Reward is not reward: Differential impacts of primary and secondary rewards on expectation, outcome, and prediction error in the human brain's reward processing regions.

According to their nature, rewarding stimuli are classified as primary (e.g., food, sex) and secondary (e.g., money) rewards. Neuroimaging studies have provided valuable insights in neural reward processing and its various aspects including reward expectation, outcome and prediction error encoding. However, there is only limited evidence of whether the two different types of rewards are processed in common or distinct brain areas, in particular when considering the different functions of reward processing. We analyzed a sample of 42 healthy, male participants using task-based functional magnetic resonance imaging (fMRI) during a variant of the monetary incentive delay task. We aimed to investigate the effects of three different rewarding stimuli-two primary (food and sex) and one secondary (money)-on the various functions of reward processing. To provide a thorough description, we focused on 12 brain regions of interest and utilized the Bayes factor bound (BFB) to express stimulus-related main effects and pairwise differences at different levels of evidence, ranging from weak to decisive. Our results revealed a dominance of sexually charged stimuli in engaging the brain's reward structures for all investigated aspects of reward processing. Nevertheless, the ventral tegmental area, amygdala, ventral caudate, ventromedial prefrontal cortex, subgenual anterior cingulate cortex, and lateral orbitofrontal cortex were activated by both primary and secondary reward outcomes. For other reward processing functions, i.e., reward expectation and the prediction error, effects of the different stimuli were weaker, and effects from one reward type cannot easily be generalized to the other.

Lower fractional anisotropy of the corticothalamic tract and increased response time variability in adult patients with ADHD.

BACKGROUND: Intraindividual intertrial variability has been suggested as an endophenotype of attention-deficit/hyperactivity disorder (ADHD). It is usually evaluated as response time variability (RTV) in reaction time tasks, and RTV has emerged as a robust and stable feature of ADHD. Among attempts to elucidate the neurobiological underpinnings of RTV, it has been suggested that alterations in white matter microstructure may explain RTV. METHODS: We used diffusion tensor imaging (DTI) in a group of 53 adults with ADHD and 50 healthy controls. We obtained RTV parameters from a simple reaction-time task, in which participants were asked to respond to the appearance of white crosses on a screen using button presses. RESULTS: We observed significant between-group differences for the ex-Gaussian parameter τ, indicating that the mean of extremely slow responses was greater for adults with ADHD than controls. Fractional anisotropy (FA) derived from DTI was significantly different between groups in 2 clusters of the corticothalamic tract. In the ADHD group, relatively decreased FA values were significantly associated with the parameter τ, such that lower FA values in the corticothalamic tract predicted greater τ as an index of RTV. We did not observe this association in healthy controls. LIMITATIONS: For comparison with previous studies, we used FA as a dependent variable of interest. However, although this metric is sensitive to white matter structural properties, there are ambiguities in its interpretation. CONCLUSION: Even in a simple reaction-time task, RTV proved again to be a stable feature of ADHD. It was associated with altered white matter structural properties of the corticothalamic tract in adults with ADHD.

FAAH polymorphism (rs324420) modulates extinction recall in healthy humans: an fMRI study.

Gold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State-Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

Adolescent depression and brain development: evidence from voxel-based morphometry

Background: Investigating adolescents and young adults may provide a unique opportunity to understand developmental aspects of the neurobiology of depression. During adolescence, a considerable physiologic reorganization of both grey and white matter of the brain takes place, and it has been suggested that differences in grey-matter volumes during adolescence may reflect different maturational processes. Methods: We investigated grey-matter volumes in a comparatively large sample (n = 103) of adolescents and young adults (aged 12 to 27 years), 60 of them with a diagnosis of current depression. Results: Replicating previous studies, we found a clear wholebrain effect of age: the older the participants, the lower their global grey-matter volumes, particularly in the paracingulate and prefrontal cortices. Contrasting depressed and healthy youth in a whole-brain approach, we found greater grey-matter volumes in the dorsolateral prefrontal cortex of those with depression. Furthermore, a region-of-interest analysis indicated lower grey-matter volumes in the hippocampus in participants with depression compared with healthy controls. Limitations: The present study was limited because of a skewed sex distribution, its cross-sectional design and the fact that some participants were taking an antidepressant. Conclusion: During adolescence, restructuring of the brain is characterized by marked decreases in prefrontal grey-matter volumes, interpreted as a correlate of brain maturation. Findings of greater volumes in the prefrontal cortex, particularly in younger adolescents with depression, may suggest that these participants were more prone to delayed brain maturation or increased neuroplasticity. This finding may represent a risk factor for depression or constitute an effect of developing depression.

