Personalizing Deep Brain Stimulation Therapy for Parkinson's Disease With Whole-Brain MRI Radiomics and Machine Learning.

Background Deep brain stimulation (DBS) is a well-recognised treatment for advanced Parkinson's disease (PD) patients. Structural brain alterations of the white matter can correlate with disease progression and act as a biomarker for DBS therapy outcomes. This study aims to develop a machine learning-driven predictive model for DBS patient selection using whole-brain white matter radiomics and common clinical variables. Methodology A total of 120 PD patients underwent DBS of the subthalamic nucleus. Their therapy effect was assessed at the one-year follow-up with the Unified Parkinson's Disease Rating Scale-part III (UPDRSIII) motor component. Radiomics analysis of whole-brain white matter was performed with PyRadiomics. The following machine learning methods were used: logistic regression (LR), support vector machine, naïve Bayes, K-nearest neighbours, and random forest (RF) to allow prediction of clinically meaningful UPRDSIII motor response before and after. Clinical variables were also added to the model to improve accuracy. Results The RF model showed the best performance on the final whole dataset with an area under the curve (AUC) of 0.99, accuracy of 0.95, sensitivity of 0.93, and specificity of 0.97. At the same time, the LR model showed an AUC of 0.93, accuracy of 0.88, sensitivity of 0.84, and specificity of 0.91. Conclusions Machine learning models can be used in clinical decision support tools which can deliver true personalised therapy recommendations for PD patients. Clinicians and engineers should choose between best-performing, less interpretable models vs. most interpretable, lesser-performing models. Larger clinical trials would allow to build trust among clinicians and patients to widely use these AI tools in the future.

Functional connectivity-hemodynamic (un)coupling changes in chronic mild brain injury are associated with mental health and neurocognitive indices: a resting state fMRI study.

PURPOSE: To examine hemodynamic and functional connectivity alterations and their association with neurocognitive and mental health indices in patients with chronic mild traumatic brain injury (mTBI). METHODS: Resting-state functional MRI (rs-fMRI) and neuropsychological assessment of 37 patients with chronic mTBI were performed. Intrinsic connectivity contrast (ICC) and time-shift analysis (TSA) of the rs-fMRI data allowed the assessment of regional hemodynamic and functional connectivity disturbances and their coupling (or uncoupling). Thirty-nine healthy age- and gender-matched participants were also examined. RESULTS: Patients with chronic mTBI displayed hypoconnectivity in bilateral hippocampi and parahippocampal gyri and increased connectivity in parietal areas (right angular gyrus and left superior parietal lobule (SPL)). Slower perfusion (hemodynamic lag) in the left anterior hippocampus was associated with higher self-reported symptoms of depression (r = - 0.53, p = .0006) and anxiety (r = - 0.484, p = .002), while faster perfusion (hemodynamic lead) in the left SPL was associated with lower semantic fluency (r = - 0.474, p = .002). Finally, functional coupling (high connectivity and hemodynamic lead) in the right anterior cingulate cortex (ACC)) was associated with lower performance on attention and visuomotor coordination (r = - 0.50, p = .001), while dysfunctional coupling (low connectivity and hemodynamic lag) in the left ventral posterior cingulate cortex (PCC) and right SPL was associated with lower scores on immediate passage memory (r = - 0.52, p = .001; r = - 0.53, p = .0006, respectively). Uncoupling in the right extrastriate visual cortex and posterior middle temporal gyrus was negatively associated with cognitive flexibility (r = - 0.50, p = .001). CONCLUSION: Hemodynamic and functional connectivity differences, indicating neurovascular (un)coupling, may be linked to mental health and neurocognitive indices in patients with chronic mTBI.

The current status of noninvasive intracranial pressure monitoring: A literature review.

Elevated intracranial pressure (ICP) is a life-threatening condition that must be promptly diagnosed. However, the gold standard methods for ICP monitoring are invasive, time-consuming, and they involve certain risks. To address these risks, many noninvasive approaches have been proposed. This study undertakes a literature review of the existing noninvasive methods, which have reported promising results. The experimental base on which they are established, however, prevents their application in emergency conditions and thus none of them are capable of replacing the traditional invasive methods to date. On the other hand, contemporary methods leverage Machine Learning (ML) which has already shown unprecedented results in several medical research areas. That said, only a few publications exist on ML-based approaches for ICP estimation, which are not appropriate for emergency conditions due to their restricted capability of employing the medical imaging data available in intensive care units. The lack of such image-based ML models to estimate ICP is attributed to the scarcity of annotated datasets requiring directly measured ICP data. This ascertainment highlights an active and unexplored scientific frontier, calling for further research and development in the field of ICP estimation, particularly leveraging the untapped potential of ML techniques.

