Elena Pavlova

Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography

In the human brain the monoaminooxidase-B enzyme or MAO-B is highly abundant in astrocytes. As astrocyte activity and, consequently, the activity of the MAO-B enzyme, is up-regulated in neuroinflammatory processes, radiolabelled analogues of deprenyl may serve as an imaging biomarker in neuroinflammation and neurodegeneration, including Alzheimers disease. In the present study [(11)C]-L-deprenyl, the PET radioligand version of L-deprenyl or selegiline®, a selective irreversible MAO-B inhibitor was used in whole hemisphere autoradiographic experiments in human brain sections in order to test the radioligands binding to the MAO-B enzyme in human brain tissue, with an eye on exploring the radioligands applicability as a molecular imaging biomarker in human PET studies, with special regard to diagnostic detection of reactive astrogliosis. Whole hemisphere brain sections obtained from Alzheimer patients and from age matched control subjects were examined. In control brains the binding of [(11)C]-L-deprenyl was the highest in the hippocampus, in the basal ganglia, the thalamus, the substantia nigra, the corpus geniculatum laterale, the nucleus accumbens and the periventricular grey matter. In Alzheimer brains significantly higher binding was observed in the temporal lobes and the white matter. Furthermore, in the Alzheimer brains in the hippocampus, temporal lobe and white matter the binding negatively correlated with Braak stages. The highest binding was observed in Braak I-II, whereas it decreased with increasing Braak grades. The increased regional binding in Alzheimer brains coincided with the presence of an increased number of activated astrocytes, as demonstrated by correlative immunohistochemical studies with GFAP in adjacent brain slices. Deprenyl itself as well as the MAO-B antagonist rasagiline did effectively block the binding of the radioligand, whereas the MAO-A antagonist pirlindole did not affect it. Compounds with high affinity for the PBR system did not block the radioligand binding either, providing evidence for the specificity of [(11)C]-L-deprenyl for the MAO-B enzyme. In conclusion, the present observations indicate that [(11)C]-L-deprenyl may be a promising and selective imaging biomarker of increased MAO-B activity in the human brain and can therefore serve as a prospective PET tracer targeting neuroinflammation and neurodegeneration.

The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: A post-mortem autoradiographic study

Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimers disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD.

Transcranial direct current stimulation of the premotor cortex: Effects on hand dexterity

UNLABELLED Premotor cortex activity is associated with complex motor performance and motor learning and offers a potential target to improve dexterity by transcranial direct current stimulation (tDCS). We explored the effects of tDCS of premotor cortex on performance of a Strength-Dexterity test in healthy subjects. METHODS During the test a slender spring held between thumb and index finger should be compressed as much as possible without buckling. Finger forces assessed in the test provided a measure of dexterity. First, task performance was tested in 12 persons during anodal tDCS to the primary motor cortex (M1) contralateral to the performing hand, and sham stimulation. Another 12 persons participated in five sessions of anodal and cathodal tDCS over the left and the right premotor cortex and sham stimulation. RESULTS tDCS over M1 as well as over the left, but not the right premotor cortex resulted in significant improvement of performance. Performance alterations correlated positively between left anodal and right cathodal tDCS and negatively between anodal tDCS of the two sides. Effective polarity for premotor stimulation to improve task performance differed between participants. Individuals who improved with anodal stimulation used lower finger force and experienced the test as more difficult compared to those who improved with cathodal stimulation. CONCLUSIONS This study demonstrates that tDCS over the left premotor cortex can improve performance of a dexterity demanding task. The effective polarity of stimulation depends on the task performance strategies. The study moreover shows a functional relevance of interactions between the left and right premotor cortex.

Activity in the brain network for dynamic manipulation of unstable objects is robust to acute tactile nerve block: An fMRI study.

OBJECTIVE To study whether a temporary block of the tactile afferents from the fingers causes altered activity in the neural network for dexterous manipulation. METHODS Whole-brain functional Magnetic Resonance Imaging (fMRI) was conducted in 18 healthy subjects, while they compressed an unstable spring between the thumb and index finger of the right hand. Two sensory conditions--with and without tactile input from the fingers--were employed. In the latter condition the digital nerves were blocked by local anesthesia. RESULTS Compression of the unstable spring was associated with activity in an earlier described network for object manipulation. We found that this entire network remained active after a nerve block, and the activity was increased in the dorsal premotor cortex. CONCLUSIONS The neural network for dexterous manipulation is robust with only minor alterations after acute loss of tactile information from the fingers. There was no loss of activity, but, unexpectedly, an increased activity in some parts of the network. SIGNIFICANCE This study gives new insights to possible neural compensatory mechanisms that make fine motor control possible after acute disruption of tactile information in natural situations like cold weather or wearing surgical gloves.

