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Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [11C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [11C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40–50 minutes) and intervention (60–85 minutes) revealed an average 12.6% decrease in [11C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST ( r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus ( r=−0.87, P=0.003) and putamen ( r=−0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.

Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP ND ) with μ-opioid receptor selective radiotracer [ 11 C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects. Later, we recruited these subjects to participate in a separate psychophysical testing session to measure cold pressor pain threshold, cold pressor pain tolerance and tactile sensitivity with von Frey monofilaments. We used both voxel-by-voxel and region-of-interest image analyses to examine the potential associations between μ-opioid receptor BP ND and psychophysical measures. The results show that striatal μ-opioid receptor BP ND predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density is involved in setting individual pain threshold.

Objective: The aim of this study was to investigate whether cognitively preserved monozygotic or dizygotic cotwins of persons with Alzheimer disease (AD) exhibit increased brain amyloid accumulation. Methods: We performed a cross-sectional carbon-11 labeled 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ( 11 C)–Pittsburgh compound B (PiB) PET study on 9 monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment as well as on 9 healthy elderly control subjects. 11 C-PiB uptake was analyzed with Statistical Parametric Mapping and with region of interest analysis with the region-to-cerebellum ratio as a measure of tracer uptake. Results: Cognitively preserved monozygotic cotwins of cognitively impaired probands had increased cortical 11 C-PiB uptake (117%–121% of control mean) in their temporal and parietal cortices and the posterior cingulate. Cognitively preserved dizygotic subjects did not differ from the controls. Further, the cognitively preserved monozygotic subjects showed similar 11 C-PiB uptake patterns as their cognitively impaired cotwins. The cognitively impaired subjects (monozygotic and dizygotic individuals combined) showed typical Alzheimer-like patterns of 11 C-PiB uptake. Conclusions: Genetic factors appear to influence the development of Alzheimer-like β-amyloid plaque pathology. The dissociation between cognitive impairment and brain β-amyloidosis in monozygotic twins implies that there may be important environmental/acquired factors that modulate the relationship between brain amyloidosis and neurodegeneration. AD may be detectable in high-risk individuals in its presymptomatic stage with 11 C-PiB PET, but clinical follow-up will be needed to confirm this.

Positron emission tomography (PET) imaging of small striatal brain structures such as the ventral striatum (VST) has been hampered by low spatial resolution causing partial-volume effects. The high-resolution research tomograph (HRRT) is a brain-dedicated PET scanner that has considerably better spatial resolution than its predecessors. However, its superior spatial resolution is associated with a lower signal-to-noise ratio. We evaluated the test–retest reliability of the striatal and thalamic dopamine D2 receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [11C]raclopride PET scans with a 2.5-hour interval. Dopamine D2 receptor availability was quantified as binding potential (BPND) using the simplified reference tissue model. To evaluate the reproducibility of repeated BPND estimations, absolute variability (VAR) and intraclass correlation coefficients (ICCs) were calculated. VAR values indicated fairly good reproducibility and were 3.6% to 4.5% for the caudate nucleus and putamen and 4.5% to 6.4% for the lateral and medial part of the thalamus. In the VST, the VAR value was 5.8% when the definition was made in the coronal plane. However, the ICC values were only moderate, in the range of 0.34 to 0.66, for all regions except the putamen (0.87). Experimental signal processing methods improved neither ICC nor VAR values significantly.

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic gamma-amino-butyric (GABA)-dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D(2/3) receptor binding using Positron-Emission Tomography (PET) and the high-affinity D(2/3)-receptor ligand [(11)C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D(2)/D(3) receptor binding potential was measured with the reference tissue method in several extrastriatal D(2)-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D(2)/D(3) receptor BP(ND) in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC. In conclusion, lorazepam decreased [(11)C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA-dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D(2)/D(3) receptor binding potential (BP) change further supports this hypothesis.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

Frontal lobe dysfunction and other cognitive deficits have been described in Parkinson's disease (PD), which may lead to dementia. Both striatal dopaminergic deficiency and regional or global brain volume loss have been suggested to contribute to cognitive decline in PD. We therefore performed a neuropsychological evaluation, structural brain MRI and Fdopa PET in patients with PD and healthy elderly volunteers. PD patients had impaired cognitive performance in many neuropsychological tests compared to controls, not limited just to frontal lobe function tests. Caudate Fdopa correlated positively with performance in verbal (immediate and delayed) and visual memory. Patients with PD showed atrophy in the hippocampus and the prefrontal cortex and hippocampal atrophy was related to impaired memory. Our findings suggest that striatal dopaminergic depletion and global brain volume loss contribute to cognitive impairment in non-demented PD patients, but dysfunction of extra-striatal dopaminergic or non-dopaminergic systems probably plays a role especially in more generalized cognitive impairment.