Chronic Mild Traumatic Brain Injury: Aberrant Static and Dynamic Connectomic Features Identified Through Machine Learning Model Fusion.

Traumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms.

Impact of Intracranial Hypertension on Outcome of Severe Traumatic Brain Injury Pediatric Patients: A 15-Year Single Center Experience.

Background: Intracranial hypertension (IC-HTN) is significantly associated with higher risk for an unfavorable outcome in pediatric trauma. Intracranial pressure (ICP) monitoring is widely becoming a standard of neurocritical care for children. Methods: The present study was designed to evaluate influences of IC-HTN on clinical outcomes of pediatric TBI patients. Demographic, injury severity, radiologic characteristics were used as possible predictors of IC-HTN or of functional outcome. Results: A total of 118 pediatric intensive care unit (PICU) patients with severe TBI (sTBI) were included. Among sTBI cases, patients with GCS < 5 had significantly higher risk for IC-HTN and for mortality. Moreover, there was a statistically significant positive correlation between IC-HTN and severity scoring systems. Kaplan−Meier analysis determined a significant difference for good recovery among patients who had no ICP elevations, compared to those who had at least one episode of IC-HTN (log-rank chi-square = 11.16, p = 0.001). A multivariable predictive logistic regression analysis distinguished the ICP-monitored patients at risk for developing IC-HTN. The model finally revealed that higher ISS and Helsinki CT score increased the odds for developing IC-HTN (p < 0.05). Conclusion: The present study highlights the importance of ICP-guided clinical practices, which may lead to increasing percentages of good recovery for children.

Acute paraplegia due to thoracolumbar schwannoma following trauma: A case report and literature review.

Spinal schwannomas account for one third of primary spinal neoplasms. Clinical presentation is related to the tumor location. An atypical case of acute paraplegia following a fall, on the ground of a thoracolumbar schwannoma, without intratumoral hemorrhage, in a previously asymptomatic patient is reported. A 58-year-old male patient presented with acute paraplegia, and urinary and bowel incontinence, following a fall. The patient had no previous history of back and/or leg pain or neurological symptoms. Magnetic resonance imaging revealed a subdural mass, as well as a fracture of the right T12-L1 facet joint and the right transverse process. The patient underwent emergency T11-L1 wide laminectomy, exploration of the subdural space and T10-L2 posterolateral transpedicular stabilization and fusion. An intradural, extramedullary mass, causing severe cord compression, was found and excised. Pathology revealed schwannoma, without intratumoral hemorrhage. The patient recovered completely 6 months postoperatively. To the best of our knowledge, this is the first report of spinal intradural schwannoma causing sudden paraplegia in a previously asymptomatic patient in the setting of trauma, without intratumoral hemorrhage. Emergency canal decompression and complete excision of the tumor represent the optimal management of such cases.

Intraoperative squash Cytology of diffuse glioma not otherwise specified, of the Cerebellum.

OBJECTIVE: Diffuse glioma arises anywhere in the CNS, but most frequent in the cerebral hemispheres. The tumor tends to be seen in children and in younger adults aged 20-30. We report one such case in an older female patient presenting the intraoperative cytology of the tumor. CASE REPORT: A 48-year-old female was diagnosed by MRI with a tumor of cerebellum. Cytologic material was obtained during the resection of the tumor and diagnosed cytologically as glioma. CONCLUSION: This case is presented to focus the ability of the intraoperative cytology in diagnosis of the glioma, using immunocytology and confirmed by histo- immunohistology.

Cerebrospinal fluid and intraoperative squash cytology of childhood ependymoma.

Ependymomas are glial neoplasms of central nervous system originated from the ependymal lining of the brain ventricles and spinal cord central canal, and rarely exfoliated into cerebrospinal fluid (CSF). In this case we report the cytomorphological and immunocytomorphological features of ependymoma in CSF and intraoperative squash preparations, confirmed by histology. Case report. The patient  was a nineteen months old female presented at the University hospital of Heraklion, Crete, in a hemicoma, and was intubated. Computed tomography, scanning and magnetic resonance imaging (MRI), were performed and a mass in the posterior fossa was found. A sample of cerebrospinal fluid (CSF) was sent for cytologic evaluation. A diagnosis of ependymoma was rendered, followed by tumor resection, during which intraoperative squash smears for cytologic interpretation were obtained. Cytological consultation disclosed a grade II ependymoma (WHO grade II), with focally anaplastic features (WHO grade III).