Impact of Tactile Sensation on Dexterity: A Cross-Sectional Study of Patients With Impaired Hand Function After Stroke

ABSTRACT The authors sought to explore the impact of tactile sensation on manual dexterity and the validity of the strength-dexterity test in subjects with chronic impairments after stroke in a cross-sectional study of 24 patients with impaired hand function after stroke. Dexterity was assessed by the strength-dexterity test, Box and Blocks, and Nine-Hole Peg Test, and the ABILHAND questionnaire. Sensation was measured by pinprick, cotton-wool, graphesthesia, and 2-point discrimination tests. Sensation in the paretic hand had strong association with paretic hand performance in the strength-dexterity test and Nine-Hole Peg Test and explained 13% of the variance. Sensation in the nonparetic hand was associated with the results of the ABILHAND questionnaire. Among sensory tests, 2-point discrimination had the strongest association with dexterity tests. No significant correlations between sensation, pinch force, and dexterity tests were found for the nonparetic hand. The strength-dexterity test exhibited strong correlations with the other dexterity measures and with pinch force. There is an association between tactile sensation and dexterous performance in the paretic hand; activity level performance is associated with sensation in the nonparetic hand. The study supports the validity of the strength-dexterity test when applied in subjects in the chronic stage after stroke.

Transcranial direct current stimulation of 20- and 30-minutes combined with sertraline for the treatment of depression

Background: Transcranial direct current stimulation (tDCS) can be an effective treatment for depression, however, the duration of the stimulation session, among other parameters, needs to be optimized. Methods: 69 mild to moderately depressed patients (age 37.6 ± 10.5 years, 19 men) were randomized into three groups – 30‐, 20‐minute or sham tDCS. 10 daily sessions of anodal/sham tDCS of the left DLPFC (0.5 mA; electrode 3,5 × 7 cm) combined with 50 mg/day of sertraline were performed. Mood, cognition and BDNF level were assessed before and after the treatment. Results: A significant difference between groups was observed in the percent change of the Hamilton Depression Rating Scale (F(2, 66) = 10.1; p < 0.001). Sham group (43.4% ± 18.1) had a smaller improvement compared to the 30‐minute (63.8% ± 13.4; 95% CI: 11.23–29.44; p = 0.00003) and 20‐minute group (53.2% ± 15.3; 95% CI: 0.21–19.26; p = 0.045). 30‐minute group had significantly greater percent improvement than 20‐minute group (95% CI: 1.74–19.46; p = 0.02). Responders constituted 89%, 68%, and 50% and remitters – 70%, 27%, and 35% in the 30‐, 20‐minute and sham groups, respectively. A significant difference in the number of responders was observed between 30‐minute vs. sham group (odds ratio = 8; 95% CI, 2.59–24.69; p = 0.001), in remission rate – between 30‐minute vs. sham (odds ratio = 4.40; 95% CI, 2.02–9.57; p = 0.02) and vs. 20‐minute (odds ratio = 6.33; 95% CI, 2.85–14.10; p = 0.003) groups. Two hypomania cases and one case of blood pressure elevation were detected in the 20‐minute group. Among neuropsychological tests, only the change in Digit Span Backwards test showed a significant interaction between groups (TIME*GROUP; F(2, 65) = 6,6, p = 0.002); a greater improvement was observed in both active groups compared to sham (p < 0.05). The change in BDNF level after the treatment did not show the significant difference between groups. Conclusions: tDCS of 20‐ or 30‐minutes combined with sertraline are efficient for the treatment of mild and moderate depression; the effect of 30 min stimulation exceeds the one obtained from 20 min. Highlights69 depressed patients were randomized into three groups: 30‐, 20‐minute or sham tDCS.10 daily sessions of tDCS of the DLPFC combined with 50 mg sertraline were performed.Significant augmenting effect of active tDCS on sertraline treatment was shown.Effect of tDCS during 30 min exceeds one obtained during 20 min.2 hypomania cases and 1 case of blood pressure elevation were detected.

