Vicente Ibáñez

Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease

Objective To determine whether the hypometabolism observed in PET images of patients with Alzheimers disease (AD) is due entirely to brain atrophy. Background Reduced brain glucose metabolism in AD patients measured using PET has been reported by numerous authors. Actual glucose metabolic values in AD may be reduced artificially because of brain atrophy, which accentuates the partial volume effect (PVE) on data collected by PET. Methods Using segmented MR images, we corrected regional cerebral metabolic rates for glucose for PVEs to evaluate the effect of atrophy on uncorrected values for brain metabolism in AD patients and healthy control subjects. Results Global glucose metabolism was reduced significantly before and after correction in AD patients compared with controls. Before PVE correction, glucose metabolic values in patients were lower than in control subjects in the inferior parietal, frontal, and lateral temporal cortex; in the posterior cingulate; and in the precuneus. These reductions remained significantly lower after PVE correction, although in the posterior cingulate the difference in metabolism between AD patients and control subjects lessened. Regional glucose metabolism of these areas with PVE correction was lower in moderately-severely demented patients than in mildly demented patients. Conclusion Reduced glucose metabolism measured by PET in AD is not simply an artifact due to an increase in CSF space induced by atrophy, but reflects a true metabolic reduction per gram of tissue.

Cerebral processes related to visuomotor imagery and generation of simple finger movements studied with positron emission tomography.

Positron emission tomography was used to compare the functional anatomy of visual imagination and generation of movement. Subjects were asked to generate visual images of their finger movement in response to a preparatory signal. Four conditions were tested: in two, no actual movement was required; in the other two, a second signal prompted the subjects to execute the imagined movement. Which movement to imagine was either specified by the preparatory stimulus or freely selected by the subjects. Compared with a rest condition, tasks involving only imagination activated several cortical regions (inferoparietal cortex, presupplementary motor area, anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex) contralateral to the imagined movement. Tasks involving both imagination and movement additionally increased activity in the ipsilateral cerebellum, thalamus, contralateral anteroparietal, and motor cortex and decreased activity in the inferior frontal cortex. These results support the hypothesis that distinct functional systems are involved in visuomotor imagination and generation of simple finger movements: associative parietofrontal areas are primarily related to visuomotor imagination, with inferior frontal cortex likely engaged in active motor suppression, and primary motor structures contribute mainly to movement execution.

Deficient activation of the motor cortical network in patients with writer's cramp

Objective: To study regional cerebral blood flow (rCBF) in patients with simple writer’s cramp using PET to identify regions that malfunction. Background: Several lines of evidence indicate impaired cortical function in patients with focal dystonia, but the precise pathophysiology is still unknown. Methods: Seven patients with writer’s cramp were compared with seven age- and sex-matched control subjects. Control subjects and patients were scanned during sustained contraction, tapping, and writing with the right hand. After realignment and stereotactic normalization of the scans, all tasks were compared with a rest condition. For each task, an intra- and intergroup comparison was performed using statistical parametric mapping. For each condition and within groups, rCBF correlation analysis was performed between some selected regions that were activated during movement. Results: In control subjects and patients, significant increases of rCBF were observed for each task in areas already known to be activated in motor paradigms. The intergroup comparison disclosed less activation in writer’s cramp patients for several areas for all three tasks. This decrease reached significance for the sensorimotor cortex during the sustained contraction task and for the premotor cortex during writing. rCBF correlation analysis showed different patterns between control subjects and patients. At rest and during writing, the correlations between the putamen and premotor cortical regions and between the premotor cortical regions themselves were stronger in control subjects. Conclusions: Deficient activation of premotor cortex and decreased correlation between premotor cortical regions and putamen suggest a dysfunction of the premotor cortical network in patients with writer’s cramp possibly arising in the basal ganglia. The dysfunction is compatible with a loss of inhibition during the generation of motor commands, which in turn could be responsible for the dystonic movements.