Cerebral perfusion disturbances in chronic mild traumatic brain injury correlate with psychoemotional outcomes.

The study explored associations between hemodynamic changes and psychoemotional status in 32 patients with chronic mild traumatic brain injury (mTBI) and 31 age-matched healthy volunteers. Cerebral blood flow (CBF) and cerebral blood volume (CBV) values were obtained using Dynamic Susceptibility Contrast Magnetic Resonance Imaging in brain regions suspected to play a role in anxiety and depression. Patients were administered self-report measures of anxiety and depression symptoms and underwent neuropsychological assessment. As a group mTBI patients scored significantly below age- and education-adjusted population norms on multiple cognitive domains and reported high rates of anxiety and depression symptomatology. Significantly reduced CBF values were detected in the mTBI group compared to controls in dorsolateral prefrontal areas, putamen, and hippocampus, bilaterally. Within the mTBI group, depressive symptomatology was significantly associated with lower perfusion in the left anterior cingulate gyrus and higher perfusion in the putamen, bilaterally. The latter association was independent from verbal working memory capacity. Moreover, anxiety symptomatology was associated with lower perfusion in the hippocampus (after controlling for verbal episodic memory difficulties). Associations between regional perfusion and psychoemotional scores were specific to depression or anxiety, respectively, and independent of the presence of visible lesions on conventional MRI. Results are discussed in relation to the role of specific limbic and paralimbic regions in the pathogenesis of symptoms of depression and anxiety.

A 3D tumor spheroid model for the T98G Glioblastoma cell line phenotypic characterization.

Major Glioblastoma's hallmarks include proliferation, invasion and heterogeneity. Biological 3D tumor spheroid models can serve as intermediate systems between traditional 2D cell culture and complex in vivo models. Tumor spheroids have been shown to more accurately reproduce the spatial organization and microenvironmental factors of in vivo micro-tumors, such as relevant gradients of nutrients and other molecular agents, while they maintain cell-to-cell and cell-to-matrix interactions. In vitro 3D assays are useful to monitor these properties. Here, we test the suitability of the well-known T98 G Glioblastoma cell line in such a 3D assay. The doubling time and death rate parameters of T98 G are estimated, as well as their spheroidal growth-expansion curves with and without the presence of basement membrane substrate. The T98 G invasive profile is characterized by collective morphology and proliferation-associated invasion. We show that the T98 G secondary GB cell line exhibits both invasive and proliferative capabilities in 3D and thus, can serve as control cell line for the 3D in vitro study of primary GB cell cultures.

Schwannoma of right cerebellopontine angle. A cytologic diagnosis.

Schwannomas affect mainly head and neck peripheral nerves, are benign tumors and derive from Schwann cells. Schwannoma of right cerebellopontine angle is extremely rare to diagnose by cytology. We report one such rare case presenting the cytological features in material obtained during the resection of the tumor. Case report: A 47-year-old female was diagnosed by MRI with a tumor of right cerebellopontine angle.. Cytologic material from the tumor was obtained intraoperatively and diagnosed cytologically as a neurilemoma. Conclusion: This case is presented here to focus the ability of cytology in diagnosis of schwannoma in intraoperative material of the tumor, using immunohistochemistry and confirmed by histology- immunohistochemistry.

Childhood central nervous system tumours: Incidence and time trends in 13 Southern and Eastern European cancer registries.

AIM: Following completion of the first 5-year nationwide childhood (0-14 years) registration in Greece, central nervous system (CNS) tumour incidence rates are compared with those of 12 registries operating in 10 Southern-Eastern European countries. METHODS: All CNS tumours, as defined by the International Classification of Childhood Cancer (ICCC-3) and registered in any period between 1983 and 2014 were collected from the collaborating cancer registries. Data were evaluated using standard International Agency for Research on Cancer (IARC) criteria. Crude and age-adjusted incidence rates (AIR) by age/gender/diagnostic subgroup were calculated, whereas time trends were assessed through Poisson and Joinpoint regression models. RESULTS: 6062 CNS tumours were retrieved with non-malignant CNS tumours recorded in eight registries; therefore, the analyses were performed on 5191 malignant tumours. Proportion of death certificate only cases was low and morphologic verification overall high; yet five registries presented >10% unspecified neoplasms. The male/female ratio was 1.3 and incidence decreased gradually with age, apart from Turkey and Ukraine. Overall AIR for malignant tumours was 23/10(6) children, with the highest rates noted in Croatia and Serbia. A statistically significant AIR increase was noted in Bulgaria, whereas significant decreases were noted in Belarus, Croatia, Cyprus and Serbia. Although astrocytomas were overall the most common subgroup (30%) followed by embryonal tumours (26%), the latter was the predominant subgroup in six registries. CONCLUSION: Childhood cancer registration is expanding in Southern-Eastern Europe. The heterogeneity in registration practices and incidence patterns of CNS tumours necessitates further investigation aiming to provide clues in aetiology and direct investments into surveillance and early tumour detection.

