Assessing hypo-arousal during reward anticipation with pupillometry in patients with major depressive disorder: replication and correlations with anhedonia.

Major depressive disorder (MDD) is a devastating and heterogenous disorder for which there are no approved biomarkers in clinical practice. We recently identified anticipatory hypo-arousal indexed by pupil responses as a candidate mechanism subserving depression symptomatology. Here, we conducted a replication and extension study of these findings. We analyzed a replication sample of 40 unmedicated patients with a diagnosis of depression and 30 healthy control participants, who performed a reward anticipation task while pupil responses were measured. Using a Bayesian modelling approach taking measurement uncertainty into account, we could show that the negative correlation between pupil dilation and symptom load during reward anticipation is replicable within MDD patients, albeit with a lower effect size. Furthermore, with the combined sample of 136 participants (81 unmedicated depressed and 55 healthy control participants), we further showed that reduced pupil dilation in anticipation of reward is inversely associated with anhedonia items of the Beck Depression Inventory in particular. Moreover, using simultaneous fMRI, particularly the right anterior insula as part of the salience network was negatively correlated with depressive symptom load in general and anhedonia items specifically. The present study supports the utility of pupillometry in assessing noradrenergically mediated hypo-arousal during reward anticipation in MDD, a physiological process that appears to subserve anhedonia.

Impact of autofluorescence for detection of parathyroid glands during thyroidectomy on postoperative parathyroid hormone levels: parallel multicentre randomized clinical trial.

BACKGROUND: Techniques for autofluorescence have been introduced to visualize the parathyroid glands during surgery and to reduce hypoparathyroidism after thyroidectomy. METHODS: This parallel multicentre RCT investigated the use of Fluobeam® LX to visualize the parathyroid glands by autofluorescence during total thyroidectomy compared with no use. There was no restriction on the indication for surgery. Patients were randomized 1 : 1 and were blinded to the group allocation. The hypothesis was that autofluorescence enables identification and protection of the parathyroid glands during thyroidectomy. The primary endpoint was the rate of low parathyroid hormone (PTH) levels the day after surgery. RESULTS: Some 535 patients were randomized, and 486 patients received an intervention according to the study protocol, 246 in the Fluobeam® LX group and 240 in the control group. Some 64 patients (26.0 per cent) in the Fluobeam® LX group and 77 (32.1 per cent) in the control group had low levels of PTH after thyroidectomy (P = 0.141; relative risk (RR) 0.81, 95 per cent c.i. 0.61 to 1.07). Subanalysis of 174 patients undergoing central lymph node clearance showed that 15 of 82 (18 per cent) in the Fluobeam® LX group and 31 of 92 (33 per cent) in the control group had low levels of PTH on postoperative day 1 (P = 0.021; RR 0.54, 0.31 to 0.93). More parathyroid glands were identified during operation in patients who had surgery with Fluobeam® LX, and fewer parathyroid glands in the surgical specimen on definitive histopathology. No specific harm related to the use of Fluobeam® LX was reported. CONCLUSION: The use of autofluorescence during thyroidectomy did not reduce the rate of low PTH levels on postoperative day 1 in the whole group of patients. It did, however, reduce the rate in a subgroup of patients. Registration number: NCT04509011 (http://www.clinicaltrials.gov).

Augmented Reality-Assisted versus Freehand Ventriculostomy in a Head Model.

BACKGROUND: Ventriculostomy (VST) is a frequent neurosurgical procedure. Freehand catheter placement represents the standard current practice. However, multiple attempts are often required. We present augmented reality (AR) headset guided VST with in-house developed head models. We conducted a proof of concept study in which we tested AR-guided as well as freehand VST. Repeated AR punctures were conducted to investigate if a learning curve can be derived. METHODS: Five custom-made 3D-printed head models, each holding an anatomically different ventricular system, were filled with agarose gel. Eleven surgeons placed two AR-guided as well as two freehand ventricular drains per head. A subgroup of four surgeons did a total of three series of AR-guided punctures each to test for a learning curve. A Microsoft HoloLens served as the hardware platform. The marker-based tracking did not require rigid head fixation. Catheter tip position was evaluated in computed tomography scans. RESULTS: Marker-tracking, image segmentation, and holographic display worked satisfactorily. In freehand VST, a success rate of 72.7% was achieved, which was higher than under AR guidance (68.2%, difference not statistically significant). Repeated AR-guided punctures increased the success rate from 65 to 95%. We assume a steep learning curve as repeated AR-guided punctures led to an increase in successful attempts. Overall user experience showed positive feedback. CONCLUSIONS: We achieved promising results that encourage the continued development and technical improvement. However, several more developmental steps have to be taken before an application in humans can be considered. In the future, AR headset-based holograms have the potential to serve as a compact navigational help inside and outside the operating room.

