Machine Learning on a Genome-Wide Association Study to Predict Late Genitourinary Toxicity Following Prostate Radiotherapy

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sangkyu Lee, Sarah Kerns, Harry Ostrer, Barry Rosenstein, Joseph O. Deasy, Jung Hun Oh
PurposeLate genitourinary (GU) toxicity after radiotherapy limits the quality of life of prostate cancer survivors, but efforts to explain GU toxicity using patient/dose information remain unsuccessful. We aimed to identify patients with higher congenital GU toxicity risk by identifying and integrating patterns in genome-wide single nucleotide polymorphisms (SNPs).Materials and MethodsWe applied a pre-conditioned random forest regression (PRFR) method for predicting risk from the genome-wide data to combine the effects of multiple SNPs and overcome statistical power limitations of single-SNP analysis. We studied a cohort of 324 prostate cancer patients who were self-assessed for four urinary symptoms at 2 years after radiotherapy using the International Prostate Symptom Score.ResultsThe predictive accuracy of the methodology varied across symptoms. Only for the weak stream endpoint, it achieved a significant area under the curve of 0.70 (95% confidence interval: 0.54 – 0.86, p = 0.01) on hold-out validation data that outperformed competing methods. Gene ontology analysis highlighted key biological processes, such as neurogenesis and ion transport, from the genes known to be important for urinary tract functions.ConclusionWe applied machine learning methods and bioinformatics tools to genome-wide data to predict and explain GU toxicity. Our approach enabled designing a more powerful predictive model and finding plausible biomarkers and biological processes associated with GU toxicity.



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Protective effects of flagellin A N/C against radiation-induced NLR pyrin domain containing 3 inflammasome-dependent pyroptosis in intestinal cells

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Dongming Wu, Rong Han, Shihua Deng, Teng Liu, Ting Zhang, Hongxiang Xie, Ying Xu
PurposeRadiation-induced enteropathy is among the most prevalent dose-limiting radiation toxicities. Despite its prevalence and burden, there are currently no effective treatments for radiation-induced intestinal injury, and understanding of this pathology remains poor. The present study aimed to investigate changes induced in mouse intestines after irradiation and to explore the potential radioprotective effects of flagellin A (FlaA) N/C.MethodsA mouse model of radiation-induced enteropathy was used in this study. A 10 Gy abdominal irradiation was performed on FlaA N/C- and vehicle-injected mice to explore the role of FlaA N/C in intestinal radiation injury and to study the molecular mechanism in this process. In the intestinal tissue, pathological changes were investigated by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry; western blotting and quantitative reverse transcription polymerase chain reaction were used to determine the changes in protein and mRNA levels, respectively; and an enzyme-linked immunosorbent assay was performed to determine protein concentration in serum. The involvement of the ROS pathway was investigated by determining superoxide dismutase, glutathione (GSH) peroxidase, GSH reductase (GR), and GSH disulfide (GSSG) plus GSH (GSSG + GSH) activities.ResultsFlaAN/C inhibited radiation-induced ROS production, decreased NLRP3 activity, and reduced the occurrence of caspase-1-dependent pyroptosis. The results revealed that oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in radiation-induced intestinal injury. FlaAN/C exerted a protective effect by blunting the activation of NLRP3 inflammasome signaling, thereby reducing the inflammatory response and occurrence of caspase-1-dependent pyroptosis in the intestine. Therefore, treatment of mice with FlaAN/C reduced radiation-induced intestinal injury.ConclusionROS-induced NLRP3 inflammasomes mediated radiation-induced pyroptosis of the intestinal cells, and FlaAN/C suppressed pyroptosis to protect the intestinal tissue. These results provide novel insights into the mechanisms underlying radiation-induced cytotoxicity, and FlaAN/C might be a potential preventive therapy for radiation-induced intestinal injury in patients with cancer.



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Sensitization of hypoxic tumors to radiation therapy using ultrasound sensitive oxygen microbubbles

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): John R. Eisenbrey, Rawan Shraim, Ji-Bin Liu, Jingzhi Li, Maria Stanczak, Brian Oeffinger, Dennis B. Leeper, Scott W. Keith, Lauren J. Jablonowski, Flemming Forsberg, Patrick O'Kane, Margaret A. Wheatley
Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment which has been shown to result in both chemo- and radiotherapy resistance. Systemic delivery of oxygen prior to therapy has proven largely ineffective in reversing this resistance. Surfactant-shelled oxygen microbubbles that can be injected intravenously and used to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound have been previously reported. In this work, we show that these agents successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline or untriggered oxygen microbubbles (p < 0.001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (p < 0.03). Findings from this study demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform.



