation during movement.     

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.     

Regional cerebral blood flow pattern in focal epileptiform seizures in the monkey

The [¹⁴C]antipyrine method for measuring regional cerebral blood flow was utilized in experimental focal epilepsy, to explore its usefulness in identifying cortical and subcortical structures implicated in the propagation of paroxysmal activity. During a unilateral seizure induced by injecting penicillin into the right sensorimotor cortex of the monkey, increased cerebral blood flow was observed in the cortical area contiguous to the primary focus, the contralateral sensorimotor cortex, and the ipsilateral putamen, globus pallidus, thalamic nuclei, substantia nigra, contralateral cerebellar hemisphere and dentate nucleus. The principal advantage of this procedure is the global appraisal of brain activity at one phase in the seizure production. The method, other than by inference, does not demonstrate the neuronal pathways nor the sequence of nuclear involvement.     

Functional reorganization of the brain in recovery from striatocapsular infarction in man.

We used positron emission tomography (PET) to study organizational changes in the functional anatomy of the brain in 10 patients following recovery from striatocapsular motor strokes. Comparisons of regional cerebral blood flow maps at rest between the patients and 10 normal subjects revealed significantly lower regional cerebral blood flow in the basal ganglia, thalamus, sensorimotor, insular, and dorsolateral prefrontal cortices, in the brainstem, and in the ipsilateral cerebellum in patients, contralateral to the side of the recovered hand. These deficits reflect the distribution of dysfunction caused by the ischemic lesion. Regional cerebral blood flow was significantly increased in the contralateral posterior cingulate and premotor cortices, and in the caudate nucleus ipsilateral to the recovered hand. During the performance of a motor task by the recovered hand, patients activated the contralateral cortical motor areas and ipsilateral cerebellum to the same extent as did normal subjects. However, activation was greater than in normal subjects in both insulae; in the inferior parietal (area 40), prefrontal and anterior cingulate cortices; in the ipsilateral premotor cortex and basal ganglia; and in the contralateral cerebellum. The pattern of cortical activation was also abnormal when the unaffected hand, contralateral to the hemiplegia, performed the task. We showed that bilateral activation of motor pathways and the recruitment of additional sensorimotor areas and of other specific cortical areas are associated with recovery from motor stroke due to striatocapsular infarction. Activation of anterior and posterior cingulate and prefrontal cortices suggests that selective attentional and intentional mechanisms may be important in the recovery process. Our findings suggest that there is considerable scope for functional plasticity in the adult human cerebral cortex.     

A positron emission tomography study of essential tremor: Evidence for overactivity of cerebellar connections

The origin of essential tremor is unknown. Animal models have suggested that the inferior olivary nucleus may act as a tremor generator. We used positron emission tomography to study changes in regional cerebral blood flow associated with involuntary postural tremor and passive wrist oscillation in patients with essential tremor. Activation due to voluntary wrist oscillation and arm extension without tremor was studied in normal control subjects. The essential tremor group had bilaterally increased cerebellar blood flow at rest (without tremor) compared with the control group. Involuntary postural tremor was associated with further bilateral cerebellar activation, and also contralateral striatal, thalamic, and sensorimotor cortex activation. Voluntary wrist oscillation, maintained arm extension without tremor, and passive wrist oscillation were all associated with significant ipsilateral rather than bilateral cerebellar activation. We conclude that essential tremor is associated with increased bilateral cerebellar activity both at rest and during tremor.     

Effects of cerebral angiomas on perifocal and remote tissue: a multivariate positron emission tomography study.

