Antidepressant drugs and risk of developing glioma: a national registry-based case control study and a meta-analysis.

The aim of the present study was to investigate if use of antidepressants is related to the risk of developing lower (WHO grade 2-3) and higher grade (WHO grade 4) glioma. A registry-based case-control study was performed using 1283 glioma cases and 6400 age-, sex- and geographically matched controls, diagnosed in Sweden 2009-2013. Conditional logistic regression was used to analyze whether Selective Serotonin Reuptake Inhibitors (SSRIs) or non-SSRIs were associated with the risk of developing lower- or higher-grade glioma in the study population. Our results show that use of antidepressant medication was not associated with the risk of developing glioma. We also performed a meta-analysis in which the dataset from the present study was combined with results from two previous epidemiological studies to answer the same questions. The meta-analysis showed a modest risk reduction of developing glioma in relation to antidepressant treatment (OR 0.90 [95% CI 0.83-0.97]), when all glioma subgroups and all forms of antidepressant medications were combined. In conclusion, it remains possible that antidepressants may have common monoaminergic mechanism(s) that reduce the risk of developing glioma.

Antidepressants and survival in glioma-A registry-based retrospective cohort study.

Background: Depression and treatment with antidepressant medication is common in patients with malignant glioma. However, the extent to which antidepressants may affect the disease is not fully understood. Therefore, the purpose of the present study was to investigate possible associations between treatment with antidepressant medication and survival in glioma patients. Methods: We performed a registry-based cohort study including 1231 patients with malignant glioma (WHO grades 2, 3, and 4) having undergone surgery, and 6400 matched controls without glioma. All data were extracted from the RISK North database, which contains information from multiple national population-based registries in Sweden. Results: Treatment with antidepressants is more common in patients with malignant glioma (27%), compared to controls (16%), P < .001. Treatment with antidepressants after surgery for glioma was significantly associated with poorer survival. These effects were observed both for selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. In grade 4 glioma, SSRI treatment was associated with a hazard ratio (HR) of 3.32 (95% CI 2.69-4.10, P < .001), and non-SSRI treatment a HR of 3.54 (95% CI 2.52-4.99, P < .001), compared to glioma patients without antidepressants. In grade 2-3 glioma, the HR for SSRI treatment was 3.26 (95% CI 2.19-4.85, P < .001), and for non-SSRI treatment was 7.71 (95% CI 4.22-14.12, P < .001). Conclusions: Our results demonstrate a negative association between antidepressant medication and survival in glioma. Further research will be needed to clarify causation.

[Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients]. / Neurokirurgin alltjämt kärnan i behandlingen av hjärntumörer.

Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines: neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.

Brain stimulation and elicited memories.

BACKGROUND: Since the late 1930s, electric brain stimulation (EBS) in awake patients has been known to occasionally elicit patient descriptions of a form of memory flashbacks, known as experiential phenomena. One understanding of these sensations are as caused by an augmentation of the capacity for memory retrieval. However, an alternative hypothesis holds that memory flashbacks during EBS are "synthetic constructions" in the form of mental events, falsely interpreted as memories. METHODS: A critical narrative review is used to discuss the false memory hypothesis in relation to the current empirical literature and source attribution theory. RESULTS: EBS as well as situational demands in the form of interaction between patient and neurosurgeon may both lead to the creation of mental events and influence their interpretation in a way that may create false memories. The false memory hypothesis provides a potential explanation for several apparent inconsistencies in the current literature such as (a) the fragmented nature of experiential reports, (b) the ability of EBS to induce memory retrieval errors in controlled studies, (c) that Penfield's elicitations of experiential phenomena are so rarely replicated in the modern era, and (d) the limited utility of techniques that elicit experiential phenomena in the treatment of memory disorders. CONCLUSIONS: The hypothesis that experiential phenomena may largely be "synthetic constructions" deserves serious consideration by neurosurgeons.

