Sargo Aalto

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.

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.

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. (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. 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. 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: 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 (¹¹C)–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. ¹¹C-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 ¹¹C-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 ¹¹C-PiB uptake patterns as their cognitively impaired cotwins. The cognitively impaired subjects (monozygotic and dizygotic individuals combined) showed typical Alzheimer-like patterns of ¹¹C-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 ¹¹C-PiB PET, but clinical follow-up will be needed to confirm this.

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 [¹¹C] 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 [¹¹C] 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 [¹¹C] 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 [¹¹C] 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 [¹¹C] 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 [¹¹C] 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 (P < 0.05) 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 D_2/3 receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D_2/3 receptor binding was quantified before and after treatment as the binding potential ( BP_ND) 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 D_2/3 receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [¹¹C]raclopride BP_ND 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.

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 (BP_ND) using the simplified reference tissue model. To evaluate the reproducibility of repeated BP_ND 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.