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Use of radiation within the last year of life among cancer patients

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yolanda D. Tseng, Nathan W. Gouwens, Simon S. Lo, Lia M. Halasz, Phil Spady, Irina Mezheritsky, Elizabeth Loggers
BackgroundWe examined radiotherapy (RT) utilization within the last year of life (LYOL). As palliative RT (PRT) has been well studied in patients with ≥6-week life expectancies, we hypothesized that PRT use would be constant over the LYOL, except for the last 30 days, when use would decline given lack of prospective data supporting its use.MethodsAt a single institution, 870 cancer patients died between 10/1/2014-9/30/2015 and had ≥3 evaluation and management visits within the LYOL. Claims and RT data were extracted and linked. Over the LYOL, we evaluated RT utilization by intent (curative versus palliative) and indications.ResultsWithin the LYOL, one-third of patients (RT365) underwent RT to 444 sites, which decreased to 24.3% and 8.5% in the last 180 and 30 days of life, respectively. RT365 patients were younger at death and had a higher proportion of lung, sarcoma, and transplant disease groups. One-quarter of sites were irradiated with curative intent, which remained constant over the LYOL. In contrast, PRT was utilized at a supralinear rate, in which treatment of bone metastases and use of single-fraction PRT increased closer to death.ConclusionsPRT appears to be disproportionately utilized closer to death with an increasing proportion of irradiated sites being bone metastases. This may be secondary to increased symptoms from advanced cancer toward the end of life (EOL). As patients with very poor prognosis (e.g. within 30 days of death) are generally not included in RT clinical trials, further studies are warranted to assess whether PRT for bone metastases at the EOL is efficacious.

Teaser

Utilization of RT over the last year of life among cancer patients is not well characterized. In this large, single institution retrospective study, we found that RT is variably used across histologies and over the last year of life, with palliative RT being disproportionately delivered closer to death.


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Head and Neck Tumor Control Probability: Radiation Dose-Volume Effects in SBRT for Locally-Recurrent Previously-Irradiated Head and Neck Cancer

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): John A. Vargo, Vitali Moiseenko, Jimm Grimm, Jimmy Caudell, David A. Clump, Ellen Yorke, Jinyu Xue, Yevgeniy Vinogradskiy, Eduardo G. Moros, Panayiotis Mavroidis, Sheena Jain, Issam El Naqa, Lawrence B. Marks, Dwight E. Heron
Stereotactic Body Radiotherapy (SBRT) as emerged as a viable re-irradiation strategy for locally-recurrent previously-irradiated head-and-neck cancer. Doses in the literature have varied which challenges clinical application of SBRT as well as clinical trial design. A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally-recurrent previously-irradiated head and neck cancer. Dose response models are generated that present tumor control probability as a function of dose. Data from over 300 cases in 8 publications suggests that there is a dose-response relationship with superior local control and possibly improved overall survival, for doses of 35-45Gy (in 5 fractions) compared to <30 Gy. SBRT doses equivalent to 5 fraction doses of 40-50Gy are suggested for re-treatment.

Teaser

In a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally-recurrent previously-irradiated head-and-neck cancer, data from over 300 cases in 8 publications suggests that there is a dose-response relationship with superior local control and possibly improved overall survival, for doses of 35-45Gy (in 5 fractions) compared to <30 Gy. SBRT doses equivalent to 5 fraction doses of 40-50Gy are suggested for re-treatment.