Glucose Modulates Human Ventral Tegmental Activity in Response to Sexual Stimuli.

BACKGROUND: Attribution of salience to sexual stimuli is mediated by the dopaminergic midbrain, including the ventral tegmental area (VTA). The existence of glucose-sensing neurons in the VTA, as suggested by animal studies, offers the opportunity to modulate aberrant salience coding involved in sexual disorders such as sexual addiction. Recent neuroimaging work supported that VTA activity in humans can be modulated by intravenously infusing a small bolus of glucose. However, that study used appetitive food stimuli, leaving the possibility that glucose modulation of VTA-mediated salience coding might be bound to this class of stimuli. AIM: To test whether glucose-modulatory effects generalize to food-unrelated stimuli despite being in the class of primary reinforcers. METHODS: During functional imaging, 37 healthy men were exposed to images showing nude or clothed female upper bodies. At the end of the 1st quarter (∼6 minutes) of the experiment, 18 participants received a small amount of intravenously infused glucose. RESULTS: Before glucose administration, VTA activity was higher for nude than for clothed female stimuli. After infusion of glucose, this pattern reversed such that VTA activity was higher for clothed than for nude female stimuli. The effect was at its maximum approximately 7 to 12 minutes after glucose infusion, changing back during the experiment's 4th phase. In another 19 participants not treated with glucose, VTA activity was consistently higher for nude than for clothed female stimuli throughout the experiment. CONCLUSION: The present findings show that glucose modulates VTA-mediated salience coding of sexual stimuli. These results suggest that glucose might affect salience coding in a stimulus-general way. However, future studies are necessary to address the question of whether glucose modulation also affects the VTA's salience coding of secondary reinforcers. Ulrich M, Stauß P, Grön G. Glucose Modulates Human Ventral Tegmental Activity in Response to Sexual Stimuli. J Sex Med 2018;15:20-28.

The neural correlates of flow experience explored with transcranial direct current stimulation.

The experience of flow ensues when humans engage in a demanding task while task demands are balanced with the individual's level of skill or ability. Here, we further tested the hypothesis that the medial prefrontal cortex (MPFC) plays a causal role in mediating flow experience using transcranial direct current stimulation (tDCS) to interfere with MPFC's deactivation evoked by a flow paradigm and measured by magnetic resonance (MR)-based perfusion imaging. In a balanced, within-subjects repeated measure design, three treatments of tDCS (sham, anodal, cathodal) were applied in a sample of 22 healthy male participants. tDCS-modulatory effects on flow-specific regional cerebral blood flow (rCBF) and subjective flow experience significantly depended on participants' baseline level of flow experience during sham tDCS. Those participants with lower-flow experience during sham tDCS (LF) benefitted from tDCS, particularly from the anodal polarity, whereas both active treatments did not substantially affect subjects with relatively higher baseline flow experience (HF). Functionally, in LF subjects, relative deactivation of the right amygdala got more pronounced under anodal and cathodal tDCS, and changed inconsistently in HF subjects. Inter-individual regression analyses of rCBF data suggested that involvement of the subgenual anterior cingulate cortex appears crucial for affecting the response pattern in the right amygdala and can be modulated by tDCS. Present data support the notion that valuable insights into the neural mechanism of flow can be obtained using tDCS. However, a clearer understanding of tDCS' baseline dependency in terms of individual variations in brain connectivity states appears a necessary prerequisite to exploit this technique further.