[(11)C]Carfentanil has been widely used in positron emission tomography (PET) studies for measuring micro-opioid receptor binding in humans, but the reproducibility of the binding parameter estimates is unknown.Eight healthy volunteers were scanned twice during the same day with [(11)C]carfentanil PET, and binding to receptors was assessed with both reference tissue and arterial plasma input-based models using region of interest (ROI) and voxel-based quantification.The two-tissue compartmental model distribution volume (V(T)) was highly reproducible as indicated by low variability (VAR6%) and high intraclass correlation coefficients (ICC0.93). BP(ND) (BP relative to the nondisplaceable tissue compartment) was also highly reproducible (VAR10%, ICC0.90) both at ROI- and voxel-level, and reference tissue-based models provided stable estimates after 40 min.The reproducibility of [(11)C]carfentanil binding parameter estimates is excellent with outcome measures based on both arterial plasma and reference tissue input, and a scanning time of 40 min appears sufficient.

[(11)C]Flumazenil is widely used in positron emission tomography (PET) studies to measure GABA(A) receptors in vivo in humans. Although several different methods have been applied for the quantification of [(11)C]flumazenil binding, the reproducibility of these methods has not been previously examined. The reproducibility of a single bolus [(11)C]flumazenil measurements was studied by scanning eight healthy volunteers twice during the same day. Grey matter regions were analyzed using both regions-of-interest (ROI) and voxel-based analysis methods. Compartmental kinetic modelling using both arterial and reference region input function were applied to derive the total tissue distribution volume (V(T)) and the binding potential (BP) (BP(P) and BP(ND)) of [(11)C]flumazenil. To measure the reproducibility and reliability of each [(11)C]flumazenil binding parameter, absolute variability values (VAR) and intraclass correlation coefficients (ICC) were calculated. Tissue radioactivity concentration over time was best modelled with a 2-tissue compartmental model. V(T) showed with all methods good to excellent reproducibility and reliability with low VARs (mean of all brain regions) (5.57%-6.26%) and high ICCs (mean of all brain regions) (0.83-0.88) when using conventional ROI analysis. Also voxel-based analysis methods yielded excellent reproducibility (VAR 5.75% and ICC 0.81). In contrast, the BP estimates using pons as the reference tissue yielded higher VARs (8.08%-9.08%) and lower ICCs (0.35-0.80). In conclusion, the reproducibility of [(11)C]flumazenil measurements is considerably better with outcome measures based on arterial input function than those using pons as the reference tissue. The voxel-based analysis methods are proper alternative as the reliability is preserved and analysis automated.

Background: There are few studies comparing the efficacy of short-term psychodynamic psychotherapy (STPP) and pharmacotherapy in major depressive disorder. We conducted a comparative study on the efficacy of STPP versus fluoxetine treatment in patients with major depressive disorder in a primary care setting. Methods: Fifty-one patients with major depressive disorder (DSM-IV) of mild or moderate severity were recruited through occupational health services providing primary health care. Patients were randomized to receive either STPP (1 session/week) or fluoxetine treatment (20–40 mg/day) for 16 weeks. The outcome measures included the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI), and the Social and Occupational Functioning Assessment Scale (SOFAS). Results: Intent-to-treat analyses indicated that both treatments were highly effective in reducing the HDRS (p < 0.0001) and BDI (p < 0.0001) scores, as well as in improving functional ability (SOFAS; p < 0.0001), with no statistically significant differences between the treatments. Of those 40 subjects who completed the follow-up, 57% in the psychotherapy group and 68% in the fluoxetine group showed full remission (HDRS ≤7) after 4 months. Conclusions: Both STPP and pharmacological treatment with fluoxetine are effective in reducing symptoms and in improving functional ability of primary care patients with mild or moderate depression. This study suggests no marked differences in the therapeutic effects of these two treatment forms in a primary care setting.

Background: In mild cognitive impairment (MCI), Alzheimer’s disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [11C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI. Methods: We studied 15 patients with amnestic MCI and 22 controls with PET using [11C]PIB. In MCI patients, CSF levels of Aβ42, pTAU, totalTAU and the Aβ42/pTAU ratio were measured. Results: In MCI patients, CSF Aβ42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Aβ42/pTAU ratio in 64%. A composite neocortical [11C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [11C]PIB-positive subjects showed AD-type Aβ42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Aβ42 was found in 3 patients, pTAU in 3 patients and Aβ42/pTAU ratio in 4 patients. Conclusion: Follow-up studies are needed to confirm whether [11C]PIB uptake might be more sensitive than CSF Aβ42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

