Jani Penttilä

Diffusion Tensor Tractography in Mesencephalic Bundles: Relation to Mental Flexibility in Detoxified Alcohol-Dependent Subjects

Components of the corticocerebellar circuit and the midbrain individually play a central role in addictive processes and have been associated with altered volumes and impairment of cognitive flexibility in alcohol-dependent subjects. The microstructure of white matter bundles composing the corticocerebellar network and passing through the midbrain was studied using diffusion tensor imaging in a group of detoxified alcohol-dependent men (n=20) and a group of healthy men (n=24). The relationship between properties of these white matter bundles and cognitive flexibility performance was investigated in alcohol-dependent subjects. Bundles connecting two regions of interest were analyzed using a fiber-tracking quantitative approach, which provided estimates of the fractional anisotropy and the apparent diffusion coefficient, as well as the number of tracked fibers normalized by the volume of regions of interest. Within the bundles running between the midbrain and pons, a mean of 18% fewer fibers per unit volume were tracked in alcohol-dependent men than in healthy controls. In addition, the normalized number of these fibers correlated with the performance in the Trail-Making Test part-B. Even though the alcohol-dependent subjects were detoxified and apparently neurologically intact, their earlier excessive use of alcohol seems to be associated with altered neural microstructure of mesencephalic white matter bundles, which may contribute to their cognitive flexibility impairment.

The Brain's Response to Reward Anticipation and Depression in Adolescence: Dimensionality, Specificity, and Longitudinal Predictions in a Community-Based Sample.

OBJECTIVE The authors examined whether alterations in the brains reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes. METHOD Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally. RESULTS Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses. CONCLUSIONS The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.

Cerebral monoamine oxidase A inhibition in tobacco smokers confirmed with PET and [11C]befloxatone.

The inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand [11C]befloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of [11C]befloxatone binding potential (BP) in cortical areas (average reduction, −60%) and a similar trend in caudate and thalamus (−40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco.

Cortical folding difference between patients with early-onset and patients with intermediate-onset bipolar disorder

OBJECTIVES Cerebral abnormalities have been detected in patients with bipolar disorder (BD). In comparison to BD with a later onset, early-onset BD has been found to have a poorer outcome. However, it is yet unknown whether neuroanatomical abnormalities differ between age-at-onset subgroups of the illness. We searched for cortical folding differences between early-onset (before 25 years) and intermediate-onset (between 25 and 45 years) BD patients. METHODS Magnetic resonance images of 22 early-onset BD patients, 14 intermediate-onset BD patients, and 50 healthy participants were analyzed using a fully automated method to extract, label, and measure the sulcal area in the whole cortex. Cortical folding was assessed by computing global sulcal indices (the ratio between total sulcal area and total outer cortex area) for each hemisphere, and local sulcal indices for 12 predefined regions in both hemispheres. RESULTS Intermediate-onset BD patients had a significantly reduced local sulcal index in the right dorsolateral prefrontal cortex in comparison to both early-onset BD patients and healthy subjects, and lower global sulcal indices in both hemispheres in comparison to healthy subjects (p < 0.05, Bonferroni corrected). Brain tissue volumes did not differ between groups. CONCLUSIONS This study provided the first evidence of a neuroanatomic difference between intermediate-onset and early-onset BD, which lends further support to the existence of different age-at-onset subgroups of BD.