Theta-burst modulation of mid-ventrolateral prefrontal cortex affects salience coding in the human ventral tegmental area.

In the context of hedonic (over-)eating the ventral tegmental area (VTA) as a core part of the dopaminergic reward system plays a central role in coding incentive salience of high-caloric food. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate whether transcranial magnetic theta-burst stimulation (TBS) over the right mid-ventrolateral prefrontal cortex (mid-VLPFC) can induce modulation of calorie-sensitive brain activation in the VTA. The prefrontal location for TBS had been predetermined by seed-based resting-state fMRI with a functionally defined portion of the VTA serving as seed region obtained from an independent second fMRI experiment. In a sample of 15 healthy male participants, modulation of calorie-sensitive VTA activation did not significantly differ between the two TBS protocols. Comparisons with baseline revealed that both TBS protocols significantly affected calorie-sensitive neural processing of the mid-VLPFC in a rather similar way. In the VTA significant modulation of calorie-sensitive activation was observed after continuous TBS, whereas the modulatory effect of intermittent TBS was less reliable but also associated with a decrease of activation for high-caloric food images. Neurostimulation of right mid-VLPFC is suggestive as a main entry point of downstream signal changes for high- and low-caloric food cues that could enforce a shift in valuating stimuli of initially different incentive salience.

Glucose modulates food-related salience coding of midbrain neurons in humans.

Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low-caloric food (LC), high-caloric food (HC), and non-food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment-specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376-4384, 2016. © 2016 Wiley Periodicals, Inc.

Neural signature of the Food Craving Questionnaire (FCQ)-Trait.

The Trait and State versions of the Food Craving Questionnaire (FCQ) have been used in numerous behavioral and physiological eating studies. However, the neurobiological signature of the FCQ has not been reported yet. In the present study, 20 healthy male participants performed a food/non-food discrimination task during functional magnetic resonance imaging (fMRI). We investigated where in the brain greater activation upon high-caloric minus low-caloric food cues correlated with participants' scores on the German version of the FCQ-Trait, with the FCQ-State total scores included as a covariate, and vice versa. It was also tested whether individual subscales would map onto distinguishable neural correlates. Significant positive correlations with total scores on the FCQ-Trait were evident in several bilateral loci of the striatum, and in the right middle/lateral orbitofrontal cortex (OFC). Correlations with scores on the FCQ-Trait subscales Reinforcement and Hunger were found for subsets of voxels within the ventral striatum, whereas the FCQ-Trait subscales Intentions/Lack of control and Thoughts/Guilt mapped onto right OFC. There were no significant correlations between calorie-sensitive brain activation and scores on the FCQ-State when including the total scores on the FCQ-Trait as a covariate. Present findings show that the trait version of the FCQ associates with neural correlates known to be involved in coding motivational salience, detecting and estimating reward value, and representing information of expected outcomes.

Baseline brain perfusion and brain structure in patients with major depression: a multimodal magnetic resonance imaging study.

BACKGROUND: Abnormal regional cerebral blood flow (rCBF) and grey matter volume have been frequently reported in patients with major depressive disorder (MDD). However, it is unclear to what extent structural and functional change co-occurs in patients with MDD and whether markers of neural activity, such as rCBF, can be predicted by structural change. METHODS: Using MRI, we investigated resting-state rCBF and brain structure in patients with MDD and healthy controls between July 2008 and January 2013. We acquired perfusion images obtained with continuous arterial spin labelling, used voxel-based morphometry to assess grey matter volume and integrated biological parametric mapping analyses to investigate the impact of brain atrophy on rCBF. RESULTS: We included 43 patients and 29 controls in our study. Frontotemporal grey matter volume was reduced in patients compared with controls. In patients, rCBF was reduced in the anterior cingulate and bilateral parahippocampal areas and increased in frontoparietal and striatal regions. These abnormalities were confirmed by analyses with brain volume as a covariate. In patients with MDD there were significant negative correlations between the extent of depressive symptoms and bilateral parahippocampal rCBF. We found a positive correlation between depressive symptoms and rCBF for right middle frontal cortical blood flow. LIMITATIONS: Medication use in patients has to be considered as a limitation of our study. CONCLUSION: Our data suggest that while changes of cerebral blood flow and brain volume co-occur in patients with MDD, structural change is not sufficient to explain altered neural activity in patients at rest. Abnormal brain structure and function in patients with MDD appear to reflect distinct levels of neuropathology.