The noble gas xenon acts as an anesthetic with favorable hemodynamic and neuroprotective properties. Based on animal and in vitro data, it is thought to exert its anesthetic effects by inhibiting glutamatergic signaling, but effects on gamma-aminobutyric acid type A (GABA(A)) receptors also have been reported. The mechanism of anesthetic action of xenon in the living human brain still remains to be determined.We used the specific GABA(A) receptor benzodiazepine-site ligand 11C-flumazenil and positron emission tomography to study the GABAergic effects of xenon in eight healthy male volunteers. Each subject underwent two dynamic 60-min positron emission tomography studies awake and during approximately one minimum alveolar concentration of xenon (65%). Bispectral index was recorded. Cortical and subcortical gray matter regions were analyzed using both automated regions-of-interest analysis and voxel-based analysis.During anesthesia, the mean +/- sd bispectral index was 23 +/- 7, and there were no significant changes in heart rate or mean arterial blood pressure. Xenon did not significantly affect 11C-flumazenil binding in any brain region.Xenon did not affect 11C-flumazenil binding in the living human brain, indicating that the anesthetic effect of xenon is not mediated via the GABA(A) receptor system.

The objective was to investigate the association between extrastriatal dopamine D 2 /D 3 receptor binding and performance on the Wisconsin Card Sorting Test (WCST), a measure of executive functioning. Thirty-two healthy volunteers performed the WCST and underwent positron emission tomography and a high-affinity D 2 /D 3 receptor tracer, [ 11 C]FLB 457. All WCST error parameters, in particular nonperseverative errors, correlated positively with [ 11 C]FLB 457 binding in the cognitive division of the right anterior cingulate cortex. An independent voxel-based receptor parametric mapping analysis confirmed these findings. The results indicate that executive functioning in healthy volunteers is modulated by D 2 /D 3 receptors in the anterior cingulate cortex.

Background Animal studies have demonstrated a strong neuroprotective property of xenon. Its usefulness in patients with cerebral pathology could be compromised by deleterious effects on regional cerebral blood flow (rCBF). Methods 15O-labeled water was used to determine rCBF in nine healthy male subjects at baseline and during 1 minimum alveolar concentration (MAC) of xenon (63%). Anesthesia was based solely on xenon. Absolute changes in rCBF were quantified using region-of-interest analysis and voxel-based analysis. Results Mean arterial blood pressure and arterial partial pressure for carbon dioxide remained unchanged. The mean (+/-SD) xenon concentration during anesthesia was 65.2+/-2.3%. Xenon anesthesia decreased absolute rCBF by 34.7+/-9.8% in the cerebellum (P Conclusions One MAC of xenon decreased rCBF in several areas studied. The greatest decreases were detected in the cerebellum, the thalamus and the cortical areas. Increases in rCBF were observed in the white matter and in the pre- and postcentral gyri. These results are in clear contradiction with ketamine, another N-methyl-D-aspartate antagonist and neuroprotectant, which induces a general increase in cerebral blood flow at anesthetic concentrations.

PET studies with N-methyl-[(11)C]2-(4':-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) have revealed an increased tracer uptake in several brain regions in Alzheimer disease (AD).To employ voxel-based analysis method to identify brain regions with significant increases in [(11)C]PIB uptake in AD vs healthy control subjects, indicative of increased amyloid accumulation in these regions.We studied 17 patients with AD and 11 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating a region-to-cerebellum ratio over 60 to 90 minutes in each voxel. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis.SPM showed increased uptake (p0.001) in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate and the striatum. No significant differences in uptake were found in the primary sensory and motor cortices, primary visual cortex, thalamus, and medial temporal lobe. These results were supported by automated ROI analysis, with most prominent increases in AD subjects in the frontal cortex ([(11)C]PIB uptake 163% of the control mean) and posterior cingulate (146%) followed by the parietal (146%) and temporal (145%) cortices and striatum (133%), as well as small increases in the occipital cortex (117%) and thalamus (115%).Voxel-based analysis revealed widespread distribution of increased [(11)C]PIB uptake in Alzheimer disease (AD). These findings are in accordance with the distribution and phases of amyloid pathology in AD, previously documented in postmortem studies.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD. © 2006 Movement Disorder Society

Mobile phones create a radio-frequency electromagnetic field (EMF) around them when in use, the effects of which on brain physiology in humans are not well known. We studied the effects of a commercial mobile phone on regional cerebral blood flow (rCBF) in healthy humans using positron emission tomography (PET) imaging. Positron emission tomography data was acquired using a double-blind, counterbalanced study design with 12 male subjects performing a computer-controlled verbal working memory task (letter 1-back). Explorative and objective voxel-based statistical analysis revealed that a mobile phone in operation induces a local decrease in rCBF beneath the antenna in the inferior temporal cortex and an increase more distantly in the prefrontal cortex. Our results provide the first evidence, suggesting that the EMF emitted by a commercial mobile phone affects rCBF in humans. These results are consistent with the postulation that EMF induces changes in neuronal activity.