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Patterns of Failure in Patients with Double Hit or Double Expressor Lymphomas: Implications for Radiation Therapy

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vasu Tumati, Lakshya Trivedi, Hsiao-Ching Li, Prapti Patel, Pier P. Scaglioni, Madhuri Vusirikala, Navid Sadeghi, Syed Rizvi, Weina Chen, Jason Wachsmann, Robert Collins, Neil B. Desai
PurposeLymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL-2 protein overexpression, classified as double-hit (DHL) or double expressor (DEL) lymphomas respectively, are associated with poorer response to standard immunochemotherapy. Optimal therapy is not clear, and little information exists on the contribution of consolidative radiotherapy in these patients. This study describes the patterns of failure of DHL/DEL in relation to initial sites of disease and indications for radiotherapy in unselected diffuse large B-cell lymphoma (DLBCL).Materials/MethodsA retrospective single institution study of all patients diagnosed with non-Hodgkin lymphoma between 2011 and 2015 was performed. DHL status was determined by fluorescence in-situ hybridization, and DEL status was determined by immunohistochemistry. Progression-free survival (PFS) was calculated from the end of chemotherapy using the Kaplan-Meier method. Cox modeling was used for multivariable analysis.ResultsScreening of 275 DLBCL patients yielded a fifty-three patient cohort, including 32 patients with DHL, 10 with DEL, 9 with a triple-rearrangement, and 2 triple expressors. Of the 26 patients whose disease progressed, 15 had primary refractory disease. The remaining 11 failures were relapses following complete response to initial chemotherapy. Of these, 6 (55%) failed at initially involved site(s), and 4 (36%) were isolated initial site relapses. Consolidative radiotherapy was associated significantly with improved PFS on multivariable analysis (hazard ratio 0.17, 95% CI 0.02-0.94, p=0.04).ConclusionDHL/DEL are associated with high relapse rates which preferentially occur at initially involved sites. Amongst patients achieving complete response to chemotherapy, consolidative radiotherapy was associated with improved PFS. This provides a rationale for the continued role of RT in the treatment of DHL and DEL and requires validation in larger cohort.



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In a Heartbeat: An Assessment of Dynamic Dose Variation to Cardiac Structures using Dual Source Computed Tomography

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Houda Bahig, Jacques de Guise, Toni Vu, Danis Blais, Carl Chartrand-Lefebvre, Nhu Tram Nguyen, Sophie Lavertu, Jean-Pierre Guay, David Roberge
PurposeTo assess radiation dose variation to the left anterior descending artery (LAD), left main coronary artery (LMCA), left ventricle (LV) and whole heart (WH) during the cardiac cycle using dual source computed tomography (DSCT).MethodsThis prospective study included patients with left breast cancer planned for tangential radiotherapy. An electrocardiogram-synchronized contrast-injected DSCT was obtained in treatment position, in deep-inspiration breath-hold (DIBH), using retrospective sequential acquisition. WH, LV, LMCA as well as proximal, middle and distal LAD segments were contoured on each phase of the cardiac cycle. Maximum, minimum and mean Hausdorff distance between each structure and the tangential fields was assessed in ventricular systole vs. diastole. Four-dimensional dose-volume histograms were used to compare systolic vs. diastolic dosimetries.ResultsTen patients were enrolled. Average maximum, minimum and mean Hausdorff distance variation from systole to diastole was ≤4 mm for LV and LMCA, and ≤3 mm for the heart and LAD segments. WH maximum dose and volume receiving 5Gy were decreased in systole vs. diastole (42.9 Gy vs. 44.5 Gy, p=0.03 and 21.7 cm3 vs. 27.7 cm3, p=0.01), but mean dose remained similar throughout the cycle. Maximum and mean dose to distal LAD was 21.2 Gy vs. 26.6 Gy (p=0.005) and 8.6 Gy vs. 13.2 Gy (p=0.006), in systole vs. diastole, respectively. Maximum and mean dose to middle LAD was 18.4 Gy vs. 25.1 Gy (p=0.005) and 8.5 Gy vs. 10.2 Gy, in systole vs. diastole (p=0.005). Maximum dose to LV was lower in systole vs. diastole (21.5 Gy vs. 26.7 Gy, p=0.005).ConclusionBeyond DIBH, systolic irradiation would be associated with decrease in dose to LAD, LV and WH. In addition to potential use in planning for cardiac gating, DSCT imaging can be used to help define a planning organ at risk volume for clinically important cardiac sub-structures.

Teaser

Dynamic dose variation to cardiac substructures was assessed in left breast tangential irradiation using dual-source computed tomography. Maximum and mean dose to left anterior descending artery and maximum dose to whole heart and left ventricle were significantly decreased in systole vs. diastole. The described method allows for precise segmentation of cardiac substructures and can be used for definition of a planning organ at risk volume for clinically important cardiac substructures.