Transcranial direct current stimulation combined with visuo-motor training as treatment for chronic stroke patients

BACKGROUND Recent studies exploring the combined effect of motor learning and transcranial direct current stimulation (tDCS) for stroke rehabilitation have shown partially conflicting results. OBJECTIVE To test the efficacy of an optimized hand training approach combined with tDCS in stroke patients. METHODS In the present pilot study we investigated motor effects of four-week training with a visuomotor grip force tracking task combined with tDCS in 11 chronic stroke patients. Anodal (0.5 mA) or sham tDCS was applied over the primary motor cortex of the lesioned side for 20 minutes, twice a day, during training. RESULTS No difference between the Active and Sham groups in the total upper extremity (UE) Fugl-Meyer Assessment (FMA) score was found. The most prominent recovery occurred in the shoulder-elbow FMA sub-score; in this segment a significantly greater improvement in the Active compared to the Sham group was observed up to two months after the intervention. Mean hold force during the first treatment session predicted the change in the total UE FMA score after treatment. CONCLUSION Four-week visuo-motor training combined with tDCS showed no difference between the Active and Sham groups in the total UE FMA score, which may be explained by heterogeneity of the degree of recovery in the Active group. However, the shoulder-elbow FMA sub-score improved significantly more in the Active compared to the Sham group, which deserves further study.

LP13: Activity in the brain network for dynamic manipulation of unstable objects is robust to acute tactile deafferentation: an fMRI study

malized CT images were segmented to identify cranial bones using simple thresholding and morphological operations. A signed distance function was first generated for each CT dataset based on its segmented cranial bones. A shape model for cranial bones was then reconstructed by applying the principal component analysis (PCA) on the signed distance functions. The fontanels were identified as gaps between the cranial bones in the shape model. Using a probabilistic atlas, the intracranial tissues (brain and CSF) were segmented from the normalized and averaged MR images. The scalp was then obtained by removing the segmented tissues from the averaged MR images. Finally, the segmented tissues were surface rendered and used to generate a realistic head model. Results: Figure 1 shows the different compartments of the realistic neonatal head model including brain, CSF, scalp, cranial bones and fontanels (Fig. 1a) as well as their 3D reconstruction (Fig. 1b). Conclusion: In this paper we developed a method to create a realistic neonatal head model based on the co-registration of CT and MR images from neonates. The model included the geometry of brain, CSF, scalp, cranial bones and fontanels. With a specific conductivity value assigned to each compartment, the model can be used for EEG/MEG source localization in neonates.

P 77. Transcranial direct current stimulation of the premotor cortex aimed to improve fine motor skills of the hand

Introduction Transcranial direct current stimulation (tDCS) is a non-invasive method for modulation of brain activity and excitability. Anodal stimulation leads to an increase of excitability under the electrode, whereas cathodal tDCS decreases it ( Nitsche et al., 2008 ). tDCS of the primary motor cortex has been shown its principal efficacy to improve motor functions ( Nowak et al., 2009 ). However, not much is known about the effects of premotor tDCS on performance. In this study we investigated the influence of tDCS of the dorsal premotor cortex (PMd) on fine motor skills of the hand, referred to as dexterity. It was assessed by a newly-developed spring compression task ( Valero-Cuevas et al., 2003 ). Methods Two experiments were performed. In the first experiment 12 healthy persons received anodal tDCS to the primary motor cortex (M1) contralateral to the performing hand and sham stimulation to assess the sensitivity of the spring compression task for modulation by tDCS. In the second experiment, another group of 12 healthy persons participated in five sessions of stimulation comprising anodal and cathodal stimulation of the left and the right PMd and sham stimulation. The spring compression task was performed before and during stimulation. In this task, an unstable spring, held between the right thumb and index finger, is supposed to be compressed as much as possible without buckling. The force in the fingers, recorded by two sensors, serves as a measure of dexterity. tDCS-related performance alterations are expressed as percent change of the force during the stimulation compared to before stimulation. Results tDCS over M1 in the experiment 1 as well as over the left, but not the right PMd in experiment 2 resulted in significant improvement of motor performance ( Fig. 1 ). The effects of premotor tDCS were heterogeneous: Some participants benefitted from cathodal premotor stimulation (group 1), some from anodal (group 2) and others did not have a considerable effect (group 3). The effect of stimulation polarity correlated with variability (SD) of task performance and subjective task difficulty: participants of the group 2 had lowest variability and higher subjective task difficulty than group 2 ( Fig. 2 ). Conclusions The improvement of fine motor control during tDCS of the left dorsal premotor cortex makes this area a promising candidate for future investigations in the field. Acknowledgements This study has been funded by Erik och Edith Fernstroms stiftelse for medicinsk forskning and Stiftelsen Promobilia.