BACKGROUND AND PURPOSE: Using multitracer positron emission tomography, I investigated regional hemodynamic and metabolic changes in both perifocal and remote tissues of cerebral angiomas, with special reference to steal phenomena. METHODS: In 22 patients (14 with arteriovenous malformations and eight with cavernomas) cerebral blood flow, cerebral blood volume, mean vascular transit time, cerebral metabolic rate for oxygen, oxygen extraction fraction, cerebral metabolic rate for glucose, and glucose extraction fraction were measured using standard positron emission tomographic methods. Twelve patients also had their cerebral glucose metabolism assessed during psychophysical activation. Regions of interest representing the angioma, perifocal and remote tissues, contralateral mirror regions, and standard brain regions were analyzed. RESULTS: There were no significant changes in hemodynamic variables or oxygen metabolism in the ipsilateral cerebral hemisphere, but ipsilateral glucose metabolism was reduced both at rest (p less than 0.01) and during activation (p less than 0.05). Glucose (p less than 0.001) and oxygen (p less than 0.001) metabolism in regions of perifocal tissue with low blood flow were decreased, with substrate extraction fractions showing no increase to compensate for insufficient blood flow. Functional recruitment of the cortex overlying the angioma beyond its periphery and supplied by the same arterial branches was subnormal (p less than 0.05) despite relatively unchanged hemodynamics in this tissue compartment. CONCLUSIONS: These data suggest that dysfunction of the cortex supplied by arterial branches also feeding the vascular malformation is related to neuronal deafferentation, while the proportionate decrease in blood flow and metabolism of perifocal tissue may be ascribed to neuronal loss in chronically hypoperfused areas, rather than to persistent hemodynamic steal effects.     

Depressed cerebellar glucose metabolism in supratentorial tumors

Fifty-four patients with supratentorial tumor and one with brainstem tumor were examined with emission tomography (PET) using [¹⁸F]fluoro-deoxyglucose (FDG). Twenty-one of these cases had satisfactory studies of the cerebellum. Of these, 12 showed significant metabolic asymmetry between the two cerebellar hemispheres, with the rate of glucose utilization in the hemisphere contralateral to the cerebral tumor being 8–34% lower than on the ipsilateral side, as compared with a right-left asymmetry of only— 1.6% ± 2.1% standard deviation for a group of 5 normal subjects. In these 12 cases the tumor involved the sensorimotor cortex and/or the thalamus with varying degrees of hemiparesis being present. For the remaining 9 patients with no significant cerebellar metabolic asymmetry, the tumor involved regions other than the sensorimotor cortex, and unilateral motor dysfunction was not a prominent clinical feature.The correlation between cerebellar metabolic suppression and unilateral motor dysfunction observed in our cases appears to be due to impairment or interruption of the cortico-thalamo-ponto-olivo-cerebellar circuitry by either the tumor itself or by edema. These results illustrate the ability of FDG-PET scans to detect metabolic changes, not apparent on CT scans, in areas of the brain remote from the primary lesion.     

Regional comparisons of brain glucose influx

The regional influx of glucose across the blood-brain barrier and regional blood flow were studied simultaneously in conscious and restrained rats using the single pass bolus injection of [¹⁴C]butanol and [³H] -glucose method. Glucose extraction by the cerebellum was about twice that of other brain regions. Thus, despite the lower cerebellar blood flow, the influx of glucose into the cerebellum was equivalent to that of the cerebral cortex and higher than that of the hippocampus over a wide range of plasma glucose concentrations. Because the local metabolic rate for glucose is higher in the cerebral cortex than in the cerebellum, the equal influx of glucose in these two regions means a relative oversupply of glucose to the cerebellum. In vivo analysis of blood to brain glucose transport kinetics showed similar plasma glucose concentrations at half-maximal transport (K_t) in all brain regions that were studied. The values for K_t ranged between 4.4 and 5.1 mM. Maximal transport capability (T_max), on the other hand, was similar in the cerebral cortex and cerebellum but significantly lower in the hippocampus (P < 0.05). The higher ratio of glucose influx to glucose utilization in the cerebellum may explain the clinical and experimental findings of relative resistance of the cerebellum to hypoglycemia while the lower T_max in the hippocampus may be the mechanism underlying its selective vulnerability during pathophysiologic conditions associated with marked increments in brain oxidative metabolism, such as status epilepticus.     