��������� � �� ���������� VO2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

The noncompetitive glutamate N-methyl-d-aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested. The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex. The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis. Ketamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices. Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate–dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.

Experimental studies on animals have shown that dopamine is a key neurotransmitter in the regulation of working memory (WM) functions in the prefrontal cortex. In humans, blood flow studies show prefrontal involvement in WM functions, but direct evidence for the involvement of the dopaminergic system in WM is lacking. Using positron emission tomography with a recently developed high-affinity dopamine D2receptor tracer, [11C]FLB 457, we explored frontal, temporal, and parietal D2receptor availability in 12 healthy volunteers while they were performing verbal WM and sustained attention tasks. During the performance of both tasks, reduced D2receptor availability was observed in the left ventral anterior cingulate, suggesting an attention or arousal-related increase in dopamine release during these tasks. Compared with the sustained attention task, the verbal WM task reduced D2receptor availability in the ventrolateral frontal cortex bilaterally and in the left medial temporal structures (amygdala, hippocampus), suggesting that dopamine release in these regions might have a specific role in WM. In addition, correlation analyses indicated that increased dopamine release in the right ventrolateral frontal cortex and the left ventral anterior cingulate during the WM task was associated with faster and more stable WM performance, respectively. Our results indicate that regionally specific components of the frontotemporal dopaminergic network are functionally involved in WM performance in humans.

Novelty seeking is a temperament trait characterized by impulsiveness and exploratory behavior. Dopamine has been suggested to be the primary neurotransmitter modulator of novelty seeking, and in young healthy subjects, a correlation between increased novelty seeking and decreased insular cortical dopamine D2 receptor availability has been reported. The proposed link between dopamine deficiency and reduction in novelty seeking in Parkinson's disease is controversial. The present study examined whether a link between insular D2 receptor availability and novelty seeking can be replicated in Parkinson's disease patients. [11C]FLB 457 positron emission tomography imaging was carried out in 28 patients with Parkinson's disease, and the data were analyzed using voxel-based statistical analysis. The results demonstrated a negative correlation between the novelty seeking score and the dopamine D2 availability bilaterally in the insular cortex (corrected P = 0.001; r = −0.74 [right hemisphere]; r = −0.66 [left hemisphere]). The results provide further support for a relationship between novelty seeking and insular D2 receptors. They indicate that the association is cross-cultural, independent of age, and unaffected by dopaminergic degeneration. © 2004 Movement Disorder Society

The etiology of Asperger syndrome is essentially unknown, but abnormality of the dopamine system has been shown in clinically overlapping disorders. The present study was designed to investigate the presynaptic dopamine function in Asperger syndrome. Eight healthy, drug-free males with Asperger syndrome and five healthy male controls were examined with positron emission tomography using 6-[18F]fluoro-L-DOPA ([18F]FDOPA) as a tracer. In the Asperger syndrome group, the [18F]FDOPA influx (Ki) values were increased in the striatum, i.e. in the putamen and caudate nucleus and in the frontal cortex. The results indicate that the dopamine system is affected in subjects with Asperger syndrome. Partially similar results have also been obtained in schizophrenia, suggesting an overlap not only of the clinical features but also of pathogenesis.

Recent neuroimaging studies indicate that placebo treatments can induce clinically relevant neurobiological responses in patients with Parkinson's disease, depression and pain. The present study aimed to investigate neurotransmitter function in psychostimulant expectation, with the focus on dopaminergic effects of placebo caffeine in healthy human subjects. Eight habitual coffee drinkers were examined twice with [ 1 1 C]raclopride positron emission tomography after no treatment and after oral placebo tablets in a counterbalanced setting. During the placebo condition the subjects were instructed that they had a 50% chance of receiving caffeine, but all received placebo. As compared with no treatment, placebo induced a significant bilateral dopamine release in the thalamus, as reflected by a 15% reduction in thalamic [ 1 1 C]raclopride binding (P < 0.001). The level of arousal after placebo correlated positively with the tracer binding in the putamen (r= -0.91, P= 0.004). The results indicate that caffeine expectation induces dopaminergic placebo effects, and that these effects are similar to previous findings with oral caffeine. The results therefore suggest that caffeine and placebo caffeine may share some dopaminergic mechanisms of action.