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Editorial - New perspectives for the action of steroids in the brain

Abstract

The present Special Issue is a collection of some of the lectures presented at the 9th International Meeting on Steroids and the Nervous System, held in February 2017. These reviews provide an update on the state of the art of recent discoveries in three main fields of current research on the role of neuroactive steroids in the brain, with special emphasis on brain development and sexual differentiation, the cellular and molecular mechanisms involved in the action of neuroactive steroids, and clinical implications for the understanding of brain disease and for the potential therapeutic use of these molecules or their analogues.

This article is protected by copyright. All rights reserved.

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The relationship between plasma vascular endothelial growth factor and erythrocyte 2,3-bisphosphoglycerate: the putative role of chronic hypoxia

Publication date: Available online 31 January 2018
Source:Medical Hypotheses
Author(s): B.K. Puri, J.A. Monro
The non-invasive assessment of chronic tissue hypoxia is difficult. Pulse oximetry only allows the peripheral oxygen saturation to be measured, while the detection of hyperlactataemia needs to take into account the fact that the accumulation of lactic acid may result from several causes other than prolonged tissue hypoxia. Arterial blood oxygen measurement is invasive and often does not give a good indication of the level of tissue hypoxia. Other suggested methods include the use of positron emission tomography, magnetic resonance T2^∗ relaxation time measurement, photoacoustics and high-frequency ultrasound. Tissue hypoxia leads to increased levels of hypoxia-inducible factor-1α, which in turn upregulates VEGFA, leading to increased levels of vascular endothelial growth factor (VEGF), which promote angiogenesis. Hypoxia lasting for more than a few hours is associated with increased synthesis in erythrocytes of 2,3-bisphosphoglycerate (BPG), a powerful regulator of the allosteric properties of haemoglobin, via the Rapoport-Luebering phosphoglycerate cycle. We therefore hypothesised that plasma VEGF and erythrocyte BPG levels should be positively correlated. Venous blood samples from 34 patients (18 male, mean age (standard error) 43.4 (3.2) y) were analysed; plasma VEGF was measured using an enzyme-linked immunosorbent assay while the erythrocyte BPG was assessed by quantitative Fourier transform infrared spectrometry following gel electrophoresis. The Pearson product-moment correlation between the two variables was 0.622 (p < 0.0001). Based on our findings, we suggest that it may be useful to measure both erythrocyte BPG and plasma VEGF, together, when assessing chronic hypoxia; elevated levels of both are likely to indicate hypoxia.



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Hypothesis: Is there a link between the immune response to Human Herpes Virus type 6Α (HHV-6Α) infection and the interaction network (interactome) of the genes encoding the CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3 and BST2 proteins?

Publication date: Available online 31 January 2018
Source:Medical Hypotheses
Author(s): Rouka Erasmia
Human Herpes Virus type 6 (HHV-6) is a ubiquitous virus consisting of two viral species, HHV-6A and HHV-6B that have been associated with numerous and diverse pathologies. As many other viruses HHV-6 modulates the apoptotic machinery of its host to subvert immune response to infection, yet the exact mechanisms behind this process remain under investigation. The genes encoding the CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3 and BST2 proteins have been linked to HHV-6Α related neurologic diseases whilst also associated with apoptosis. This study aimed at the identification and functional analysis of the gene interaction network (interactome) of CTSS-PTX3-CHI3L1-Mx1-CXCL16-BIRC3-BST2 so as to evaluate the hypothesis of a probable link between the latter and host's immune response to HHV-6A infection.