The Benefit of Intraoperative Magnetic Resonance Imaging in Endoscopic and Microscopic Transsphenoidal Resection of Recurrent Pituitary Adenomas.

The surgical treatment of recurrent adenomas can be challenging. Intraoperative magnetic resonance imaging (iMRI) can improve the orientation and increase the safe extent of resection. We conducted a quantitative and qualitative retrospective analysis of recurrent adenomas treated by endoscopic or microscopic iMRI-assisted transsphenoidal surgery. A total number of 59 resections were selected. Detailed volumetric measurements, tumor characteristics, and MRI features of intraoperative remnants were evaluated. Intraoperative MRI increased the gross total resection (GTR) rate from 33.9% to 49.2%. Common locations of tumor remnants after iMRI were the clivus, the wall of the cavernous sinus or the perforation of the diaphragm. Increasing tumor volume and the microscopic technique were significantly associated with further resection after iMRI in the univariate analysis (p = 0.004, OR 1.6; p = 0.009, OR 4.4). Only the increasing tumor volume was an independent predictor for further resection (p = 0.007, OR 1.5). A significantly higher proportion of GTRs was achieved with the endoscopic technique (p = 0.001). Patients with a large recurrent pituitary adenoma who underwent microscopic transsphenoidal resection were the most likely to benefit from iMRI regarding the extent of resection. Occult invasions of the cavernous sinus and/or the clivus were the most common findings leading to further resection of tumor remnants after iMRI.

Augmented reality-assisted ventriculostomy.

OBJECTIVE: Placement of a ventricular drain is one of the most common neurosurgical procedures. However, a higher rate of successful placements with this freehand procedure is desirable. The authors' objective was to develop a compact navigational augmented reality (AR)-based tool that does not require rigid patient head fixation, to support the surgeon during the operation. METHODS: Segmentation and tracking algorithms were developed. A commercially available Microsoft HoloLens AR headset in conjunction with Vuforia marker-based tracking was used to provide guidance for ventriculostomy in a custom-made 3D-printed head model. Eleven surgeons conducted a series of tests to place a total of 110 external ventricular drains under holographic guidance. The HoloLens was the sole active component; no rigid head fixation was necessary. CT was used to obtain puncture results and quantify success rates as well as precision of the suggested setup. RESULTS: In the proposed setup, the system worked reliably and performed well. The reported application showed an overall ventriculostomy success rate of 68.2%. The offset from the reference trajectory as displayed in the hologram was 5.2 ± 2.6 mm (mean ± standard deviation). A subgroup conducted a second series of punctures in which results and precision improved significantly. For most participants it was their first encounter with AR headset technology and the overall feedback was positive. CONCLUSIONS: To the authors' knowledge, this is the first report on marker-based, AR-guided ventriculostomy. The results from this first application are encouraging. The authors would expect good acceptance of this compact navigation device in a supposed clinical implementation and assume a steep learning curve in the application of this technique. To achieve this translation, further development of the marker system and implementation of the new hardware generation are planned. Further testing to address visuospatial issues is needed prior to application in humans.

Pupil Dilation during Reward Anticipation Is Correlated to Depressive Symptom Load in Patients with Major Depressive Disorder.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.

Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and ß-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function.NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to ß-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.

[Modern thyroid surgery - the surgeon's endocrine-surgical understanding and his responsibility for the extent of surgery and complication rate]. / Moderne Schilddrüsenchirurgie ­ das endokrin-chirurgische Verständnis des Operateurs und seine Verantwortung für Resektionsausmaß und Komplikationsrate.