Epidemiological studies have provided evidence that caffeine, an adenosine receptor antagonist, reduces the risk for Parkinson's disease. There are indications of specific interactions between striatal adenosine A(2A) and dopamine D(2) receptors, but the in vivo effects of caffeine on human dopamine system have not been investigated. In the present study, the dopaminergic effects of caffeine were examined with [(11)C]raclopride positron emission tomography (PET) in eight healthy habitual coffee drinkers after 24 h caffeine abstinence. Compared to oral placebo, 200 mg oral caffeine induced a 12% decrease in midline thalamic binding potential (p < 0.001). A trend-level increase in ventral striatal [(11)C]raclopride binding potential was seen with a correlation between caffeine-related arousal and putaminal dopamine D(2) receptor binding (r = -0.81, p = 0.03). The findings indicate that caffeine has effects on dopaminergic neurotransmission in the human brain, which may be differential in the striatum and the thalamus.

Lack of theory of mind (ToM) has been considered to be a key feature in Asperger syndrome (AS). The main aim of the present study was to determine whether an exclusively auditory input of ToM stories activated the same brain areas as demonstrated previously using visual stimuli. Eight right-handed otherwise healthy men with AS and eight healthy right-handed male controls participated in a PET activation study using auditory given ToM stories and stories about physical events for induction. Both subjects with AS and controls showed increased activation in the occipitotemporal area bilaterally and in thalamus during ToM tasks. Both groups also showed activation in the medial frontal area during ToM tests.However, this activation was more intensive and extensive in the control group, especially when a more sensitive analysis method was used. As a group, unrelated to the tasks, the AS subjects showed increased activation of the cerebellum. It was concluded that the activation pattern was mainly in agreement with earlier studies using comparable stimuli administered differently. There was no support for a right hemisphere specific dysfunction.

Most antiparkinsonian drugs are known to act through central dopamine D(2) receptor agonism. A previous longitudinal positron emission tomography (PET) study has indicated that, in the striatum of Parkinson's disease (PD) patients, dopamine D(2) receptor binding declines at a relatively fast annual rate of 2-4% (compared to the rate of1%/year in healthy individuals). In the present study, the examination of longitudinal changes in D(2) receptors was extended to extrastriatal brain regions in PD. Eight early PD patients were examined twice with PET, approximately 3 years apart, using a high-affinity extrastriatal D(2)/D(3) receptor tracer, [(11)C]FLB 457. Both the MRI-referenced region-of-interest method and the voxel-based statistical analysis method were used independently in the analysis. Regional D(2)-like availabilities (binding potentials) in the left dorsolateral prefrontal cortex, the left temporal cortex and the left and right medial thalami were significantly decreased at the second examination by 20-37% (corresponding to an annual decline of 6-11%). Thus, the annual loss of extrastriatal D(2) availability in PD is up to three times faster than the rate previously reported in the putamen. Our longitudinal study shows first evidence concerning cortical D(2) receptor loss in the progression of PD, although it is not possible to distinguish between the effects of the therapy and the disease.

Rationale. A glutamate–dopamine interaction has been implicated in the psychosis-like effects of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine. However, recent imaging studies addressing striatal glutamate–dopamine interaction directly in vivo in man have been controversial. Objectives. To examine whether the NMDA receptor antagonist ketamine in high subanesthetic concentrations decreases striatal [11C]raclopride binding potential in man. To further evaluate whether changes in striatal [11C]raclopride binding are associated with ketamine-induced behavioral effects. Methods. The effect of computer-driven subanesthetic ketamine infusion on striatal dopamine release was studied in healthy male subjects using a controlled study design. Dopamine release was studied using positron emission tomography and the [11C]raclopride displacement paradigm. A conventional region of interest-based analysis and voxel-based analysis were applied to the positron emission tomography data. Results. The average plasma ketamine concentration was 293±29 ng/ml. Ketamine did not alter striatal [11C]raclopride binding. Ketamine induced typical behavioral effects, such as hallucinations but there was no correlation between these effects and displacement of [11C]raclopride binding. Conclusions. This controlled study indicates that ketamine does not decrease striatal [11C]raclopride binding. Striatal dopamine release is of minor importance in the psychosis-like effects of ketamine.

Background. Somatization is a clinical phenomenon characterized by multiple, medically unexplained somatic symptoms. The pathophysiology remains unknown. We aimed to test the hypothesis of a central nervous system dysfunction in the pathophysiology of this disorder.Methods. We studied 10 female patients diagnosed as having somatization disorder or undifferentiated somatoform disorder with no current Axis I disorders according to DSM-IV. They were compared with 17 healthy female volunteers using brain [18F]-fluorodeoxyglucose-PET with MRI reference.Results. The patients had lower cerebral metabolism rates of glucose (PConclusions. This is the first study to demonstrate changes in brain metabolism in somatizing women. The regional cerebral hypometabolism is probably associated with the pathophysiology of somatization.

One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge.

Background/Aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.

