Functional Connectivity Mechanisms Underlying Symptom Reduction Following Lisdexamfetamine Treatment in Binge-Eating Disorder: A Clinical Trial.

Background: Speculation exists as to whether lisdexamfetamine dimesylate (LDX) acts on the functional connectivity (FC) of brain networks that modulate appetite, reward, or inhibitory control in binge-eating disorder (BED). Better insights into its action may help guide the development of more targeted therapeutics and identify who will benefit most from this medication. Here, we use a comprehensive data-driven approach to investigate the brain FC changes that underlie the therapeutic action of LDX in patients with BED. Methods: Forty-six participants with moderate to severe BED received LDX titrated to 50 or 70 mg for an 8-week period. Twenty age-matched healthy control participants were also recruited. Resting-state functional magnetic resonance imaging was used to probe changes in brain FC pre- and post treatment and correlated with change in clinical measures. Results: Ninety-seven percent of trial completers (n = 31) experienced remission or a reduction to mild BED during the 8-week LDX trial. Widespread neural FC changes occurred, with changes in default mode to limbic, executive control to subcortical, and default mode to executive control networks associated with improvements in clinical outcomes. These connections were not distinct from control participants at pretreatment but were different from control participants following LDX treatment. Pretreatment connectivity did not predict treatment response. Conclusions: FC between networks associated with self-referential processing, executive function, and reward seem to underlie the therapeutic effect of LDX in BED. This suggests that LDX activates change via multiple systems, with most changes in compensatory networks rather than in those characterizing the BED diagnosis.

Functional Magnetic Resonance Imaging of the Amygdala and Subregions at 3 Tesla: A Scoping Review.

The amygdalae are a pair of small brain structures, each of which is composed of three main subregions and whose function is implicated in neuropsychiatric conditions. Functional Magnetic Resonance Imaging (fMRI) has been utilized extensively in investigation of amygdala activation and functional connectivity (FC) with most clinical research sites now utilizing 3 Tesla (3T) MR systems. However, accurate imaging and analysis remains challenging not just due to the small size of the amygdala, but also its location deep in the temporal lobe. Selection of imaging parameters can significantly impact data quality with implications for the accuracy of study results and validity of conclusions. Wide variation exists in acquisition protocols with spatial resolution of some protocols suboptimal for accurate assessment of the amygdala as a whole, and for measuring activation and FC of the three main subregions, each of which contains multiple nuclei with specialized roles. The primary objective of this scoping review is to provide a broad overview of 3T fMRI protocols in use to image the activation and FC of the amygdala with particular reference to spatial resolution. The secondary objective is to provide context for a discussion culminating in recommendations for a standardized protocol for imaging activation of the amygdala and its subregions. As the advantages of big data and protocol harmonization in imaging become more apparent so, too, do the disadvantages of data heterogeneity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Common and differential neural mechanisms underlying mood disorders.

BACKGROUND: Despite homogenous clinical presentations between bipolar and unipolar disorders, there are distinct neurobiological differences. Chronicity of illness may be a factor impacting and sustaining certain neural features. The goal of this study was to investigate common and shared neural mechanisms underlying mood disorders, and possible sustained neural changes relating to illness chronicity by investigating a cohort of euthymic patients with bipolar disorder (BD), unipolar depression who had responded to treatment (treatment-sensitive depression, TSD), and a chronically treatment-resistant depressed (TRD) group. METHODS: One hundred and seventy-two participants (40 BD, 39 TSD, 40 TRD, and 53 age-gender-matched healthy controls) underwent resting-state fMRI scans. Seed-based and independent component analyses were performed to investigate group differences in resting-state connectivity between the four groups. RESULTS: All three clinical groups had significantly lower connectivity within the frontoparietal network (FPN) relative to controls. TRD and BD were significantly different from TSD (TRD, BD > TSD) but were not significantly different from each other. TRDs were also significantly different from both BD and TSD for salience network connectivity with the posterior cingulate (DMN) and the FPN with frontal pole (DMN). Additionally, the BD group exhibited greater DMN-FPN (sgACC-RDLPFC) connectivity relative to TRD, TSD, and controls, which was correlated with a previous number of depressive episodes, in the BD group only. CONCLUSIONS: BD demonstrated shared and differential connectivity features relative to symptomatic TRD and euthymic TSD groups. The increased sgACC-RDLPFC connectivity in BD and its correlation with a number of depressive episodes could be a neural feature associated with illness chronicity.