High quality thyroid surgery implies a surgeon with an endocrine-surgical understanding aiming at best possible outcome. This includes an appropriate extent of the resection and a low rate of complications. It is important that the surgeon is involved at an early stage being part of the decision process for or against partial or total thyroidectomy. Furthermore, the surgeon should not only be able to perform thyroid and cervical lymph node sonography, but also to be capable to interpret cross-sectional imaging modalities and nuclear medicine imaging procedures. A thorough knowledge of modern principles of radicality is essential.Benign goiters require individualized surgical strategy: solitary nodules can be treated with a tissue-preserving selective nodular resection. However, a multinodular goiter does not necessarily require total thyroidectomy-prevention of a permanent hypoparathyroidism is of paramount importance. For recurrent goiters, removal of the dominant side and therefore, unilateral procedure is favored. Nowadays, there is an increasing tendency to set the indication for thyroid surgery separately for each lobe. Graves' disease requires thyroidectomy, and occasionally, hypertrophic Hashimoto's thyroiditis may also result in surgery.The principles of radical surgical treatment of malignant goiters have changed significantly over the past few years and, so far, strict indication for postoperative radioiodine treatment is being reconsidered. This is especially relevant for papillary thyroid microcarcinomas and minimally invasive follicular tumors. Even the radical surgical treatment of medullary thyroid carcinoma, especially considering synchronous or metachronous lateral neck dissection, is currently under review.Hypoparathyroidism is the most relevant complication in radical thyroid surgery and has devastating influence on the patients' life quality. Nowadays, permanent recurrent laryngeal nerve injury and postoperative hemorrhage rarely occur due to subtle surgical techniques. Extracervical surgical access to the thyroid is still a matter of clinical trials and should be restricted to centers. Radiofrequency ablation is an alternative method for benign lesions or hyperfunctioning nodules in patients with high surgical risk.

The laryngeal twitch response - Can it avoid unnecessary two-stage thyroidectomy? - A retrospective cohort study.

BACKGROUND: The objective of this study was to determine if the laryngeal twitch response, when compared to neuromonitoring, can predict postoperative vocal cord function and can thus be used in case of technical failure of the EMG-recording electrode. METHODS: A total of 640 nerves at risk were included in this study based on a prospective protocol. The laryngeal twitch response and the EMG-records were compared with the results of the postoperative laryngoscopy. RESULTS: Of the 640 nerves at risk, 582 showed a normal postoperative vocal cord function. A recurrent laryngeal nerve paralysis (no vocal fold movement) was observed in 39 cases and recurrent laryngeal nerve paresis (reduced vocal cord movement) was diagnosed in 19 cases. The overall negative predictive value (NPV) in final vagus nerve stimulation (V2) was 95.0% for the EMG-records and 94.8% for the laryngeal twitch response. When pareses were excluded, the NPV was 96.8% and 96.6% respectively. The positive predictive value (PPV) of vagus nerve stimulation lies between 51.4% and 57.1% excluding the pareses. It rises to values between 60.0% and 65.1% if they are included. CONCLUSIONS: The laryngeal twitch response and the EMG-records show similar results, and the NPV is good in both. Thus, in case of technical failure or displacement of the EMG-recording electrode, the laryngeal twitch can be used in decision-making for or against a two-stage thyroidectomy.

Complete and incomplete recurrent laryngeal nerve injury after thyroid and parathyroid surgery: Characterizing paralysis and paresis.

BACKGROUND: Injury of the recurrent laryngeal nerve and consequent disorder of vocal fold movement is a typical complication in thyroid and parathyroid surgery. During postoperative laryngoscopy we observed not only a complete standstill (vocal fold paralysis), but also a hypomobility (paresis). In this prospective study, we investigated the difference in incidence and prognosis as well as risk-factors, intraoperative neuromonitoring, and symptoms between vocal fold paralysis and vocal fold paresis. METHODS: Data were prospectively collected and analyzed in a single high-volume thyroid center between 2012 and 2016. Vocal fold paresis was defined as hypomobility in abduction or adduction, a reduction in range and speed of vocal fold movement. Vocal fold paralysis was defined as asymmetry and missing purposeful vocal fold movement. RESULTS: The study included 4,707 surgeries and 7,992 at-risk nerves at risk. Vocal fold paralysis was diagnosed in 374 patients (4.68% of 7,992 nerves at risk) and vocal fold paresis in 114 patients (1.43%). Exclusively in the paralysis group, 36 patients (0.45%) developed permanent loss of vocal fold function (P < .001). In follow-up, vocal fold paresis patients regain normal vocal fold function significantly earlier than vocal fold paralysis (mean duration: 6.96 ± 6.506 vs 10.77 ± 7,827 weeks) and presented with significantly less symptoms like hoarseness, diplophonia, dysphagia, and dyspnea (68.8% vs 95.9 %). In intraoperative neuromonitoring, vocal fold paresis showed a significantly higher postresectional N. vagus amplitude than vocal fold paralysis patients (0.349 mV vs 0.114 mV, P < .001). CONCLUSION: After thyroidectomy, vocal fold paresis must be distinguished from vocal fold paralysis and should be implemented as a separate outcome parameter in the postoperative quality assessment.

