Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson's disease.

BACKGROUND: The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson's disease. METHODS: Thirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios. RESULTS: Subcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects. CONCLUSIONS: Our study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.

Effective connectivity underlying reward-based executive control.

Motivational influences on cognitive control play an important role in shaping human behavior. Cognitive facilitation through motivators such as prospective reward or punishment is thought to depend on regions from the dopaminergic mesocortical network, primarily the ventral tegmental area (VTA), inferior frontal junction (IFJ), and anterior cingulate cortex (ACC). However, how interactions between these regions relate to motivated control remains elusive. In the present functional magnetic resonance imaging study, we used dynamic causal modeling (DCM) to investigate effective connectivity between left IFJ, ACC, and VTA in a task-switching paradigm comprising three distinct motivational conditions (prospective monetary reward or punishment and a control condition). We found that while prospective punishment significantly facilitated switching between tasks on a behavioral level, interactions between IFJ, ACC, and VTA were characterized by modulations through prospective reward but not punishment. Our DCM results show that IFJ and VTA modulate ACC activity in parallel rather than by interaction to serve task demands in reward-based cognitive control. Our findings further demonstrate that prospective reward and punishment differentially affect neural control mechanisms to initiate decision-making.

Effects of galvanic vestibular stimulation on resting state brain activity in patients with bilateral vestibulopathy.

We examined the effect of galvanic vestibular stimulation (GVS) on resting state brain activity using fMRI (rs-fMRI) in patients with bilateral vestibulopathy. Based on our previous findings, we hypothesized that GVS, which excites the vestibular nerve fibers, (a) increases functional connectivity in temporoparietal regions processing vestibular signals, and (b) alleviates abnormal visual-vestibular interaction. Rs-fMRI of 26 patients and 26 age-matched healthy control subjects was compared before and after GVS. The stimulation elicited a motion percept in all participants. Using different analyses (degree centrality, DC; fractional amplitude of low frequency fluctuations [fALFF] and seed-based functional connectivity, FC), group comparisons revealed smaller rs-fMRI in the right Rolandic operculum of patients. After GVS, rs-fMRI increased in the right Rolandic operculum in both groups and in the patients' cerebellar Crus 1 which was related to vestibular hypofunction. GVS elicited a fALFF increase in the visual cortex of patients that was inversely correlated with the patients' rating of perceived dizziness. After GVS, FC between parietoinsular cortex and higher visual areas increased in healthy controls but not in patients. In conclusion, short-term GVS is able to modulate rs-fMRI in healthy controls and BV patients. GVS elicits an increase of the reduced rs-fMRI in the patients' right Rolandic operculum, which may be an important contribution to restore the disturbed visual-vestibular interaction. The GVS-induced changes in the cerebellum and the visual cortex were associated with lower dizziness-related handicaps in patients, possibly reflecting beneficial neural plasticity that might subserve visual-vestibular compensation of deficient self-motion perception.

Imaging gradual neurodegeneration in a basal ganglia model disease.

OBJECTIVE: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present. METHODS: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls. RESULTS: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004). INTERPRETATION: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526.

Neural basis of shame and guilt experience in women with borderline personality disorder.

Borderline personality disorder (BPD) is characterized by instability of affect, emotion dysregulation, and interpersonal dysfunction. Especially shame and guilt, so-called self-conscious emotions, are of central clinical relevance to BPD. However, only few experimental studies have focused on shame or guilt in BPD and none investigated their neurobiological underpinnings. In the present functional magnetic resonance imaging study, we took a scenario-based approach to experimentally induce feelings of shame, guilt, and disgust with neutral scenarios as control condition. We included 19 women with BPD (age 26.4 ± 5.8 years; DSM-IV diagnosed; medicated) and 22 healthy female control subjects (age 26.4 ± 4.6 years; matched for age and verbal IQ). Compared to controls, women with BPD reported more intense feelings when being confronted with affective scenarios, especially higher levels of shame, guilt, and fear. We found increased amygdala reactivity in BPD compared to controls for shame and guilt, but not for disgust scenarios (p = 0.05 FWE corrected at the cluster level; p < 0.0001 cluster defining threshold). Exploratory analyses showed that this was caused by a diminished habituation in women with BPD relative to control participants. This effect was specific to guilt and shame scenarios as both groups showed amygdala habituation to disgust scenarios. Our work suggests that heightened shame and guilt experience in BPD is not related to increased amygdala activity per se, but rather to decreased habituation to self-conscious emotions. This provides an explanation for the inconsistencies in previous imaging work on amygdala involvement in BPD as well as the typically slow progress in the psychotherapy of dysfunctional self-conscious emotions in this patient group.