Comparative assessment of motion averaged free-breathing or breath-held cardiac magnetic resonance imaging protocols in a porcine myocardial infarction model.

Breath-held (BH) cardiac magnetic resonance imaging (CMR) is the gold standard for volumetric quantification. However, large animals for pre-clinical research are unable to voluntarily breath-hold, necessitating general anaesthesia and mechanical ventilation, increasing research costs and affecting cardiovascular physiology. Conducting CMR in lightly sedated, free-breathing (FB) animal subjects is an alternative strategy which can overcome these constraints, however, may result in poorer image quality due to breathing motion artefact. We sought to assess the reproducibility of CMR metrics between FB and BH CMR in a porcine model of ischaemic cardiomyopathy. FB or BH CMR was performed in 38 porcine subjects following percutaneous induction of myocardial infarction. Analysis was performed by two independent, blinded observers according to standard reporting guidelines. Subjective and objective image quality was significantly improved in the BH cohort (image quality score: 3.9/5 vs. 2.4/5; p < 0.0001 and myocardium:blood pool intensity ratio: 2.6-3.3 vs. 1.9-2.3; p < 0.001), along with scan acquisition time (4 min 06 s ± 1 min 55 s vs. 8 min 53 s ± 2 min 39 s; p < 0.000). Intra- and inter-observer reproducibility of volumetric analysis was substantially improved in BH scans (correlation coefficients: 0.94-0.99 vs. 0.76-0.91; coefficients of variation: < 5% in BH and > 5% in FB; Bland-Altman limits of agreement: < 10 in BH and > 10 in FB). Interstudy variation between approaches was used to calculate sample sizes, with BH CMR resulting in greater than 85% reduction in animal numbers required to show clinically significant treatment effects. In summary, BH porcine CMR produces superior image quality, shorter scan acquisition, greater reproducibility, and requires smaller sample sizes for pre-clinical trials as compared to FB acquisition.

Default-mode and fronto-parietal network connectivity during rest distinguishes asymptomatic patients with bipolar disorder and major depressive disorder.

Bipolar disorder (BD) is commonly misdiagnosed as major depressive disorder (MDD). This is understandable, as depression often precedes mania and is otherwise indistinguishable in both. It is therefore imperative to identify neural mechanisms that can differentiate the two disorders. Interrogating resting brain neural activity may reveal core distinguishing abnormalities. We adopted an a priori approach, examining three key networks documented in previous mood disorder literature subserving executive function, salience and rumination that may differentiate euthymic BD and MDD patients. Thirty-eight patients with BD, 39 patients with MDD matched for depression severity, and 39 age-gender matched healthy controls, completed resting-state fMRI scans. Seed-based and data-driven Independent Component analyses (ICA) were implemented to examine group differences in resting-state connectivity (pFDR < 0.05). Seed analysis masks were target regions identified from the fronto-parietal (FPN), salience (SN) and default-mode (DMN) networks. Seed-based analyses identified significantly greater connectivity between the subgenual cingulate cortex (DMN) and right dorsolateral prefrontal cortex (FPN) in BD relative to MDD and controls. The ICA analyses also found greater connectivity between the DMN and inferior frontal gyrus, an FPN region in BD relative to MDD. There were also significant group differences across the three networks in both clinical groups relative to controls. Altered DMN-FPN functional connectivity is thought to underlie deficits in the processing, management and regulation of affective stimuli. Our results suggest that connectivity between these networks could potentially distinguish the two disorders and could be a possible trait mechanism in BD persisting even in the absence of symptoms.