Global and Temporal Cortical Folding in Patients With Early-Onset Schizophrenia

OBJECTIVE Adult-onset schizophrenia has repeatedly been associated with disturbances in the temporal lobes and alterations in cortical folding, which are thought to reflect neurodevelopmental impairment. Early-onset schizophrenia (EOS; onset before 18 years) is considered to involve even more pronounced neurodevelopmental deviance across a wide range of brain structural measures. We hypothesized that overall alteration of cortical folding also applies to EOS, and EOS involves prominent structural aberrations in superior temporal and collateral sulci. METHOD Magnetic resonance T1 images of 51 patients with EOS and 59 healthy participants were investigated. A fully automated method was applied to the images to extract, label, and measure the sulcus area in the whole cortex. Cortical folding was assessed by computing global sulcal indices (the ratio between total sulcal area and total outer cortex area) for each hemisphere and local sulcal indices (the ratio between the area of labeled sulcus and total outer cortex area in the corresponding hemisphere) for superior temporal and collateral sulci. RESULTS Relative to healthy individuals, patients with EOS had significantly lower global sulcal indices in both hemispheres and a lower local sulcal index in the left collateral sulcus. CONCLUSIONS Reduced hemispheric sulcation appears to be a feature of schizophrenia, irrespective of age at onset. Structural aberration involving the left collateral sulcus may contribute to neurobiological substrate of EOS.

The effects of surgical levels of sevoflurane and propofol anaesthesia on heart rate variability

BACKGROUND AND OBJECTIVE We compared heart rate dynamics during surgical levels of propofol and sevoflurane anaesthesia in a highly standardized setting. METHODS We recorded electrocardiography from 24 anaesthetized healthy male subjects. In the first parallel part of the study, the subjects were anaesthetized either with sevoflurane (n = 8) or propofol (n = 8) targeted to match 1.0, 1.5 and 2.0 minimal alveolar concentration/effective concentration 50. In the second part, a separate group (n = 8) underwent four different anaesthetic regimens targeted to bispectral index 40: sevoflurane alone, sevoflurane + 70% nitrous oxide, propofol alone and propofol + 70% nitrous oxide. The electrocardiography data were analysed using conventional time and frequency domain methods, and the approximate entropy method, which estimates the complexity of the data. RESULTS The induction of anaesthesia was followed by an overall reduction of heart rate variability, evident in all frequency bands in the spectral analysis, and also in the time domain measures. Approximate entropy decreased at 1 effective concentration 50 with propofol and at 2 minimal alveolar concentration with sevoflurane. In the second part of the study, the time domain variables and high-frequency spectral power were all similarly reduced by sevoflurane and propofol anaesthesia, with and without nitrous oxide. Approximate entropy tended to decrease during propofol anaesthesia. CONCLUSIONS Hypnotic levels of sevoflurane and propofol anaesthesia suppressed the heart rate variability measured using conventional analysis methods. Deeper surgical levels of anaesthesia also reduce the complexity of heart rate variability.Background and objective: Analgesics and anaesthetics have diverse synaptic actions that nonetheless have a common net inhibitory action on neuronal discharge. It is puzzling, therefore, that these two classes of compounds have fundamentally different affects, one blocking pain and the other consciousness. Indeed, beyond the isolated synapse, little is known of the larger scale mechanisms that mediate actual function, for example, transient neuronal assemblies. It was hypothesized that the two classes of drugs might have, respectively, differential effects on transient activation of these assemblies of neurons working together. Methods: Hippocampal tissue from juvenile Wistar rats was used for in vitro optical imaging with voltage‐sensitive dyes and simultaneous field potential recordings. The response to paired pulse stimulation of the hippocampus was recorded in the presence and absence of two types of analgesic (morphine and gabapentin) and two types of anaesthetic (thiopental and propofol). Results: Optical imaging and electrophysiology used in parallel yield quite different results. Most consistently, the imaging technique was able to detect an enhanced period of activation following anaesthetic, but not analgesic application. This effect was not readily seen from electrophysiology field potential recordings. Conclusions: These findings suggest that, irrespective of the effects of the two drug classes at a synaptic level, the dynamics of transient neuronal assemblies are modified selectively by anaesthetics and not analgesics.