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Attention as the ‘Glue’ for Object Integration in Parietal Extinction

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Markus Conci, Julia Groß, Ingo Keller, Hermann J. Müller, Kathrin Finke
Patients with unilateral, parietal brain damage frequently show visual extinction, which manifests in a failure to identify contralesional stimuli when presented simultaneously with other, ipsilesional stimuli (but full awareness for single stimulus presentations). Extinction reflects an impairment of spatial selective attention, leaving basic preattentive processing unaffected. For instance, access to bilaterally grouped objects is usually spared in extinction, suggesting that grouping occurs at a stage preceding (in the patients: abnormally biased) spatial-attentional selection. Here, we reinvestigated this notion by comparing (largely between participants, but also within a single-case participant) conditions with objects that varied in their dominant direction of grouping: from the attended to the non-attended hemifield (data from Conci et al., 2009) versus from the non-attended to the attended hemifield (new data). We observe complete absence of extinction when shape completion extended from the attended hemifield. By contrast, extinction was not diminished when object groupings propagate from the unattended hemifield. Moreover, we found the individual severity of the attentional impairment (assessed by a standard "inattention" test) to be directly related to the degree of completion in the unattended hemifield. This pattern indicates that grouping can overcome visual extinction only when object integration departs from the attended visual field, implying, contrary to many previous accounts, that attention is crucial for grouping to be initiated.



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Insula mediates heartbeat related effects on visual consciousness

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Roy Salomon, Roberta Ronchi, Jonathan Dönz, Javier Bello-Ruiz, Bruno Herbelin, Nathan Faivre, Karl Schaller, Olaf Blanke
Interoceptive signals, such as the heartbeat, are processed in a network of brain regions including the insular cortex. Recent studies have shown that such signals modulate perceptual and cognitive processing, and that they impact visual awareness. For example, visual stimuli presented synchronously to the heartbeat take longer to enter visual awareness than the same stimuli presented asynchronously to the heartbeat, and this is reflected in anterior insular activation. This finding demonstrated a link between the processing of interoceptive and exteroceptive signals as well as visual awareness in the insular cortex. The advantage for visual stimuli which are asynchronous to the heartbeat to enter visual consciousness may indicate a role for the anterior insula in the suppression of the sensory consequences of cardiac signals. Here, we present data from the detailed investigation of two patients with insular lesions (as well as four patients with non-insular lesions and healthy age matched controls) indicating that a lesion of the anterior insular cortex, but not of other regions, abolished this cardio-visual suppression effect. The present data provide causal evidence for the role of the anterior insula in the integration of internal interoceptive and external sensory signals for visual awareness.



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Accelerated long-term forgetting in focal epilepsies with special consideration given to patients with diagnosed and suspected limbic encephalitis

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Christoph Helmstaedter, Babette Winter, Nico Melzer, Hubertus Lohmann, Juri-Alexander Witt
RationaleAccelerated long-term forgetting (ALF) is a phenomenon found in late onset epilepsy and in transient epileptic amnesia. Here we evaluated ALF in patients with focal epilepsies and limbic encephalitis in particular.MethodsALF was assessed in 36 patients with focal epilepsy and 154 healthy subjects using an extended version of the German Auditory Verbal Learning Test (VLMT), with free recall after 30 min and again after one week. From these patients, 89% had temporal lobe epilepsy; 42% left-lateralized; 39% right; 19% bilateral; 17% were diagnosed with hippocampal sclerosis; 64% displayed features indicating limbic encephalitis; 52% with amygdala pathology, and 61% were antibody positive. ALF was defined as either having unimpaired free recall after 30 min and impaired recall after a week (A) or as a loss in recall exceeding the absolute (B) and percentage loss (C) in the interval of the 30 min. and one week recall seen in controls by more than one standard deviation.ResultsRepeated measures analysis revealed an association between limbic encephalitis and ALF. Depending on its definition (A, B, or C), ALF was evident in 31%, 42%, or 67% of the patients. Poor verbal memory and ALF (C) were prominent in left-lateralized epilepsies. ALF (A) appeared more frequently in auto-antibody negative patients with limbic encephalitis, ALF (B) less frequently with hippocampal sclerosis. Seizures during the interval did not explain ALF.ConclusionDepending on its definition, ALF is seen in patients with normal or impaired memory at ½ hour. ALF seems related to limbic encephalitis but might as well be the first sign of memory impairment in patients with milder epilepsies and not yet definite structural temporal lobe pathology. Longitudinal assessment would be essential for discerning when ALF becomes evident, whether conditions exist in which ALF precedes short-term forgetting, and whether ALF responds to treatment.