Frequency-Dependent Changes of Regional Cerebral Blood Flow during Finger Movements: Functional MRI Compared to PET

To evaluate the effect of the repetition rate of a simple movement on the magnitude of neuronal recruitment in the primary sensorimotor cortex, we used a blood flow-sensitive, echo planar functional magnetic resonance imaging (fMRI) sequence in six normal volunteers. Three of the volunteers also had [15O]water positron emission tomography (PET) studies using the same paradigm. Previous PET studies had shown an increase in regional CBF (rCBF) with movement frequencies up to 2 Hz and then a plateau of regional cerebral blood flow (rCBF) at faster frequencies. To evaluate the extent of the activation, the correlation coefficient (cc) of the Fourier-transformed time-signal intensity change with the Fourier-transformed reference function was calculated pixel by pixel. The degree of activation was measured as the signal percent change of each region of interest with a cc > 0.5. The left primary sensorimotor cortex was constantly activated at 1, 1.5, 2, and 4 Hz, while there was only inconsistent activation at 0.25 and 0.5 Hz. Percent change in signal intensity linearly increased from 1 to 4 Hz. Area of activation increased up to 2 Hz and showed a tendency to decrease at higher frequencies. Individual analysis of PET data showed activation in the same location as that revealed by fMRI. The combination of progressively increasing signal intensity with an area that increases to 2 Hz and declines at faster frequencies explains the PET finding of plateau of rCBF at the faster frequencies. Functional magnetic resonance imaging shows similar results to PET, but is better able to dissociate area and magnitude of change.

Frequency-Dependent Changes of Regional Cerebral Blood Flow during Finger Movements

To study the effect of the repetition rate of a simple movement on the distribution and magnitude of neuronal recruitment, we measured regional CBF (rCBF) in eight normal volunteers, using positron emission tomography and 15O-labeled water. An auditory-cued, repetitive flexion movement of the right index finger against the thumb was performed at very slow (0.25 and 0.5 Hz), slow (0.75 and 1 Hz), fast (2 and 2.5 Hz), and very fast (3 and 4 Hz) rates. The increase of rCBF during movement relative to the resting condition was calculated for each pair of movement conditions. Left primary sensorimotor cortex showed no significant activation at the very slow rates. There was a rapid rise of rCBF between the slow and the fast rates, but no further increase at the very fast rates. The right cerebellum showed similar changes. Changes in the left primary sensorimotor cortex and the cerebellum likely reflect the effect of the movement rate. The posterior supplementary motor area (SMA) showed its highest activation at the very slow rates but no significant activation at the very fast rates. Changes correlating with those in the SMA were found in the anterior cingulate gyrus, right prefrontal area, and right thalamus. The decreases in CBF may reflect a progressive change in performance from reactive to predictive.

Working memory load-related electroencephalographic parameters can differentiate progressive from stable mild cognitive impairment

Recent studies described several changes of endogenous event-related potentials (ERP) and brain rhythm synchronization during memory activation in patients with Alzheimers disease (AD). To examine whether memory-related EEG parameters may predict cognitive decline in mild cognitive impairment (MCI), we assessed P200 and N200 latencies as well as beta event-related synchronization (ERS) in 16 elderly controls (EC), 29 MCI cases and 10 patients with AD during the successful performance of a pure attentional detection task as compared with a highly working memory demanding two-back task. At 1 year follow-up, 16 MCI patients showed progressive cognitive decline (PMCI) and 13 remained stable (SMCI). Both P200 and N200 latencies in the two-back task were longer in PMCI and AD cases compared with EC and SMCI cases. During the interval 1000 ms to 1700 ms after stimulus, beta ERS at parietal electrodes was of lower amplitude in PMCI and AD compared with EC and SMCI cases. Univariate models showed that P200, N200 and log% beta values were significantly related to the SMCI/PMCI distinction with areas under the receiver operating characteristic curve of 0.93, 0.78 and 0.72, respectively. The combination of all three EEG hallmarks was the stronger predictor of MCI deterioration with 90% of correctly classified MCI cases. Our data reveal that PMCI and clinically overt AD share the same pattern of working memory-related EEG activation characterized by increased P200-N200 latencies and decreased beta ERS. They also show that P200 latency during the two-back task may be a simple and promising EEG marker of rapid cognitive decline in MCI.