Effects of fluoxetine on dopamine D2 receptors in the human brain: a positron emission tomography study with [11C]raclopride

We have previously reported that repeated dosing with the selective serotonin reuptake inhibitor (SSRI) citalopram decreases striatal [11C]raclopride binding in healthy volunteers. As the SSRI-class antidepressant drugs are believed to have a similar mechanism of action, we wanted to explore whether the prototype SSRI drug, fluoxetine, shares the effects of citalopram on subcortical dopamine neurotransmission. Eight healthy male volunteers were studied using a randomized double-blind placebo-controlled study design. Striatal and thalamic D2-receptor binding was measured at baseline, after a single oral dose (20 mg) of fluoxetine, and after repeated dosing (2 wk, 20 mg/d). The D2-receptor binding potential (BP) was assessed using [11C]raclopride and 3D positron emission tomography. Repeated dosing of fluoxetine decreased BP in the right medial thalamus (p=0.022). Fluoxetine did not decrease striatal BP, but there was a trend (p=0.090) towards increased BP in the left putamen after repeated dosing. A single dose of fluoxetine did not affect BP in the thalamus or striatum. Fluoxetine appears to have a regionally selective effect on the dopaminergic neurotransmission in various areas of the brain. The current results after fluoxetine together with our previous data on citalopram suggest that the modulatory effects of these drugs on striatal dopaminergic neurotransmission are different upon repeated dosing and further substantiates pharmacological differences between SSRI-class drugs.

Analysis of rapid heart rate variability in the assessment of anticholinergic drug effects in humans

Anticholinergic agents have widespread therapeutic indications in clinical medicine. In addition, certain other drug groups–such as neuroleptics, antidepressants and antihistamines–possess distinct anticholinergic properties that reduce tolerance and compliance. Especially in patients with heart disease, attention should be paid to cardiac anticholinergic drug effects. The analysis of short-term heart rate variability (HRV) provides a noninvasive tool to estimate vagal cholinergic outflow. In this review article, we present the basic principles of the most relevant techniques to study rapid HRV: the time domain analysis methods RMSSD and pNN50, and the high-frequency (HF) spectral component of HRV. We provide examples of previously reported effects of anticholinergic agents on these measures and also describe how adrenergic drugs may influence them. We have the following recommendations for a clinical pharmacologist investigating anticholinergic agents. (1) If the breathing rate of the study subject can be controlled during the assessment and the electrocardiogram recordings contain good-quality, stationary segments that are at least a few minutes long, then the HF power of HRV should be the method of choice. (2) During uncontrolled conditions, RMSSD should be included in the analyses, because it is less affected by changes in the respiratory pattern and it can be measured from shorter segments of electrocardiogram data. (3) Reduced short-term HRV suggests an anticholinergic, but not necessarily an antimuscarinic drug effect, since the inhibition of cholinergic vagal efferent activity may also originate from central or peripheral adrenergic influences.

Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods.

ObjectiveCardiac output (CO) has traditionally been measured using invasive techniques, which involve an element of risk. Thus, a reliable less-invasive method for determining CO would be very valuable for research use. We tested whether simple analysis of the arterial pulse waveform, not requiring large-vessel catheterisation or expensive equipment, could provide an estimate of CO that is accurate enough for pharmacological studies.MethodsWe measured CO in 11 healthy male subjects who received low and high doses of dexmedetomidine (α2-adrenoceptor agonist), using pulse contour analysis, echocardiography and pulmonary thermodilution techniques.ResultsAt baseline, these methods gave the following mean (SD) values of CO: 6.18 (1.59), 5.22 (1.35) and 7.03 (1.54) l/min, respectively. High-dose dexmedetomidine reduced CO to 4.50 (0.68), 3.65 (0.65) and 4.80 (0.89) l/min, corresponding to −25 (14) %, −28 (12) % and −30 (14) % reductions from baseline, respectively. The pulse contour method described these dexmedetomidine-induced changes in CO very similarly to the thermodilution and echocardiographic methods. The limits of agreement [bias (2SD)] were 0.55 (2.55) and −0.10 (2.04) l/min, respectively.ConclusionThe minimally invasive pulse contour analysis technique might be suitable for pharmacological studies for the detection of major drug-induced reductions in CO.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.