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Belief, delusion, hypnosis, and the right dorsolateral prefrontal cortex: a transcranial magnetic stimulation study

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Max Coltheart, Rochelle Cox, Paul Sowman, Hannah Morgan, Amanda Barnier, Robyn Langdon, Emily Connaughton, Lina Teichmann, Nikolas Williams, Vince Polito
According to the Two-Factor theory of delusional belief (see e.g. Coltheart at al., 2011), there exists a cognitive system dedicated to the generation, evaluation, and acceptance or rejection of beliefs. Studies of the neuropsychology of delusion provide evidence that this system is neurally realized in right dorsolateral prefrontal cortex (rDLPFC).Furthermore, we have shown that convincing analogues of many specific delusional beliefs can be created in nonclinical subjects by hypnotic suggestion and we think of hypnosis as having the effect of temporarily interfering with the operation of the belief system, which allows acceptance of the delusional suggestions. If the belief system does depend on rDLPFC, then disrupting the activity of that region of the brain by the application of repetitive transcranial magnetic stimulation (rTMS) will increase hypnotizability. Dienes and Hutton (2013) have reported such an experiment except that it was left DLPFC to which rTMS was applied. An effect on a subjective measure of hypnotizability was observed, but whether there was an effect on an objective measure could not be determined.We report two experiments. The first was an exact replication of the Dienes and Hutton experiment; here we found no effect of rTMS to lDLPFC on any hypnotic measure. Our second experiment used rTMS applied to right rather then left DLPFC. This right-sided stimulation enhanced hypnotizability (when hypnotic response was measured objectively), as predicted by our hypothesis.These results imply a role for rDLPFC in the cognitive process of belief evaluation, as is proposed in our two-factor theory of delusion. They are also consistent with a conception of the acceptance of a hypnotic suggestion as involving suspension of disbelief.



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Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Dorothée Lulé, Sarah Böhm, Hans-Peter Müller, Helena Aho-Özhan, Jürgen Keller, Martin Gorges, Markus Loose, Jochen Weishaupt, Ingo Uttner, Elmar Pinkhardt, Jan Kassubek, Kelly Del Tredici, Heiko Braak, Sharon Abrahams, Albert C. Ludolph
Sequential spread of TDP43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread.N=139 patients with ALS were tested with the Edinburgh Cognitive and Behavioural ALS screen (ECAS) in addition to DTI brain measures of pathological spread. Executive function, memory and disinhibited behaviour were selected for Cognitive-Staging criteria, as these cognitive functions are attributed to cerebral areas analogous to the pattern of MRI markers of TDP43 pathology. ROC curve analyses were performed to define cut-off scores for cognitive stages 2 (executive function), stage 3 (disinhibited behaviour) and stage 4 (memory), and staging was performed according to the cognitive profile subsequently. Associations of Cognitive-Staging (stage 2-4) and MRI-Staging measures were determined.In total, 77 patients (55%) performed below ROC cut-off scores in either executive function or memory or both and/or were reported to have disinhibited behaviour which permitted Cognitive-Staging. The cognitive profile of patients with discrete MRI stages 2 to 4 correlated significantly with DTI parameters. For those patients with cognitive impairment, there was a high congruency between MRI and Cognitive-Staging with high specificity and sensitivity of executive functions for MRI stage 2, disinhibited behaviour for MRI stage 3 and moderate of memory for MRI stage 4.Cognitive impairment follows specific patterns in ALS and these patterns can be used for Cognitive-Staging with a high specificity compared to MRI-Staging. For the individual, cognitive screening is a fast and easy to apply measurement of cerebral function giving valuable information in a clinical context.

Graphical abstract

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Arithmetic skills correlate negatively with the overlap of symbolic and non-symbolic number representations in the brain

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Jessica Bulthé, Bert De Smedt, Hans P. Op de Beeck




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Blind readers break mirror invariance as sighted do