Serum Levels of Myo-inositol Predicts Clinical Outcome 1 Year After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Early prognostication of long-term outcome in patients suffering from spontaneous subarachnoid hemorrhage (SAH) remains a challenge. No biomarkers are routinely used for prognostication. A previous study has indicated that the metabolite myo-inositol (MI) may be used to predict long-term outcome. OBJECTIVE: To investigate if MI measured in serum correlates with long-term clinical outcome in patients suffering from SAH. METHODS: We conducted an observational cohort study including 88 patients treated for SAH at Umeå University Hospital. Serum samples were collected in the hospital, and a gas chromatography/mass spectroscopy method was used to quantitatively measure MI. Patients were assessed after 1 year using the Glasgow Outcome Scale Extended and dichotomized to favorable or unfavorable outcome. Differences in MI levels between the 2 groups were analyzed. RESULTS: There was no difference in MI levels between the groups upon admission. Myo-inositol levels decreased over time in the entire study population. The decrease was significantly larger in the unfavorable outcome group. A receiver operating characteristics analysis yielded an area under the curve of 0.903 (CI 0.8-1.0, P < .001) for the MI value on day 7 to predict favorable outcome after 1 year. CONCLUSION: Myo-inositol measured in serum may aid prognostication of outcome in patients with SAH. The mechanism behind this remains unclear, although it can be theorized to reflect processes leading to delayed cerebral ischemia, which affects long-term outcome. This is the first study to quantitively measure MI in serum for prognostication of outcome in patients with SAH.

Distinct metabolic hallmarks of WHO classified adult glioma subtypes.

BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy. METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors-oligodendroglioma (n = 31), astrocytoma (n = 31) and glioblastoma (n = 162)-were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation. RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides, and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue. CONCLUSION: Key metabolic differences exist across adult glioma subtypes.

Five psychological mechanisms that might bias learning from neurosurgical complications: case discussions and a narrative review.

PURPOSE: The ability of neurosurgeons to analyze and reflect on their complications in a constructive way is important both for professional development and for patient safety. The purpose of the present paper is to highlight some psychological factors that might impair or bias the ability of the neurosurgeon to do this successfully. METHODS: Five fictitious cases, loosely inspired by real events and situations, are used as a basis for a discussion of some of the most important potential sources of psychological bias in the context of understanding neurosurgical complications. RESULTS: The issues of a) self-serving bias and the actor-observer effect; b) heuristics and biases in interpreting probabilistic events; c) emotional avoidance and denial; d) limitations of attention (dual systems theory) and e) errors of memory, are discussed. CONCLUSION: There are a number of psychological factors, that are well known to science that may be ubiquitous sources of influence on the ability of neurosurgeons to grow by reflection on their own complications. Exactly how these factors can and should be efficiently adressed by the individual neurosurgeon and/or the organisation and team in which the neurosurgeon works may vary according to type of bias, context and circumstances. However, being aware of these issues and addressing them on an individual and organizational level remains important to the quality of our craft.

Variations in the management of diffuse low-grade gliomas-A Scandinavian multicenter study.

BACKGROUND: Early extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected "high-risk" patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems. METHODS: Patients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored. RESULTS: A total of 642 patients were included (male:female ratio 1:4), and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy. CONCLUSIONS: Despite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care.

Neuropsychological Function and Quality of Life after Resection of Suspected Lower-Grade Glioma in the Face Primary Motor Area.

The negative side effects of neurosurgical resection of the lower third of the primary motor cortex (M1) are often described as relatively mild. However, detailed descriptions of how these resections affect neurocognitive function, speech, mental health and quality of life (QoL) are sparse. In the present study, seven patients with suspected lower-grade glioma (WHO II-III) in the inferior M1 were assessed for facial motor function, cognitive function, anxiety and QoL before and after awake surgical resections. The main finding was that after surgery, six of the seven patients experienced a mild facial motor dysfunction, mainly affecting the mouth, tongue and throat. At the group level, we were also able to observe a significant postoperative decline in maximum verbal speed, whereas no negative effects on measures of word production (i.e., verbal fluency) were seen. Self-reported QoL data suggest that some patients experienced increased social isolation postoperatively but do not lend support to the interpretation that this was caused by direct neurological side effects of the surgery. The results appear to support the general notion that awake surgery in the lower M1 can be performed safely and with postoperative deficits that are most often perceived by the patient as tolerable.

Free will and neurosurgical resections of the supplementary motor area: a critical review.