Clinical outcome after decompression of intraneural peroneal ganglion cyst and its morphologic correlation to postoperative nerve ultrasound.

OBJECTIVE: Intraneural ganglion cysts are rare and benign mucinous lesions that affect peripheral nerves, most frequently the common peroneal nerve (CPN). The precise pathophysiological mechanisms of intraneural ganglion cyst development remain unclear. A well-established theory suggests the spread of mucinous fluid along the articular branch of the peroneal nerve as the underlying mechanism. Clinical outcome following decompression of intraneural ganglion cysts has been demonstrated to be excellent. The aim of this study was to evaluate the correlation between clinical outcome and ultrasound-detected morphological nerve features following decompression of intraneural ganglion cysts of the CPN. METHODS: Data were retrospectively analyzed from 20 patients who underwent common peroneal nerve ganglion cyst decompression surgery at the Universität Ulm/Günzburg Neurosurgery Department between October 2003 and October 2017. Postoperative clinical outcome was evaluated by assessment of the muscular strength of the anterior tibial muscle, the extensor hallucis longus muscle, and the peroneus muscle according to the Medical Research Council grading system. Hypesthesia was measured by sensation testing. In all patients, postoperative morphological assessment of the peroneal nerve was conducted between October 2016 and October 2017 using the iU22 Philips Medical ultrasound system at the last routine follow-up appointment. Finally, the correlations between morphological changes in nerve ultrasound and postoperative clinical outcomes were evaluated. RESULTS: During the postoperative ultrasound scan an intraneural hypoechogenic ring structure located at the medial side of the peroneal nerve was detected in 15 (75%) of 20 patients, 14 of whom demonstrated an improvement in motor function. A regular intraneural fasicular structure was identified in 3 patients (15%), who also reported recovery. In 1 patient, a recurrent cyst was detected, and 1 patient showed intraneural fibrosis for which recovery did not occur in the year following the procedure. Two patients (10%) developed neuropathic pain that could not be explained by nerve ultrasound findings. CONCLUSIONS: The results of this study demonstrate significant recovery from preoperative weakness after decompression of intraneural ganglion cysts of the CPN. A favorable clinical outcome was highly correlated with an intraneural hypoechogenic ring-shaped structure on the medial side of the CPN identified during a follow-up postoperative ultrasound scan. These study results indicate the potential benefit of ultrasound scanning as a prognostic tool following decompression procedures for intraneural ganglion cysts of the CPN.

The evolution of invasive cerebral vasospasm treatment in patients with spontaneous subarachnoid hemorrhage and delayed cerebral ischemia-continuous selective intracarotid nimodipine therapy in awake patients without sedation.

Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are major factors that limit good outcome in patients with spontaneous subarachnoid hemorrhage (SAH). Continuous therapy with intra-arterial calcium channel blockers has been introduced as a new step in the invasive treatment cascade of CV and DCI. Sedation is routinely necessary for this procedure. We report about the feasibility to apply this therapy in awake compliant patients without intubation and sedation. Out of 67 patients with invasive endovascular treatment of cerebral vasospasm due to spontaneous SAH, 5 patients underwent continuous superselective intracarotid nimodipine therapy without intubation and sedation. Complications, neurological improvement, and outcome at discharge were summarized. Very good outcome was achieved in all 5 patients. The Barthel scale was 100 and the modified Rankin scale 0-1 in all cases at discharge. We found no severe complications and excellent neurological monitoring was possible in all cases due to patients' alert status. Symptoms of DCI resolved within 24 h in all 5 cases. We could demonstrate the feasibility and safety of selective intracarotid arterial nimodipine treatment in awake, compliant patients with spontaneous SAH and symptomatic CV and DCI. Using this method, an excellent monitoring of neurological function as well as early detection of other complications is possible. It might be an important step in the risk reduction of invasive CV therapy to improve the outcome with CV and DCI after SAH in selected patients.