Objective: Somatizing patients often report cognitive complaints but neuropsychological research on somatization is scarce. We investigated somatizing patients for functioning in different cognitive domains. Method: Ten female patients with somatization disorder or undifferentiated somatoform disorder and 10 non-somatizing controls participated in neuropsychological examinations. Results: The patients performed at a lower level than the controls in tests involving semantic memory, verbal episodic memory and visuo-spatial tasks, and were slower in attentional tasks. Conclusion: Somatization patients may suffer from substantial problems in cognitive performance.

Background: Patients with amnestic mild cognitive impairment (MCI) have greater risk of conversion to Alzheimer disease (AD). Increased brain amyloid burden in AD and MCI has been demonstrated with PET using [ 11 C] Pittsburgh compound B (PiB) as a tracer. Objective: To evaluate change in β-amyloid deposition in with MCI during 2-year follow-up. Methods: Patients with MCI and controls were studied with [ 11 C] PiB PET, MRI, and neuropsychometry at baseline and these investigations were repeated in patients with MCI after follow-up. Results: Those patients with MCI converting to AD during follow-up had greater [ 11 C] PiB retention in the posterior cingulate ( p = 0.020), in the lateral frontal cortex ( p = 0.006), in the temporal cortex ( p = 0.022), in the putamen ( p = 0.041), and in the caudate nucleus ( p = 0.025) as compared to nonconverters. In converters, there was no significant change in [ 11 C] PiB uptake, whereas an increase was seen as compared to baseline in nonconverters in the anterior and posterior cingulate, temporal and parietal cortices, and putamen. Hippocampal atrophy was greater in converters at baseline than in nonconverters, but increased significantly in both groups during follow-up. Conclusions: Hippocampal atrophy and amyloid deposition seem to dissociate during the evolution of MCI, the atrophy increasing clearly and [ 11 C] PiB retention changing modestly when conversion to AD occurs. Longer follow-up is needed to determine whether nonconverters would convert to AD later, which would suggest accelerated [ 11 C] PiB retention preceding clinical conversion.

Conventional time and frequency domain measures of heart rate variability (HRV) are strongly influenced by anesthetic drugs, and are therefore not able to detect subtle changes in HRV, even during light anesthesia. Approximate entropy of R-R intervals is an HRV measure that has a tendency to decrease during anesthesia, but it is severely compromised by low-frequency variations of the signal. However, the negative effect of the low-frequency variations can be eliminated by differentiating the R-R interval tachogram before analysis. We designed this study to investigate characteristics of a novel HRV measure, named δ entropy (dEn), during deepening anesthesia.Eight healthy subjects were anesthetized with sevoflurane and 8 with propofol in a stepwise manner using 3 escalating concentrations (2%, 3%, and 4% end-tidal concentration and 7.4 ± 1.7, 12.3 ± 2.6, and 18.3 ± 5.0 μg/mL plasma concentration, respectively) at 30-minute intervals. A third group of 8 subjects received a supramaximal IV dose of glycopyrrolate without anesthesia to examine the effect of cardiac vagal activity on dEn. We computed dEn at baseline, during each step of anesthesia and during the anticholinergic blockade.The dEn decreased along with deepening levels of sevoflurane and propofol anesthesia up to 33% (95% confidence interval [CI] 21%-44%) and 38% (95% CI 28%-48%), respectively. At each anesthesia level, dEn differed significantly (P0.05) from that measured at the preceding level, similarly in both the sevoflurane and propofol groups. Parasympathetic blockade by glycopyrrolate was found to decrease dEn by 17% (95% CI 6%-28%).The dEn is a novel HRV measure able to detect subtle sympathetic- and parasympathetic-mediated alterations in HRV both during deepening levels of sevoflurane and propofol anesthesia and during exceedingly deep anesthesia.

Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D2/3 receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D2/3 receptor binding was quantified before and after treatment as the binding potential ( BPND) using [11C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D2/3 receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [11C]raclopride BPND in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored.

The objective of this study was to identify possible group differences between PD patients with dementia and without dementia by combining different functional and structural imaging methods in vivo, which might provide an opportunity to disentangle the pathophysiological correlates of cognitive impairment and dementia in PD. We performed a neuropsychological evaluation, structural brain MRI, [(18)F]FDG PET and [(11)C]PIB PET in 19 PD patients [eight non-demented (PD), eleven demented (PDD)] and 24 healthy elderly volunteers. [(11)C]PIB region-to-cerebellum ratios did not differ significantly between the groups in any brain region (p > 0.05). PDD patients showed impaired glucose metabolism in cortical brain regions and this reduction was associated with the degree of cognitive impairment. PDD patients had more atrophy both in the hippocampus and the frontal cortex compared with PD patients and controls, and hippocampal atrophy was associated with impaired memory. This cross-sectional data suggests that development of dementia in PD is associated with extensive spread of hypometabolism beyond the occipital cortex, and with hippocampal and frontal atrophy but not beta-amyloid deposition consistent with a unique biological process related to PD rather than co-incidental development of AD in persons with PD.