Intrinsic functional connectivity of the default mode and cognitive control networks relate to change in behavioral performance over two years.

Understanding how brain circuitry mediates cognitive control of behavior is crucial for understanding both mental health and disease. Cognitive control describes the group of behaviors that guide goal-directed action such as sustaining attention, processing information and inhibiting impulsive responses. We rely on these behaviors for daily social, occupational and emotional functioning. Two brain networks, the cognitive control network (CCN) and default mode network (DMN), are thought to cooperate in an inverse relationship to support these functions. However, we do not yet know how connectivity within and between these networks directly relates to healthy cognitive control behaviors, and whether these interactions change over time. Here, we employed a longitudinal design to investigate if change in intrinsic connectivity in these networks will correlate with change in a range of cognitive control functions. Over two years, 109 healthy individuals, aged eight to thirty-eight, were tested twice using fMRI to assess intrinsic functional connectivity of the CCN and DMN and a validated cognitive battery. We found that increased within-network connectivity through central and left DMN was associated with increased memory performance. Additionally, decreased connectivity between posterior parietal CCN and DMN nodes and decreased connectivity between left and right dorsolateral prefrontal nodes was associated with increased cognitive performance. These findings were age and gender controlled, suggesting that age-independent plastic change in intrinsic connectivity through these networks directly relate to changing behavior. This has implications for targeting intrinsic connectivity as a possible mechanism to improve cognitive function.

Cognitive ability is associated with changes in the functional organization of the cognitive control brain network.

Cognitive control is one of the most important skills in day-to-day social and intellectual functioning but we are yet to understand the neural basis of the group of behaviors required to carry this out. Here, we probed changes over time in the brain network associated with cognitive control (the dorsolateral prefrontal cortex, the dorsal posterior parietal cortex, and the dorsal anterior cingulate cortex) using both behavioral assays and functional brain imaging during a selective working memory task in 69 healthy participants within the age range 18-38 years (mean: 25, SD: ±6), assessed twice, 2 years apart. We aimed to explore the relationship of changing network activation and connectivity with behavioral tasks associated with cognitive control in this otherwise neurodevelopmentally stable group. We found that increased connectivity between frontoparietal cognitive control network regions during the working memory task was associated with improved memory and executive functions over the 2-year period and that this association was not impacted by age, gender, or baseline performance. These results provide evidence that changes in the functional organization of the cognitive control brain network occur despite the absence of neurodevelopment, aging or targeted cognitive training effects, and could modulate cognitive performance in early to mid-adulthood. Understanding how and why this change is occurring could provide insights into the mechanisms through which cognitive control ability is cultivated over time. This could aid in the development of interventions in cases where cognitive control is impaired.

Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.

BACKGROUND AND OBJECTIVE: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests. METHODS: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed. RESULTS: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials. CLINICAL TRIAL REGISTRATION: NCT01676077.

Grey matter abnormalities in children and adolescents with functional neurological symptom disorder.