Measuring the conditioned response: A comparison of pupillometry, skin conductance, and startle electromyography.

In human fear conditioning studies, different physiological readouts can be used to track conditioned responding during fear learning. Commonly employed readouts such as skin conductance responses (SCR) or startle responses have in recent years been complemented by pupillary readouts, but to date it is unknown how pupillary readouts relate to other measures of the conditioned response. To examine differences and communalities among pupil responses, SCR, and startle responses, we simultaneously recorded pupil diameter, skin conductance, and startle electromyography in 47 healthy subjects during fear acquisition, extinction, and a recall test on 2 consecutive days. The different measures correlated only weakly, displaying most prominent differences in their response patterns during fear acquisition. Whereas SCR and startle responses habituated, pupillary measures did not. Instead, they increased in response to fear conditioned stimuli and most closely followed ratings of unconditioned stimulus (US) expectancy. Moreover, we observed that startle-induced pupil responses showed stimulus discrimination during fear acquisition, suggesting a fear potentiation of the auditory pupil reflex. We conclude that different physiological outcome measures of the conditioned response inform about different cognitive-affective processes during fear learning, with pupil responses being least affected by physiological habituation and most closely following US expectancy.

Spatial variation in determinants of agricultural land abandonment in Europe.

Agricultural abandonment is widespread and growing in many regions worldwide, often because of agricultural intensification on productive lands, conservation policies, or the spatial decoupling of agricultural production from consumption. Abandonment has major environmental and social impacts, which differ starkly depending on the geographical context, as does its potential to serve as a land reservoir for recultivation. Understanding determinants of abandonment patterns, and especially how their influence varies across broad geographic extents, is therefore important. Using a pan-European map of agricultural abandonment derived from MODIS NDVI time series between 2001 and 2012, we quantified the importance of farm management, climatic, environmental, and socio-economic variables in explaining abandonment patterns. We chose a machine learning modelling framework that accounts for spatial variation in the relationship between abandonment and its determinants. We predicted abandonment probability as well as determinant coefficients for the entire study area and summarised them for regions under selected EU support schemes. Our results highlight that agricultural abandonment was mainly explained by climate conditions suboptimal for agriculture (i.e., low/high growing degrees days). Determinants related to farm management (smaller field size, lower yields) and socio-economic conditions (high unemployment, negative migration balance) also contributed to describing agricultural abandonment patterns in Europe. Several determinants influenced abandonment in strongly non-linear ways and we found substantial spatial non-stationarity effects, although abandonment patterns were equally well-explained by predictors specified with spatially constant and varying effects. Predicted abandonment probability was similar inside and outside EU support or conservation zones, whereas observed MODIS-based abandonment was generally higher outside these zones, suggesting that schemes such as Natura 2000 or High Nature Value Farmland likely influence abandonment patterns. Our work highlights the potential value of spatial boosting for gaining insights into land-use change processes and their outcomes, which should increase the ability of such models to inform context-specific, regionalised decision making.

Disentangling reward anticipation with simultaneous pupillometry / fMRI.

The reward system may provide an interesting intermediate phenotype for anhedonia in affective disorders. Reward anticipation is characterized by an increase in arousal, and previous studies have linked the anterior cingulate cortex (ACC) to arousal responses such as dilation of the pupil. Here, we examined pupil dynamics during a reward anticipation task in forty-six healthy human subjects and evaluated its neural correlates using functional magnetic resonance imaging (fMRI). Pupil size showed a strong increase during monetary reward anticipation, a moderate increase during verbal reward anticipation and a decrease during control trials. For fMRI analyses, average pupil size and pupil change were computed in 1-s time bins during the anticipation phase. Activity in the ventral striatum was inversely related to the pupil size time course, indicating an early onset of activation and a role in reward prediction processing. Pupil dilations were linked to increased activity in the salience network (dorsal ACC and bilateral insula), which likely triggers an increase in arousal to enhance task performance. Finally, increased pupil size preceding the required motor response was associated with activity in the ventral attention network. In sum, pupillometry provides an effective tool for disentangling different phases of reward anticipation, with relevance for affective symptomatology.

Is MGMT promoter methylation to be considered in the decision making for recurrent surgery in glioblastoma patients?