BACKGROUND: Research suggests that unconscious activity in the supplementary motor area (SMA) precedes not only certain simple motor actions but also the point at which we become aware of our intention to perform such actions. The extent to which these findings have implications for our understanding of the concepts of free will and personal responsibility has been subject of intense debate during the latest four decades. METHODS: This research is discussed in relation to effects of neurosurgical removal of the SMA in a narrative review. RESULTS: Removal of the SMA typically causes a transient inability to perform non-stimulus-driven, voluntary actions. This condition, known as the SMA syndrome, does not appear to be associated with a loss of sense of volition but with a profound disruption of executive function/cognitive control. CONCLUSIONS: The role of the SMA may be to serve as a gateway between the corticospinal tract and systems for executive function. Such systems are typically seen as tools for conscious decisions. What is known about effects of SMA resections would thus seem to suggest a view that is compatible with concepts of personal responsibility. However, the philosophical question whether free will exists cannot be definitely resolved on the basis of these observations.

Phenomenology of glioma resection in the dorsal medial frontal cortex.

BACKGROUND: During the latest decades, the hypothesis that the subjective experience of free will is determined by preconscious activity in the dominant dorsal medial frontal cortex (dMFC) has repeatedly challenged our commonly held concepts of moral responsibility. AIMS OF THE STUDY: To investigate whether dMFC activity determines the sense of free will and to investigate the effects of resections in this area on quality of life (QoL). METHODS: A cohort of nine patients affected by transient declines in speech and movement skills after surgery involving the left dMFC answered questions about their post-operative, subjective experiences of volition in relation to symptoms. In eight cases, resections were performed as part of glioma surgery, and in the ninth case, a meningioma adjacent to the dMFC was resected. In addition, a QoL questionnaire was administrated before and after surgery. RESULTS: None of the patients perceived the transient disabilities related to surgery as associated with a loss or absence of volition. No declines in QoL were detected after surgery. Two QoL domains showed improved function (motor dysfunction and future uncertainty). CONCLUSIONS: The subjective sense of volition is not contingent on dMFC activity. Surgical resections of this area are not typically associated with declines in QoL.

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study.

BACKGROUND: The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males. METHODS: Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case-Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings. RESULTS: The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample. CONCLUSIONS: These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.

The supplementary motor area syndrome and cognitive control.

The Supplementary Motor Area (SMA)-syndrome is a transient disturbance of the ability to initiate voluntary motor and speech actions that will often occur immediately after neurosurgical resections in the dorsal superior frontal gyrus but will typically have disappeared after 3 months. The purpose of the present study was to investigate the extent to which this syndrome is associated with alterations in cognitive control. Five patients who were to different extents affected by the SMA-syndrome after surgery for WHO grade II gliomas in the left hemisphere, were tested with the color word interference (Stroop) test; the Bergen dichotic listening test and for letter and category verbal fluency before surgery, 1-2 days after surgery and approximately 3 months after surgery. Results suggest that the motor symptoms known as the SMA syndrome co-occur with pronounced deficits in cognitive control.

Gaze-Aware Streaming Solutions for the Next Generation of Mobile VR Experiences.

This paper presents a novel approach to content delivery for video streaming services. It exploits information from connected eye-trackers embedded in the next generation of VR Head Mounted Displays (HMDs). The proposed solution aims to deliver high visual quality, in real time, around the users' fixations points while lowering the quality everywhere else. The goal of the proposed approach is to substantially reduce the overall bandwidth requirements for supporting VR video experiences while delivering high levels of user perceived quality. The prerequisites to achieve these results are: (1) mechanisms that can cope with different degrees of latency in the system and (2) solutions that support fast adaptation of video quality in different parts of a frame, without requiring a large increase in bitrate. A novel codec configuration, capable of supporting near-instantaneous video quality adaptation in specific portions of a video frame, is presented. The proposed method exploits in-built properties of HEVC encoders and while it introduces a moderate amount of error, these errors are indetectable by users. Fast adaptation is the key to enable gaze-aware streaming and its reduction in bandwidth. A testbed implementing gaze-aware streaming, together with a prototype HMD with in-built eye tracker, is presented and was used for testing with real users. The studies quantified the bandwidth savings achievable by the proposed approach and characterize the relationships between Quality of Experience (QoE) and network latency. The results showed that up to 83% less bandwidth is required to deliver high QoE levels to the users, as compared to conventional solutions.

Witch persecutions and torture: Comment on Alison and Alison (2017).