Viewing socio-affective stimuli increases connectivity within an extended default mode network.

Empathy is an essential ability for prosocial behavior. Previous imaging studies identified a number of brain regions implicated in affective and cognitive aspects of empathy. In this study, we investigated the neural correlates of empathy from a network perspective using graph theory and beta-series correlations. Two independent data sets were acquired using the same paradigm that elicited empathic responses to socio-affective stimuli. One data set was used to define the network nodes and modular structure, the other data set was used to investigate the effects of emotional versus neutral stimuli on network connectivity. Emotional relative to neutral stimuli increased connectivity between 74 nodes belonging to different networks. Most of these nodes belonged to an extended default mode network (eDMN). The other nodes belonged to a cognitive control network or visual networks. Within the eDMN, posterior STG/TPJ regions were identified as provincial hubs. The eDMN also showed stronger connectivity to the cognitive control network encompassing lateral PFC regions. Connector hubs between the two networks were posterior cingulate cortex and ventrolateral PFC. This stresses the advantage of a network approach as regions similarly modulated by task conditions can be dissociated into distinct networks and regions crucial for network integration can be identified.

Hippocampal gray matter volume in bilateral vestibular failure.

Bilateral vestibular failure (BVF) is a severe chronic disorder of the labyrinth or the eighth cranial nerve characterized by unsteadiness of gait and disabling oscillopsia during head movements. According to animal data, vestibular input to the hippocampus is proposed to contribute to spatial memory and spatial navigation. Except for one seminal study showing the association of impaired spatial navigation and hippocampal atrophy, patient data in BVF are lacking. Therefore, we performed a voxel-wise comparison of the hippocampal gray matter volume (GMV) in a clinically representative sample of 27 patients with incomplete BVF and 29 age- and gender-matched healthy controls to test the hypothesis of hippocampal atrophy in BVF. Although the two groups did not generally differ in their hippocampal GMV, a reduction of GMV in the bilateral hippocampal CA3 region was significantly correlated with increased vestibulopathy-related clinical impairment. We propose that GMV reduction in the hippocampus of BVF patients is related to the severity of vestibular-induced disability which is in line with combined hippocampal atrophy and disorders of spatial navigation in complete vestibular deafferentation due to bilateral nerve section. Clinically, however, the most frequent etiologies of BVF cause incomplete lesions. Accordingly, hippocampus atrophy and deficits in spatial navigation occur possibly less frequently than previously suspected. Hum Brain Mapp 37:1998-2006, 2016. © 2016 Wiley Periodicals, Inc.

Orbitofrontal Cortex Reactivity to Angry Facial Expression in a Social Interaction Correlates with Aggressive Behavior.

Altered neural processing of social signals such as angry facial expressions has been associated with increased aggressive behavior, but evidence for this relationship in healthy persons using ecologically valid experimental designs is lacking. We presented socially relevant videos of facial expressions in a functional magnetic resonance imaging (fMRI) version of the well-established Taylor Aggression Paradigm and investigated 41 healthy male participants, of whom 32 were included in the analysis. In each round of this competitive reaction time task, participants observed their opponent while he selected a punishment level for him, bearing either a neutral or angry facial expression. Afterward, participants in turn selected a punishment level for their opponent. Across participants, reactivity of the medial orbitofrontal cortex (OFC) to angry facial expressions was negatively related to aggressive behavior. Within participants and across trials, activity in the anterior cingulate cortex (ACC) was positively related to aggressive behavior specifically in response to angry expressions. Moreover, we found an effect of angry expressions on neural activity patterns during later stages of the task, demonstrating that the effect of angry expressions on neural reactivity is more than just a short-lived, stimulus-driven response. Our results underscore the importance of OFC and ACC for the shaping of socially adaptive responses to provocation.