Role of the ipsilateral motor cortex in mirror movements.

The mechanism of mirror movements in two patients was investigated; one with congenital mirror movement, the other with schizencephaly. Transcranial magnetic stimulation on one side elicited motor evoked potentials (MEPs) in their thenar muscles on both sides with almost the same latencies, minimal thresholds, and cortical topographies. During voluntary contraction of the thenar muscle on one side, contralateral transcranial magnetic stimulation induced a silent period not only on the voluntary contraction side but on the mirror movement side and of the same duration. By contrast, ipsilateral transcranial magnetic stimulation elicited MEPs without silent periods in both muscles. With intended unilateral finger movements, an H2(15)O-PET activation study showed that the regional cerebral blood flow increased predominantly in the contralateral sensorimotor cortex, as seen in normal subjects, although mirror movements occurred. It is considered that the ipsilateral motor cortex plays a major part in the generation of mirror movements, which may be induced through the ipsilateral uncrossed corticospinal tract.     

Increases in both cerebral glucose utilization and blood flow during execution of a somatosensory task

To investigate local metabolic and hemodynamic interrelationships during functional activation of the brain, paired studies of local cerebral glucose utilization (lCMRGlc) and blood flow (lCBF) were carried out in 10 normal subjects (9 right-handed, 1 ambidextrous) at rest and during a unilateral discriminative somatosensory/motor task--palpation and sorting of mah-jongg tiles by engraved design. The extent of activation was assessed on the basis of percentage difference images following normalization to compensate for global shifts. The somatosensory stimulus elevated lCMRGlc by 16.9 +/- 3.5% (mean +/- standard deviation) and lCBF by 26.5 +/- 5.1% in the contralateral sensorimotor cortical focus; smaller increments were noted in the homologous ipsilateral site. The increments of lCMRGlc and lCBF correlated poorly with one another in individual subjects. Stimulation of the right hand resulted in significantly higher contralateral lCMRGlc activation (19.6%) than did stimulation of the left hand (14.1%) (p less than 0.005), whereas the lCBF response was independent of the hand stimulated. Our results indicate that both glycolytic metabolism and blood flow increase locally with the execution of an active sensorimotor task and suggest that both measures may serve as reliable markers of functional activation of the normal brain.     

Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: a glucose metabolic PET study

We employed cerebral (18)Fluoro-deoxyglucose positron emission tomography ([(18)F]FDG-PET) to visualize neuronal activation of the frontal motor and premotor cortex during suprathreshold repetitive transcranial magnetic stimulation (rTMS) applied to the left primary sensorimotor hand area (SM1(HAND)). Twelve right-handed normal subjects underwent two [(18)F]FDG-PET measurements at baseline without rTMS and during suprathreshold 2 Hz rTMS of the left SM1(HAND). In the rTMS condition, 1,800 magnetic stimuli at an intensity of 140% of motor-resting threshold were delivered immediately after intravenous injection of [(18)F]FDG. Relative differences in the normalized regional cerebral metabolic rate for glucose (rCMRglc) between the rTMS condition and baseline were determined using a voxel-by-voxel Student's t-test and a volume-of-interest analysis. Data analysis was a priori restricted to primary motor and premotor areas in the frontal cortex, namely the SM1, the supplementary motor area (SMA), the lateral premotor cortex (PMC), and the caudal anterior cingulate cortex (ACC) of either hemisphere. In addition to a relative increase in normalized rCMRglc in the stimulated SM1(HAND), suprathreshold rTMS was associated with well-localized increases in normalized rCMRglc in the caudal SMA and ACC on the medial wall of the frontal cortex and in the right precentral gyrus in the lateral PMC rostrally to the SM1. These data demonstrate that a selective activation of the SM1(HAND) is paralleled by an activation of a distinct set of remote premotor areas, suggesting a functional interaction between the primary motor and premotor cortex in humans.