In their article Alison and Alison (2017) argue that historical experiences speak against the efficacy of torture. In this comment experiences from the witch persecutions in Europe during the 15th to 17th centuries that support this notion are discussed. Converging data suggests that torture was often instrumental in making large numbers of suspects confess to flying children through the air to nocturnal satanic meetings, during this period. A comparison of the number of false self incriminating confessions given during the Swedish witch trial in the parish of Rättvik 1671 (before royal sanction of torture was given) and the parish of Ockelbo 1675 (after royal sanction of torture was given) is used to illustrate this point. (PsycINFO Database Record

Acute severe depression induced by stimulation of the right globus pallidus internus.

Depressive symptoms may occur after Deep Brain Stimulation (DBS) in the subthalamic nucleus. This is often explained by reduced pharmacological treatment after surgery, and not as a direct effect of DBS. Pallidal DBS seems not to be associated with such side effects and have not, to our knowledge, previously been reported. We present a patient with acute depressive symptoms induced by pallidal DBS. We believe this case strengthen the hypothesis that the basal ganglia and structures involved in the functional connectome of these nucleuses play a role not only in regulation of movement but also in regulation of mood.

The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males.

Herein, we examined insulin resistance (IR), insulin sensitivity (IS), beta cell activity, and glucose metabolism in subjects with antisocial personality disorder (ASPD), and whether the serotonin 2B (5-HT2B) receptor and testosterone have a role in energy metabolism. A cohort of subjects belonging to a founder population that included 98 ASPD males, aged 25-30, was divided into groups based on the presence of a heterozygous 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*; n = 9) or not (n = 89). Serum glucose and insulin levels were measured in a 5 h oral glucose tolerance test (75 g) and indices describing IR, IS, and beta cell activity were calculated. Body mass index (BMI) was also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were measured in cerebrospinal fluid, and testosterone levels from serum. An IR-like state comprising high IR, low IS, and high beta cell activity indices was observed among ASPD subjects without the HTR2B Q20* allele. By contrast, being an ASPD HTR2B Q20* carrier appeared to be preventive of these pathophysiologies. The HTR2B Q20* allele and testosterone predicted lower BMI independently, but an interaction between HTR2B Q20* and testosterone lead to increased insulin sensitivity among HTR2B Q20* carriers with low testosterone levels. The HTR2B Q20* allele also predicted reduced beta cell activity and enhanced glucose metabolism. Reduced 5-HT2B receptor function at low or normal testosterone levels may be protective of obesity. Results were observed among Finnish males having an antisocial personality disorder, which limits the generality.

Blood Metabolomic Predictors of 1-Year Outcome in Subarachnoid Hemorrhage.

BACKGROUND: Delayed neurological deficit (DND) is the most important cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH) whose aneurysms have been secured. However, the methods currently used to predict the development of DND, such as trans-cranial Doppler or levels biochemical markers in blood and cerebrospinal fluid are not very accurate. METHOD: Venous blood was drawn from 50 patients with SAH, admitted to the neurosurgical department Umeå University Hospital, at day 1-3 and day 7 after the bleed. The clinical status of the patients was followed up approximately 1 year after this episode and classified according to the Glasgow Outcome Score (GOS). RESULTS: Results showed considerable differences in blood metabolomic patterns between day 1-3 and 7 after the hemorrhage. Fifty-six out of 98 metabolites could be identified from our in-house library and 17 of these metabolites changed significantly from day 1-3 to 7 after the bleed. One of these, myo-inositol, was predictive of clinical outcome even after correction for multiple testing. An estimation of the diagnostic accuracy of high levels of this substance in predicting good outcome (GOS 4-5) yielded a sensitivity of .763 and a specificity of .5 at the optimal cut off point. CONCLUSIONS: SAH is an event with a profound effect on blood metabolomics profiles. Myo-inositol might be an interesting compound for future study to focus on in the search for metabolic markers in venous blood of delayed neurological deterioration in SAH patients.

Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson's disease.

Ear advantage during a dichotic listening task tends to mirror speech lateralization. Previous studies in stroke patients have shown that lesions in the dominant hemisphere often seem to produce changes in ear advantage. In this study six Parkinson's disease (PD) patients treated for motor symptoms with deep brain stimulation (DBS) of the left subthalamic nucleus (STN) were tested preoperatively and at approximately 6 and 18 months postoperatively with a dichotic listening task. Results show a significant decline of the right ear advantage over time. In three of the patients a right ear advantage preoperatively changed to a left ear advantage 18 months postoperatively. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in stroke patients.