Abnormal-induced theta activity supports early directed-attention network deficits in progressive MCI

The electroencephalography (EEG) theta frequency band reacts to memory and selective attention paradigms. Global theta oscillatory activity includes a posterior phase-locked component related to stimulus processing and a frontal-induced component modulated by directed attention. To investigate the presence of early deficits in the directed attention-related network in elderly individuals with mild cognitive impairment (MCI), time-frequency analysis at baseline was used to assess global and induced theta oscillatory activity (4-6Hz) during n-back working memory tasks in 29 individuals with MCI and 24 elderly controls (EC). At 1-year follow-up, 13 MCI patients were still stable and 16 had progressed. Baseline task performance was similar in stable and progressive MCI cases. Induced theta activity at baseline was significantly reduced in progressive MCI as compared to EC and stable MCI in all n-back tasks, which were similar in terms of directed attention requirements. While performance is maintained, the decrease of induced theta activity suggests early deficits in the directed-attention network in progressive MCI, whereas this network is functionally preserved in stable MCI.

Changes of middle latency auditory evoked potentials during natural sleep in humans

During natural nocturnal sleep, Na and Pa middle latency auditory evoked potentials (MLAEPs) underwent significant variations which were related to sleep stages. The deepening of sleep from stage II to stage IV was paralleled by a latency shift and an amplitude decrease of Na and Pa, while MLAEPs were similar in wakefulness and REM sleep. Moreover, Na and Pa components tended to shift over the hemisphere contralateral to the stimulated ear during sleep. These findings demonstrate that the responsiveness of the auditory cortex to acoustic stimuli is modulated during sleep. Vigilance should be monitored during MLAEP recordings in patients.

Innately low D2 receptor availability is associated with high novelty-seeking and enhanced behavioural sensitization to amphetamine.

High novelty-seeking has been related to an increased risk for developing addiction, but the neurobiological mechanism underlying this relationship is unclear. We investigated whether differences in dopamine (DA) D2/3-receptor (D2/3R) function underlie phenotypic divergence in novelty-seeking and vulnerability to addiction. Measures of D2/3R availability using the D2R-preferring antagonist [18F]Fallypride, and the D3R-preferring agonist [3H]-(+)-PHNO and of DA-related gene expression and behaviours were used to characterize DA signalling in Roman high- (RHA) and low-avoidance (RLA) rats, which respectively display high and low behavioural responsiveness both to novelty and psychostimulant exposure. When compared to RLA rats, high novelty-responding RHAs had lower levels of D2R, but not D3R, binding and mRNA in substantia nigra/ventral tegmental area (SN/VTA) and showed behavioural evidence of D2-autoreceptor subsensitivity. RHA rats also showed a higher expression of the tyrosine hydroxylase gene in SN/VTA, higher levels of extracellular DA in striatum and augmentation of the DA-releasing effects of amphetamine (Amph), suggesting hyperfunctioning of midbrain DA neurons. RHA rats also exhibited lower availabilities and functional sensitivity of D2R, but not D3R, in striatum, which were inversely correlated with individual scores of novelty-seeking, which, in turn, predicted the magnitude of Amph-induced behavioural sensitization. These results indicate that innately low levels of D2R in SN/VTA and striatum, whether they are a cause or consequence of the concomitantly observed elevated DA tone, result in a specific pattern of DA signalling that may subserve novelty-seeking and vulnerability to drug use. This suggests that D2R deficits in SN/VTA and striatum could both constitute neurochemical markers of an addiction-prone phenotype.

Aging and working memory: early deficits in EEG activation of posterior cortical areas

Summary.Using the n-back task, we recently identified, in young subjects, a positive-negative event related potential component (PNwm) in a time-range window between 140 and 280 ms after stimulus onset representing an electrophysiological correlate of working memory load. To evaluate age-related electrophysiological changes in working memory processing, we applied the same neuropsychological paradigm and compared densities of the PNwm component in 17 young (mean age: 26) and 17 healthy elderly individuals (mean age: 75). Both age groups displayed a PNwm component during the two working memory tasks. For the 1-back task, densities were similar in both young and elderly individuals. In contrast, PNwm densities increased with higher memory load (2-back>1-back) in the younger but not in the older group. This difference was mainly observed over parietal electrodes suggesting an impaired activation of neural generators within this brain region. The present results are consistent with the hypothesis of decreased brain reserve in the elderly and provide evidence for age-related deficits in the recruitment of posterior cortical neurons with increasing working memory load.