Decreased limbic and increased fronto-parietal connectivity in unmedicated patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and ritualized, repetitive behaviors, or mental acts. Convergent experimental evidence from neuroimaging and neuropsychological studies supports an orbitofronto-striato-thalamo-cortical dysfunction in OCD. Moreover, an over excitability of the amygdala and over monitoring of thoughts and actions involving the anterior cingulate, frontal and parietal cortex has been proposed as aspects of pathophysiology in OCD. We chose a data driven, graph theoretical approach to investigate brain network organization in 17 unmedicated OCD patients and 19 controls using resting-state fMRI. OCD patients showed a decreased connectivity of the limbic network to several other brain networks: the basal ganglia network, the default mode network, and the executive/attention network. The connectivity within the limbic network was also found to be decreased in OCD patients compared to healthy controls. Furthermore, we found a stronger connectivity of brain regions within the executive/attention network in OCD patients. This effect was positively correlated with disease severity. The decreased connectivity of limbic regions (amygdala, hippocampus) may be related to several neurocognitive deficits observed in OCD patients involving implicit learning, emotion processing and expectation, and processing of reward and punishment. Limbic disconnection from fronto-parietal regions relevant for (re)-appraisal may explain why intrusive thoughts become and/or remain threatening to patients but not to healthy subjects. Hyperconnectivity within the executive/attention network might be related to OCD symptoms such as excessive monitoring of thoughts and behavior as a dysfunctional strategy to cope with threat and uncertainty.

Altered brain functional connectivity in patients with resistance to thyroid hormone ß.

To investigate changes in brain network organization and possible neurobehavioral similarities to attention-deficit hyperactivity disorder (ADHD), we measured changes in brain resting-state functional connectivity (rs-fMRI) and cognitive domains in patients with resistance to thyroid hormone ß (RTHß) and compared them with those in healthy control subjects. In this prospective case-control study, twenty-one participants with genetically confirmed RTHß were matched with 21 healthy controls. The Adult ADHD Self-Report Scale (ASRS-v1.1) and ADHD Rating Scale-IV were used to assess self-reported symptoms of ADHD. A voxel-wise and atlas-based approach was used to identify changes in the brain networks. The RTHß group reported behavioral symptoms similar to those of ADHD. We found evidence of weaker network integration of the lingual and fusiform gyri in the RTHß group, which was mainly driven by weaker connectivity to the bilateral insula and supplementary motor cortex. Functional connectivity between regions of the default mode network (angular gyrus/middle temporal gyrus) and regions of the cognitive control network (bilateral middle frontal gyrus) was increased in RTHß patients compared to healthy controls. Increased connectivity between regions of the default mode network and the dorsolateral prefrontal cortex is frequently reported in ADHD and is interpreted to be associated with deficits in attention. Our finding of weaker connectivity of the lingual gyrus to the bilateral insula (salience network) in RTHß patients has also been reported previously in ADHD and may reflect decreased habituation to visual stimuli and increased distractibility. Overall, our observations support the notion of neuropsychological similarities between RTHß and ADHD.

Basal forebrain activity predicts functional degeneration in the entorhinal cortex in Alzheimer's disease.

Recent models of Alzheimer's disease suggest the nucleus basalis of Meynert (NbM) as an early origin of structural degeneration followed by the entorhinal cortex (EC). However, the functional properties of NbM and EC regarding amyloid-ß and hyperphosphorylated tau remain unclear. We analysed resting-state functional fMRI data with CSF assays from the Alzheimer's Disease Neuroimaging Initiative (n = 71) at baseline and 2 years later. At baseline, local activity, as quantified by fractional amplitude of low-frequency fluctuations, differentiated between normal and abnormal CSF groups in the NbM but not EC. Further, NbM activity linearly decreased as a function of CSF ratio, resembling the disease status. Finally, NbM activity predicted the annual percentage signal change in EC, but not the reverse, independent from CSF ratio. Our findings give novel insights into the pathogenesis of Alzheimer's disease by showing that local activity in NbM is affected by proteinopathology and predicts functional degeneration within the EC.