Publication date: Available online 31 January 2018
Source:Cortex
Author(s): Adélaïde de Heering, Olivier Collignon, Régine Kolinsky
Mirror invariance refers to a predisposition of humans, including infants and animals, which urge them to consider mirrored images as corresponding to the same object. Yet in order to learn to read a written system that incorporates mirrored letters (e.g., vs. <d> in the Latin alphabet), humans learn to break this perceptual bias. Here we examined the role visual experience and input modality play in the emergence of this bias. To this end, we tested congenital blind (CB) participants in two same-different tactile comparison tasks including pairs of mirrored and non-mirrored Braille letters as well as embossed unfamiliar geometric shapes and Latin letters, and compared their results to those of age-matched sighted participants involved in similar but visually-presented tasks. Sighted participants showed a classical pattern of results for their material of expertise, Latin letters. CB's results signed for their expertise with the Braille script compared to the other two materials that they processed according to an internal frame of reference. They also evidenced that they automatically break mirror invariance for different materials explored through the tactile modality, including Braille letters. Altogether, these results demonstrate that learning to read Braille through the tactile modality allows breaking mirror invariance in a comparable way to what is observed in sighted individuals for the mirrored letters of the Latin alphabet.



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Distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder

Publication date: Available online 31 January 2018
Source:Brain Stimulation
Author(s): Yiheng Tu, Jiliang Fang, Jin Cao, Zengjian Wang, Joel Park, Kristen Jorgenson, Courtney Lang, Jun Liu, Guolei Zhang, Yanping Zhao, Bing Zhu, Peijing Rong, Jian Kong
BackgroundMajor depression is the fourth leading cause of disability worldwide and poses a socioeconomic burden worldwide. Transcutaneous vagus nerve stimulation (tVNS) is a promising noninvasive clinical device that may reduce the severity of major depression. However, the neural mechanism underlying continuous tVNS has not yet been elucidated.ObjectiveWe aimed to explore the effect of hypothalamic subregion functional connectivity (FC) changes during continuous tVNS treatment on major depressive disorder (MDD) patients and to identify the potential biomarkers for treatment outcomes.MethodsForty-one mild to moderate MDD patients were recruited and received either real or sham tVNS treatment for 4 weeks. We used a seed-to-whole brain approach to estimate the FC changes of hypothalamic subregions and their surrounding control areas during continuous tVNS treatment and explored their association with clinical outcome changes after 4 weeks of treatment.ResultsOf the thirty-six patients that completed the study, those in the tVNS group had significantly lower scores on the 24-item Hamilton Depression (HAM-D) Rating Scale compared to the sham tVNS group after 4 weeks of treatment. The FC between the bilateral medial hypothalamus (MH) and rostral anterior cingulate cortex (rACC) was significantly decreased during tVNS but not during sham tVNS. The strength of this FC was significantly correlated with HAM-D improvements after 4 weeks of tVNS.ConclusionThe FC between the bilateral MH and rACC may serve as a potential biomarker for the tVNS state and predict treatment responses. Our results provide insights into the neural modulation mechanisms of continuous tVNS and reveal a potential therapeutic target for MDD patients.



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Reshaping the deep brain stimulation trial for treatment-resistant depression

Publication date: Available online 31 January 2018
Source:Brain Stimulation
Author(s): Chencheng Zhang, Damiaan Denys, Valerie Voon, Bomin Sun




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Rostral anterior cingulate cortex is a structural correlate of repetitive TMS treatment response in depression

Publication date: Available online 31 January 2018
Source:Brain Stimulation
Author(s): Aaron D. Boes, Brandt Uitermarkt, Fatimah Albazron, Martin J. Lan, Conor Liston, Alvaro Pascual-Leone, Marc J. Dubin, Michael D. Fox
BackgroundRepetitive transcranial magnetic stimulation (rTMS) is an effective treatment for medication-refractory major depression, yet the mechanisms of action for this intervention are poorly understood. Here we investigate cerebral cortex thickness as a possible biomarker of rTMS treatment response.MethodsLongitudinal change in cortical thickness is evaluated relative to clinical outcomes across 48 participants in 2 cohorts undergoing left dorsolateral prefrontal cortex rTMS as a treatment for depression.ResultsOur results reveal changes in thickness in a region of the left rostral anterior cingulate cortex that correlate with clinical response, with this region becoming thicker in patients who respond favorably to rTMS and thinner in patients with a less favorable response. Moreover, the baseline cortical thickness in this region correlates with rTMS treatment response – those patients with thinner cortex before treatment tended to have the most clinical improvement.ConclusionsThis study is the first analysis of longitudinal cortical thickness change with rTMS as a treatment for depression with similar results across two cohorts. These results support further investigation into the use of structural MRI as a possible biomarker of rTMS treatment response.



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