The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.The evaluation of visual classification as "normal" or "abnormal" showed good interobserver agreement (kappa = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p0.001). The most difficult visually assessed brain area was the putamen (kappa = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60).Our study shows that visual evaluation of [(11)C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.

Objective: In Alzheimer disease (AD), the accumulation pattern of β-amyloid over time and its relationship with dementia severity are unclear. We investigated the brain uptake of the amyloid ligand 11C-labeled Pittsburgh compound B ([11C]PIB) and volumetric brain changes over a 2-year follow-up in patients with AD and in aged healthy controls.Methods: Fourteen patients with AD (mean age 72 years, SD 6.6) and 13 healthy controls (mean age 68 years, SD 5.4) were examined at baseline and after 2 years (patients with AD: mean 2.0 years, SD 0.2; controls: mean 2.1 years, SD 0.6) with [11C]PIB PET, MRI, and neuropsychological assessments. [11C]PIB uptake was analyzed with a voxel-based statistical method (SPM), and quantitative data were obtained with automated region-of-interest analysis. MRI data were analyzed with voxel-wise tensor-based morphometry.Results: The [11C]PIB uptake of the patients with AD did not increase significantly during follow-up when compared with that of the controls. MRI showed progressive brain volume change in the patients with AD, e.g., in the hippocampal region, temporal cortex, and precuneus (p < 0.05). The mean Mini-Mental State Examination score of the patients with AD declined from 24.3 (SD 3.1) at baseline to 21.6 (SD 3.9) at follow-up (p = 0.009). Cognitive decline was also evident in other neuropsychological test results. Baseline neocortical [11C]PIB uptake ratios predicted subsequent volumetric brain changes in the controls (r = 0.725, p = 0.005).Conclusions: The results suggest no (or only little) increase in 11C-labeled Pittsburgh compound B ([11C]PIB) uptake during 2 years of Alzheimer disease progression, despite advancing brain atrophy and declining cognitive performance. Nevertheless, changes in [11C]PIB uptake during a longer follow-up cannot be excluded. High cortical [11C]PIB uptake may predict ongoing brain atrophy in cognitively normal individuals.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

BACKGROUND General anesthetics can alter the relationship between regional cerebral glucose metabolism (rCMR(glc)) and blood flow (rCBF). In this positron emission tomography study, our aim was to assess both rCMR(glc) and rCBF in the same individuals during xenon anesthesia. METHODS (18)F-labeled fluorodeoxyglucose and (15)O-labeled water were used to determine rCMR(glc) and rCBF, respectively, in five healthy male subjects at baseline (awake) and during 1 minimum alveolar anesthetic concentration of xenon. Anesthesia was based solely on xenon. Changes in rCMR(glc) and rCBF were quantified using region-of-interest and voxel-based analyses. RESULTS The mean (sd) xenon concentration during anesthesia was 67.2 (0.8)%. Xenon anesthesia induced a uniform reduction in rCMR(glc), whereas rCBF decreased in 7 of 13 brain regions. The mean decreases in the gray matter were 32.4 (4.0)% (P < 0.001) and 14.8 (5.9)% (P = 0.007) for rCMR(glc) and rCBF, respectively. rCMR(glc) decreased by 10.9 (6.4)% in the white matter (P = 0.030), whereas rCBF increased by 9.2 (7.3)% (P = 0.049). The rCBF/rCMR(glc) ratio was especially increased in the insula, anterior and posterior cingulate, and in the somatosensory cortex. CONCLUSIONS In general, the magnitude of the decreases in rCMR(glc) during 1 minimum alveolar anesthetic concentration xenon anesthesia exceeded the reductions in rCBF. As a result, the ratio between rCMR(glc) and rCBF was shifted to a higher level. Interestingly, xenon-induced changes in cerebral metabolism and blood flow resemble those induced by volatile anesthetics.

Posterior cortical atrophy (PCA) is a rare form of degenerative dementia, which is characterized by progressive atrophy of occipital and parietal cortical areas. It usually manifests as increasing difficulties of visuoperceptive abilities. Later on, memory and other cognitive functions are involved. Various pathologies have been associated with clinical PCA presentation, but most of the patients with autopsy have had Alzheimer-type pathology. Thus, PCA has been considered to be a rare form of Alzheimer-type dementia with unusual pathological distribution. Here we describe a patient who had a typical clinical course for this syndrome and who showed a positive accumulation of amyloid-beta in posterior areas studied with positron emission tomography.