Basal forebrain activity predicts functional degeneration in the entorhinal cortex and decreases with Alzheimer's Disease progression.

BACKGROUND AND OBJECTIVES: Recent models of Alzheimer's Disease (AD) suggest the nucleus basalis of Meynert (NbM) as the origin of structural degeneration followed by the entorhinal cortex (EC). However, the functional properties of NbM and EC regarding amyloid-ß and hyperphosphorylated tau remain unclear. METHODS: We analyzed resting-state (rs)fMRI data with CSF assays from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=71) at baseline and two years later. RESULTS: At baseline, local activity, as quantified by fractional amplitude of low-frequency fluctuations (fALFF), differentiated between normal and abnormal CSF groups in the NbM but not EC. Further, NbM activity linearly decreased as a function of CSF ratio, resembling the disease status. Finally, NbM activity predicted the annual percentage signal change in EC, but not the reverse, independent from CSF ratio. DISCUSSION: Our findings give novel insights into the pathogenesis of AD by showing that local activity in NbM is affected by proteinopathology and predicts functional degeneration within the EC.

Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations.

BACKGROUND: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. METHODS: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. CONCLUSION: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined.

Benefit from retrieval practice is linked to temporal and frontal activity in healthy young and older humans.

Retrieval practice improves retention of information in long-term memory more than restudy, but the underlying neural mechanisms of this "retrieval practice effect" (RPE) remain poorly understood. Therefore, we investigated the behavioral and neural differences between previously retrieved versus restudied items at final retrieval. Thirty younger (20-30 years old) and twenty-five older (50+ years old) adults learned familiar and new picture stimuli either through retrieval or restudy. At final recognition, hemodynamic activity was measured using functional magnetic resonance imaging (fMRI). Behaviorally, younger and older adults showed similar benefits of retrieval practice, with higher recollection, but unchanged familiarity rates. In a univariate analysis of the fMRI data, activation in medial prefrontal cortex and left temporal regions correlated with an individual's amount of behavioral benefit from retrieval practice, irrespective of age. Compatible with this observation, in a multivariate representational similarity analysis (RSA), retrieval practice led to an increase in pattern similarity for retested items in a priori defined regions of interest, including the medial temporal lobe, as well as prefrontal and parietal cortex. Our findings demonstrate that retrieval practice leads to enhanced long-term memories in younger and older adults alike, and this effect may be driven by fast consolidation processes.

Structural covariance of amygdala subregions is associated with trait aggression and endogenous testosterone in healthy individuals.

Many studies point toward volume reductions in the amygdala as a potential neurostructural marker for trait aggression. However, most of these findings stem from clinical samples, rendering unclear whether the findings generalize to non-clinical populations. Furthermore, the notion of neural networks suggests that interregional correlations in gray matter volume (i.e., structural covariance) can explain individual differences in aggressive behavior beyond local univariate associations. Here, we tested whether structural covariance between amygdala subregions and the rest of the brain is associated with self-reported aggression in a large sample of healthy young students (n = 263; 49% women). Salivary testosterone concentrations were measured for a subset of n = 40 male and n = 36 female subjects, allowing us to investigate the influence of endogenous testosterone on structural covariance. Aggressive individuals showed enhanced covariance between left superficial amygdala (SFA) and left dorsal anterior insula (dAI), but lower covariance between right laterobasal amygdala (LBA) and right dorsolateral prefrontal cortex (dlPFC). These structural patterns overlap with functional networks involved in the genesis and regulation of aggressive behavior, respectively. With increasing endogenous testosterone, we observed stronger structural covariance between right centromedial amygdala (CMA) and right medial prefrontal cortex in men and between left CMA and bilateral orbitofrontal cortex in women. These results speak for structural covariance of amygdala subregions as a robust correlate of trait aggression in healthy individuals. Moreover, regions that showed structural covariance with the amygdala modulated by either testosterone or aggression did not overlap, suggesting a complex role of testosterone in human social behavior beyond facilitating aggressiveness.