Neural correlates of experimentally induced flow experiences.

Flow refers to a positive, activity-associated, subjective experience under conditions of a perceived fit between skills and task demands. Using functional magnetic resonance perfusion imaging, we investigated the neural correlates of flow in a sample of 27 human subjects. Experimentally, in the flow condition participants worked on mental arithmetic tasks at challenging task difficulty which was automatically and continuously adjusted to individuals' skill level. Experimental settings of "boredom" and "overload" served as comparison conditions. The experience of flow was associated with relative increases in neural activity in the left anterior inferior frontal gyrus (IFG) and the left putamen. Relative decreases in neural activity were observed in the medial prefrontal cortex (MPFC) and the amygdala (AMY). Subjective ratings of the flow experience were significantly associated with changes in neural activity in the IFG, AMY, and, with trend towards significance, in the MPFC. We conclude that neural activity changes in these brain regions reflect psychological processes that map on the characteristic features of flow: coding of increased outcome probability (putamen), deeper sense of cognitive control (IFG), decreased self-referential processing (MPFC), and decreased negative arousal (AMY).

Erotic stimulus processing under amisulpride and reboxetine: a placebo-controlled fMRI study in healthy subjects.

BACKGROUND: Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. METHODS: Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4 mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. RESULTS: Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. CONCLUSIONS: In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents.

Impact of the control for corrupted diffusion tensor imaging data in comparisons at the group level: an application in Huntington disease.

BACKGROUND: Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level. METHODS: Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with similar acquisition protocols on four different MR scanners at four European study sites. A QC algorithm was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analyzed. RESULTS: The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, less small clusters of FA changes were observed, compared to the analysis without QC. However, the main pattern of regional reductions and increases in FA values with and without QC-based elimination of corrupted GD was unchanged. CONCLUSION: An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons.

Arterial Spin Labeling (ASL) in Neuroradiological Diagnostics - Methodological Overview and Use Cases.

BACKGROUND: Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI)-based technique using labeled blood-water of the brain-feeding arteries as an endogenous tracer to derive information about brain perfusion. It enables the assessment of cerebral blood flow (CBF). METHOD: This review aims to provide a methodological and technical overview of ASL techniques, and to give examples of clinical use cases for various diseases affecting the central nervous system (CNS). There is a special focus on recent developments including super-selective ASL (ssASL) and time-resolved ASL-based magnetic resonance angiography (MRA) and on diseases commonly not leading to characteristic alterations on conventional structural MRI (e. g., concussion or migraine). RESULTS: ASL-derived CBF may represent a clinically relevant parameter in various pathologies such as cerebrovascular diseases, neoplasms, or neurodegenerative diseases. Furthermore, ASL has also been used to investigate CBF in mild traumatic brain injury or migraine, potentially leading to the establishment of imaging-based biomarkers. Recent advances made possible the acquisition of ssASL by selective labeling of single brain-feeding arteries, enabling spatial perfusion territory mapping dependent on blood flow of a specific preselected artery. Furthermore, ASL-based MRA has been introduced, providing time-resolved delineation of single intracranial vessels. CONCLUSION: Perfusion imaging by ASL has shown promise in various diseases of the CNS. Given that ASL does not require intravenous administration of a gadolinium-based contrast agent, it may be of particular interest for investigations in pediatric cohorts, patients with impaired kidney function, patients with relevant allergies, or patients that undergo serial MRI for clinical indications such as disease monitoring. KEY POINTS: · ASL is an MRI technique that uses labeled blood-water as an endogenous tracer for brain perfusion imaging.. · It allows the assessment of CBF without the need for administration of a gadolinium-based contrast agent.. · CBF quantification by ASL has been used in several pathologies including brain tumors or neurodegenerative diseases.. · Vessel-selective ASL methods can provide brain perfusion territory mapping in cerebrovascular diseases.. · ASL may be of particular interest in patient cohorts with caveats concerning gadolinium administration..

Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

Brain activation during masked and unmasked semantic priming: commonalities and differences.

Using fMRI during a lexical decision task, we investigated the neural correlates of semantic priming under masked and unmasked prime presentation conditions in a repeated measurement design of the same group of 24 participants (14 women). The task was to discriminate between pseudowords and words. Masked and unmasked prime words differed in their degree of semantic relatedness with target stimuli. Neural correlates of priming were defined as significantly different neural activations upon semantically unrelated minus related trials. Left fusiform gyrus, left posterior inferior frontal gyrus, and bilateral pre-SMA showed priming effects independent of the masking condition. By contrast, bilateral superior temporal gyri, superior parietal lobules, and the SMA proper demonstrated greater neural priming in the unmasked compared with the masked condition. The inverted contrast (masked priming minus unmasked priming) did not show significant differences even at lowered thresholds of significance. The conjoint effects of priming in the left fusiform gyrus suggest its involvement as a direct consequence of the neural organization of semantic memory. Activity in brain regions showing significantly more neural priming in the unmasked condition possibly reflected participants' evaluation of the prime-target relationship, presumably in the context of semantic matching. The present results therefore indicate that masked and unmasked semantic priming partially depend on dissociable mechanisms at the neural and most likely also at the functional level.

Cigarette smoking modulates medication-associated deficits in a monetary reward task in patients with schizophrenia.

Imaging studies of reward processing have demonstrated a mesolimbic-mesocortical dopaminergic dysfunction in schizophrenia. Such studies on reward processing in patients and also in healthy controls showed that differential activations of dopaminergic brain areas are associated with adaptive changes in response speed related to different reward values. Given this relationship, we investigated reward processing on the behavioural level in a larger sample of 49 medicated patients with a diagnosis of schizophrenia (ICD-10 F20) and 49 healthy controls. Subjects were instructed to react by button press upon two different stimuli in order to retain a 60 % chance winning a previously announced high (1$) or low (20¢) amount of money paid to participants after the experiment. Concordant with previous reports on deficits in reward processing, acceleration of reaction times in patients upon low rewards differed significantly (p < 0.05) from healthy controls in our present behavioural study. This effect was pronounced in the non-smoking subgroup of patients (n = 24). In this subgroup, we also observed a significant (p < 0.05) positive correlation with medication type (relatively high vs. low D2 receptor affinity) and with the PANSS score, the latter with a trend to significance (p = 0.08). Our study demonstrates that reaction time measures in a monetary reward task might constitute a feasible behavioural proxy for dopaminergic dysfunction and its different dimensions regarding psychopathology but also medication in patients with schizophrenia. In line with clinical observations, our findings support the notion that smoking modulates medication-associated side effects on reward processing in patients with schizophrenia.

Parkinson's disease or multiple system atrophy: potential separation by quantitative susceptibility mapping.