OBJECTIVE: Functional neurological symptom disorder refers to the presence of neurological symptoms not explained by neurological disease. Although this disorder is presumed to reflect abnormal function of the brain, recent studies in adults show neuroanatomical abnormalities in brain structure. These structural brain abnormalities have been presumed to reflect long-term adaptations to the disorder, and it is unknown whether child and adolescent patients, with illness that is typically of shorter duration, show similar deficits or have normal brain structure. METHOD: High-resolution, three-dimensional T1-weighted magnetic resonance images (MRIs) were acquired in 25 patients (aged 10-18 years) and 24 healthy controls. Structure was quantified in terms of grey matter volume using voxel-based morphometry. Post hoc, we examined whether regions of structural difference related to a measure of motor readiness to emotional signals and to clinical measures of illness duration, illness severity, and anxiety/depression. RESULTS: Patients showed greater volumes in the left supplementary motor area (SMA) and right superior temporal gyrus (STG) and dorsomedial prefrontal cortex (DMPFC) (corrected p < 0.05). Previous studies of adult patients have also reported alterations of the SMA. Greater SMA volumes correlated with faster reaction times in identifying emotions but not with clinical measures. CONCLUSIONS: The SMA, STG, and DMPFC are known to be involved in the perception of emotion and the modulation of motor responses. These larger volumes may reflect the early expression of an experience-dependent plasticity process associated with increased vigilance to others' emotional states and enhanced motor readiness to organize self-protectively in the context of the long-standing relational stress that is characteristic of this disorder.

Cognitive control network anatomy correlates with neurocognitive behavior: A longitudinal study.

Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 8-38 years. One hundred and eleven of these also completed a longitudinal follow-up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age-independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631-643, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Chronic effects of dietary vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease.

Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by ∼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement.

Young Australian adults with NF1 have poor access to health care, high complication rates, and limited disease knowledge.

Neurofibromatosis type 1 (NF1) is a multisystem disease associated with a lifelong risk of debilitating and potentially life-limiting complications, however many adults with NF1 have no regular health surveillance. We interviewed and examined 17 young adults with NF1 between the ages of 25 and 33. Most had not been assessed for NF1-related complications within the previous 8 years, including patients with known serious vascular complications, for example, renal artery stenosis. Acute and/or chronic pain, particularly back and plexiform-related pain were common symptoms, and despite a significant impact on quality of life, was untreated in most instances. Symptom and examination-directed imaging revealed serious complications in 41% of the cohort. These included severe spinal cord compression (two cases), a highly SUV avid lesion suggestive of malignancy (one case), and a Juvenile Pilocytic Astrocytoma in a patient without any previous NF1-related complications. Few study participants had a good understanding of NF1, its associated risks and complications, and many had not sought appropriate medical advice as questions or problems arose. NF1-related cognitive deficits in some participants, and the lack of a clear source of expert medical advice for adults with NF1 likely contributed to poor health surveillance and management in this population. Overall, these findings suggest that many Australian adults with NF1 are at risk of serious and life-threatening medical complications, but are not accessing and receiving adequate health care. Access to multidisciplinary adult clinics that specialize in NF1 may address many of the unmet health needs of young adults with NF1.

Use of 3T MRI and an unspoiled 3D fast gradient echo sequence for porcine knee cartilage volumetry: preliminary findings.

PURPOSE: To assess the utility of knee cartilage volumetry using an unspoiled fat-suppressed 3D fast gradient echo (FGRE) sequence at 3T. MATERIALS AND METHODS: Sagittal magnetic resonance (MR) images were obtained with an unspoiled fat-suppressed 3D FGRE sequence in eight porcine knees. Manual segmentation was used to derive the cartilage volume. This volume was compared to a volume measurement of cartilage scraping specimens obtained by water displacement. Imaging was repeated five times in four of the knees to assess interscan volume measurement reproducibility and calculate precision error. A single 3D dataset was manually segmented five times at weekly intervals to assess intraobserver volume measurement reproducibility. RESULTS: Total cartilage volume obtained from MRI and water displacement correlated well (r = 0.75). The interscan reproducibility of total volume measurements, expressed as the coefficient of variation (CV), was 4.2%, and the precision error (root mean square [RMS] CV) was 4.1%. The CV of intraobserver estimates of total cartilage volume by MRI was 3.6%. CONCLUSION: Interscan reproducibility of quantification of total cartilage volume and reproducibility of the manual segmentation technique were both high (>95%). Accurate and reproducible cartilage volumetry can be obtained by using a clinical unspoiled fat-suppressed 3D FGRE acquired at 3T MRI.