Increased Subcortical Sodium Levels in Patients with Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disease characterized by an aggressive disease course. Total and intracellular-weighted sodium imaging (23Na-MRI) is a promising method for investigating neurodegeneration in vivo. We enrolled 10 patients with PSP and 20 age- and gender-matched healthy control subjects; all study subjects underwent a neurological examination, whole-brain structural, and (total and intracellular-weighted) 23Na-MRI. Voxel-wise analyses revealed increased brainstem total sodium content in PSP that correlated with disease severity. The ROI-wise analysis highlighted additional sodium level changes in other regions implicated in the pathophysiology of PSP. 23Na-MRI yields substantial benefits for the diagnostic workup of patients with PSP and adds complementary information on the underlying neurodegenerative tissue changes in PSP.

Assessment of Bioenergetic Deficits in Patients With Parkinson Disease and Progressive Supranuclear Palsy Using 31P-MRSI.

BACKGROUND: Bioenergetic disturbance, mainly caused by mitochondrial dysfunction, is an established pathophysiological phenomenon in neurodegenerative movement disorders. The in vivo assessment of brain energy metabolism by 31phosphorus magnetic resonance spectroscopy imaging could provide pathophysiological insights and serve in the differential diagnosis of parkinsonian disorders. In this study, we investigated such aspects of the underlying pathophysiology in patients with idiopathic Parkinson's disease (PwPD) and progressive supranuclear palsy (PwPSP). METHODS: In total, 30 PwPD, 16 PwPSP, and 25 healthy control subjects (HCs) underwent a clinical examination, structural magnetic resonance imaging, and 31phosphorus magnetic resonance spectroscopy imaging of the forebrain and basal ganglia in a cross-sectional study. RESULTS: High-energy phosphate metabolites were remarkably decreased in PwPD, particularly in the basal ganglia (-42% compared with healthy controls and -43% compared with PwPSP, p<.0001). This result was not confounded by morphometric brain differences. In contrast, PwPSP had normal levels of high-energy energy metabolites. Thus, the combination of morphometric and metabolic neuroimaging was able to discriminate PwPD from PwPSP with an accuracy of up to 0.93 [95%-CI: 0.91, 0.94]. DISCUSSION: Our study shows that mitochondrial dysfunction and bioenergetic depletion contribute to idiopathic Parkinson's disease pathophysiology but not to progressive supranuclear palsy. Combined morphometric and metabolic imaging could serve as an accompanying diagnostic biomarker in the neuroimaging-guided differential diagnosis of these parkinsonian disorders.

Precuneus connectivity and symptom severity in chronic depression✰.

Although abnormal resting state connectivity within several brain networks has been repeatedly reported in depression, little is known about connectivity in patients with early onset chronic depression. We compared resting state connectivity in a homogenous sample of 32 unmedicated patients with early onset chronic depression and 40 healthy control participants in a seed-to-voxel-analysis. According to previous meta-analyses on resting state connectivity in depression, 12 regions implicated in default mode, limbic, frontoparietal and ventral attention networks were chosen as seeds. We also investigated associations between connectivity values and severity of depression. Patients with chronic depression exhibited stronger connectivity between precuneus and right pre-supplementary motor area than healthy control participants, possibly reflecting aberrant information processing and emotion regulation deficits in depression. Higher depression severity scores (Hamilton Rating Scale for Depression) were strongly and selectively associated with weaker connectivity between the precuneus and the subcallosal anterior cingulate. Our findings correspond to results obtained in studies including both episodic and chronic depression. This suggests that there may be no strong differences between subtypes of depression regarding the seeds analyzed here. To further clarify this issue, future studies should directly compare patients with different courses of depression.

Reduced pituitary size in subjects with mutations in the THRB gene and thyroid hormone resistance.

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α, ß) with differential tissue distribution. Thyroid hormone receptor ß (TRß) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the ß form of the receptor (pituitary, liver). This study seeks to identify the effects of mutant TRß on pituitary size. Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHß in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist). Results: Patients with mutant TRß (resistance to thyroid hormone ß, RTHß) showed elevated free tri-iodothyronine/thyroxine levels with normal thyroid-stimulating hormone levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHß patients in comparison to healthy controls (F(1,35) = 7.05, P = 0.012, partial η2 = 0.17). Conclusion: RTHß subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.