OBJECTIVES: At present, there is no standard therapy approved for recurrent glioblastoma (rGB). In particular, the counselling of patients with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter GB remains a challenge. Our aim was to compare the overall survival (OS) and progression free survival (PFS) in patients treated surgically and non-surgically at the time of GB recurrence. This was evaluated with particular reference to the impact of recurrent surgery for patients with unmethylated MGMT promoter rGB. PATIENTS AND METHODS: The clinical and radiological data from 127 consecutive cases of rGB was retrospectively identified and evaluated. The PFS and OS from cohorts of surgically and non-surgically treated patients at time of GB recurrence were compared using Kaplan Meier estimations and Log-Rank tests. Multivariate Cox regression analysis included the major influencing variables (surgical resection, MGMT promoter methylation status, Karnofsky performance scale (KPS), age, eloquent tumor location) to analyze the survival benefit. Subgroup analysis of cases depending on the MGMT promoter methylation status was performed. RESULTS: Multiple Cox regression analysis revealed inferior OS (p = 0.029, OR = 1.731, CI 95% 1.059-2.829) of patients treated non-surgically (14 vs. 31 months). MGMT promoter methylation and age were related to longer OS (p < 0.001, OR 2.683, CI 95% 1.631-4.414 and p = 0.009, OR = 1.029, CI95% 1.007-0.052 respectively). Gross total resection (GTR) in comparison to subtotal resection (STR) lead to a median OS of 39 months vs. 22 months and a PFS of seven vs. four months respectively. In the subgroup of cases with unmethylated MGMT promoter rGB, those who underwent GTR survived significantly longer (OS: 31 months) than patients who underwent STR (OS: 15 months, p = 0.024). PFS was six vs. four months after GTR and STR respectively. CONCLUSION: Surgical management for recurrent glioblastoma appears to be a safe procedure which results in longer OS in comparison to non-surgical management. GTR may be of particular benefit to patients with unmethylated MGMT promoter rGB.

Neural correlates of pupil dilation during human fear learning.

BACKGROUND: Fear conditioning and extinction are prevailing experimental and etiological models for normal and pathological anxiety. Pupil dilations in response to conditioned stimuli are increasingly used as a robust psychophysiological readout of fear learning, but their neural correlates remain unknown. We aimed at identifying the neural correlates of pupil responses to threat and safety cues during a fear learning task. METHODS: Thirty-four healthy subjects underwent a fear conditioning and extinction paradigm with simultaneous functional magnetic resonance imaging (fMRI) and pupillometry. After a stringent preprocessing and artifact rejection procedure, trial-wise pupil responses to threat and safety cues were entered as parametric modulations to the fMRI general linear models. RESULTS: Trial-wise magnitude of pupil responses to both conditioned and safety stimuli correlated positively with activity in dorsal anterior cingulate cortex (dACC), thalamus, supramarginal gyrus and insula for the entire fear learning task, and with activity in the dACC during the fear conditioning phase in particular. Phasic pupil responses did not show habituation, but were negatively correlated with tonic baseline pupil diameter, which decreased during the task. Correcting phasic pupil responses for the tonic baseline pupil diameter revealed thalamic activity, which was also observed in an analysis employing a linear (declining) time modulation. CONCLUSION: Pupil dilations during fear conditioning and extinction provide useful readouts to track fear learning on a trial-by-trial level, particularly with simultaneous fMRI. Whereas phasic pupil responses reflect activity in brain regions involved in fear learning and threat appraisal, most prominently in dACC, tonic changes in pupil diameter may reflect changes in general arousal.

Spontaneous pupil dilations during the resting state are associated with activation of the salience network.

Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.

Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study.

We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption.

Alcohol recovery and spirituality: strangers, friends, or partners?

Alcoholics Anonymous, with its steady but nonspecific promotion of belief in a higher power and its emphasis on the group process, long held a near-monopoly in the outpatient alcohol recovery field, but its hegemony has now been challenged by two very different perspectives. The first is a nonspiritual approach that emphasizes the individual's capability to find a personal pathway to sobriety, exemplified by Rational Recovery. The second is a faith-based method, built on a religious understanding of alcoholism, of which Celebrate Recovery is a prominent example, based upon Christianity. Most communities offer a variety of approaches, so clinicians who are aware of these differences are in a good position to help patients make intelligent choices among the competing recovery philosophies.