Background: Sporadic Alzheimer disease (AD) is a multifactorial disease to which both genetic and environmental factors contribute. Therefore, twin pairs are useful in studying its pathogenesis and aetiology. Cerebral glucose metabolism has been found to be reduced in AD patients. Methods: Cerebral glucose metabolism was studied in seven monozygotic (MZ) and nine same-sexed dizygotic (DZ) twin pairs discordant for AD using positron emission tomography. To obtain objective and explorative results concerning differences in glucose metabolism, the analysis was performed utilising modern voxel-based analysis methodology statistical parametric mapping and automated region-of-interest analysis. Results: In the demented MZ and DZ co-twins, cerebral glucose metabolism was extensively reduced compared with controls. The non-demented MZ co-twins showed reduced metabolism in inferior frontal, lateral temporal, parietal and medial temporal cortices as well as in the thalamus, putamen and right amygdala. In contrast, no reductions were found in the non-demented DZ co-twins. The reduction found in the non-demented MZ co-twins may be an indicator of genetic susceptibility to AD.

The dopamine D(2)/D(3) receptor ligand [(11)C]FLB 457 and PET enable quantification of low-density extrastriatal D(2)/D(3) receptors, but it is uncertain whether [(11)C]FLB 457 can be used for measuring extrastriatal dopamine release.We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [(11)C]FLB 457 binding potential (BP(ND)) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers.The effects of d-amphetamine on [(11)C]FLB 457 BP(ND) and distribution volume (V(T)) in the frontal cortex were not different from those of placebo. Small decreases in [(11)C]FLB 457 BP(ND) were observed only in the posterior cingulate and hippocampus. The regional changes in [(11)C]FLB 457 BP(ND) did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria.This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D(2)/D(3) receptor binding. Our results indicate that [(11)C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans.

Noora M. Scheinin, Sargo Aalto, Ian Wilson, Nina Kemppainen, Kjell Nagren, Marita Kailajarvi, Mika Scheinin, Juha O. Rinne, Turku PET Centre, Turku, Finland; Turku PET Centre; Department of Psychology, Abo Akademi University, Turku, Finland; Turku Imanet Oy, GE Healthcare, Turku, Finland; Department of Pharmacology and Clinical Research Services Turku (CRST), University of Turku, Turku, Finland. Contact e-mail: nmsche@utu.fi

Objective The reduced risk for Alzheimer's disease (AD) in high-educated individuals has been proposed to reflect brain cognitive reserve, which would provide more efficient compensatory mechanisms against the underlying pathology, and thus delayed clinical expression. Our aim was to find possible differences in brain amyloid ligand 11C-labeled Pittsburgh Compound B ([11C]PIB) uptake and glucose metabolism in high- and low-educated patients with mild AD. Methods Twelve high-educated and 13 low-educated patients with the same degree of cognitive deterioration were studied with PET using [11C]PIB and 18F-fluorodeoxyglucose as ligands. The between-group differences were analyzed with voxel-based statistical method, and quantitative data were obtained with automated region-of-interest analysis. Results High-educated patients showed increased [11C]PIB uptake in the lateral frontal cortex compared with low-educated patients. Moreover, high-educated patients had significantly lower glucose metabolic rate in the temporoparietal cortical regions compared with low-educated patients. Interpretation Our results suggesting more advanced pathological and functional brain changes in high-educated patients with mild AD are in accordance with the brain cognitive reserve hypothesis and point out the importance of development of reliable markers of underlying AD pathology for early AD diagnostics. Ann Neurol 2007

Inconsistent response in freezing of gait (FOG) with levodopa treatment or STN DBS makes the pathogenesis difficult to understand. We studied brain areas associated with the expression of STN DBS effect on parkinsonian motor deficits and FOG. Ten Parkinson's disease patients with typical FOG were included. One month before STN DBS, we performed [(18)F]-deoxyglucose PET scans and measured the UPDRS motor and modified FOG (mFOG) scores during levodopa off and on periods. At two months after STN DBS, same rating scores were measured. The percentage improvement of mFOG and UPDRS motor scores by STN DBS during levodopa off period was calculated. We searched for brain areas in which glucose metabolism correlated with the improvement of mFOG and UPDRS motor scores by DBS. During levodopa off period, STN DBS improved the UPDRS motor scores by 32.3% and the mFOG scores by 56.6%. There was no correlation between the improvements of both scores. The improvement of UPDRS motor score by DBS correlated with the metabolic activities of rostral supplementary motor area (Brodmann's area 8; BA8), anterior cingulate cortex (BA32), and prefrontal cortex (BA9). On the other hand, there was a positive correlation between the improvement of mFOG score by DBS and the metabolic activity of the parietal, occipital, and temporal sensory association cortices. In conclusion, dysfunction of different cerebral cortical areas limits the beneficial effects of DBS on parkinsonian motor deficits and FOG.