Background: Due to the absence of robust biomarkers, and the low sensitivity and specificity of routine imaging techniques, the differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is challenging. High-field magnetic resonance imaging (MRI) opened up new possibilities regarding the analysis of pathological alterations associated with neurodegenerative processes. Recently, we have shown that quantitative susceptibility mapping (QSM) enables visualization and quantification of two major histopathologic hallmarks observed in MSA: reduced myelin density and iron accumulation in the basal ganglia of a transgenic murine model of MSA. It is therefore emerging as a promising imaging modality on the differential diagnosis of Parkinsonian syndromes. Objectives: To assess QSM on high-field MRI for the differential diagnosis of PD and MSA. Methods: We assessed 23 patients (nine PDs and 14 MSAs) and nine controls using QSM on 3T and 7T MRI scanners at two academic centers. Results: We observed increased susceptibility in MSA at 3T in prototypical subcortical and brainstem regions. Susceptibility measures of putamen, pallidum, and substantia nigra reached excellent diagnostic accuracy to separate both synucleinopathies. Increase toward 100% sensitivity and specificity was achieved using 7T MRI in a subset of patients. Magnetic susceptibility correlated with age in all groups, but not with disease duration in MSA. Sensitivity and specificity were particularly high for possible MSA, and reached 100% in the putamen. Conclusion: Putaminal susceptibility measures, in particular on ultra-high-field MRI, may distinguish MSA patients from both, PD and controls, allowing an early and sensitive diagnosis of MSA.

Brain activation and functional connectivity in premanifest Huntington's disease during states of intrinsic and phasic alertness.

Previous functional neuroimaging studies have shown brain activation abnormalities in clinically presymptomatic carriers of the Huntington's disease (preHD) gene mutation when performing complex cognitive tasks. However, little is known about the neural correlates of attentional processes in preHD. In this study, we used functional magnetic resonance imaging to investigate basic aspects of attentional processing in preHD individuals (n = 18) compared to healthy participants (n = 18) during an alertness task. Uni- and multivariate statistical techniques were used to assess task-related regional brain activation and functional network connectivity. Compared to healthy controls, preHD individuals near to the estimated onset of clinical signs showed lower activation of right frontostriatal regions during phasic alertness (P < 0.001, uncorrected). Decreased striatal activation in this preHD subgroup was also evident when compared with those preHD individuals far from the estimated onset of HD signs. Lower putaminal activity was associated with longer reaction times and with proximity to onset. In addition, preHD participants near to onset had lower functional connectivity of motor regions when compared with controls and preHD individuals far from onset. Our data suggest that while alertness-related performance remains normal, the underlying frontostriatal activity and motor cortex connectivity decline only when approaching the onset of unequivocal signs of HD. However, these attentional network changes might not be the sole explanation for the differences in cognitive task performance previously observed in preHD.

Substantial and reversible brain gray matter reduction but no acute brain lesions in ultramarathon runners: experience from the TransEurope-FootRace Project.

BACKGROUND: During the extremely challenging 4,487 km ultramarathon TransEurope-FootRace 2009, runners showed considerable reduction of body weight. The effects of this endurance run on brain volume changes but also possible formation of brain edema or new lesions were explored by repeated magnetic resonance imaging (MRI) studies. METHODS: A total of 15 runners signed an informed consent to participate in this study of planned brain scans before, twice during, and about 8 months after the race. Because of dropouts, global gray matter volume analysis could only be performed in ten runners covering three timepoints, and in seven runners who also had a follow-up scan. Scanning was performed on three identical 1.5 T Siemens MAGNETOM Avanto scanners, two of them located at our university. The third MRI scanner with identical sequence parameters was a mobile MRI unit escorting the runners. Volumetric 3D datasets were acquired using a magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Additionally, diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) imaging was performed. RESULTS: Average global gray matter volume as well as body weight significantly decreased by 6% during the race. After 8 months, gray matter volume returned to baseline as well as body weight. No new brain lesions were detected by DWI or FLAIR imaging. CONCLUSIONS: Physiological brain volume reduction during aging is less than 0.2% per year. Therefore a volume reduction of about 6% during the 2 months of extreme running appears to be substantial. The reconstitution in global volume measures after 8 months shows the process to be reversible. As possible mechanisms we discuss loss of protein, hypercortisolism and hyponatremia to account for both substantiality and reversibility of gray matter volume reductions. Reversible brain volume reduction during an ultramarathon suggests that extreme running might serve as a model to investigate possible mechanisms of transient brain volume changes. However, despite massive metabolic load, we found no new lesions in trained athletes participating in a multistage ultramarathon.See related commentary http://www.biomedcentral.com/1741-7015/10/171.