A comparison of acute hemorrhagic stroke outcomes in 2 populations: the Crete-Boston study.

BACKGROUND AND PURPOSE: Although corticosteroid use in acute hemorrhagic stroke is not widely adopted, management with intravenous dexamethasone has been standard of care at the University Hospital of Heraklion, Crete with observed outcomes superior to those reported in the literature. To explore this further, we conducted a retrospective, multivariable-adjusted 2-center study. METHODS: We studied 391 acute hemorrhagic stroke cases admitted to the University Hospital of Heraklion, Crete between January 1997 and July 2010 and compared them with 510 acute hemorrhagic stroke cases admitted to Massachusetts General Hospital, Boston, from January 2003 to September 2009. Of the Cretan cases, 340 received a tapering scheme of intravenous dexamethasone, starting with 16 to 32 mg/day, whereas the Boston patients were managed without steroids. RESULTS: The 2 cohorts had comparable demographics and stroke severity on admission, although anticoagulation was more frequent in Boston. The in-hospital mortality was significantly lower on Crete (23.8%, n=340) than in Boston (38.0%, n=510; P<0.001) as was the 30-day mortality (Crete: 25.4%, n=307; Boston: 39.4%, n=510; P<0.001). Exclusion of patients on anticoagulants showed even greater differences (30-day mortality: Crete 20.8%; n=259; Boston 37.0%; n=359; P<0.001). The improved survival on Crete was observed 3 days after initiation of intravenous dexamethasone and was pronounced for deep-seated hemorrhages. After adjusting for acute hemorrhagic stroke volume/location, Glasgow Coma Scale, hypertension, diabetes mellitus, smoking, coronary artery disease and statin, antiplatelet, and anticoagulant use, intravenous dexamethasone treatment was associated with better functional outcomes and significantly lower risk of death at 30 days (OR, 0.357; 95% CI, 0.174-0.732). CONCLUSIONS: This study suggests that intravenous dexamethasone improves outcome in acute hemorrhagic stroke and supports a randomized clinical trial using this approach.

Mild traumatic brain injury: graph-model characterization of brain networks for episodic memory.

Episodic memory is among the cognitive functions that can be affected in the acute phase following mild traumatic brain injury (MTBI). The present study used EEG recordings to evaluate global synchronization and network organization of rhythmic activity during the encoding and recognition phases of an episodic memory task varying in stimulus type (kaleidoscope images, pictures, words, and pseudowords). Synchronization of oscillatory activity was assessed using a linear and nonlinear connectivity estimator and network analyses were performed using algorithms derived from graph theory. Twenty five MTBI patients (tested within days post-injury) and healthy volunteers were closely matched on demographic variables, verbal ability, psychological status variables, as well as on overall task performance. Patients demonstrated sub-optimal network organization, as reflected by changes in graph parameters in the theta and alpha bands during both encoding and recognition. There were no group differences in spectral energy during task performance or on network parameters during a control condition (rest). Evidence of less optimally organized functional networks during memory tasks was more prominent for pictorial than for verbal stimuli.

Material-specific difficulties in episodic memory tasks in mild traumatic brain injury.

The study examines acute, material-specific secondary memory performance in 26 patients with mild traumatic brain injury (MTBI) and 26 healthy controls, matched on demographic variables and indexes of crystallized intelligence. Neuropsychological tests were used to evaluate primary and secondary memory, executive functions, and verbal fluency. Participants were also tested on episodic memory tasks involving words, pseudowords, pictures of common objects, and abstract kaleidoscopic images. Patients showed reduced performance on episodic memory measures, and on tasks associated with visuospatial processing and executive function (Trail Making Test part B, semantic fluency). Significant differences between groups were also noted for correct rejections and response bias on the kaleidoscope task. MTBI patients' reduced performance on memory tasks for complex, abstract stimuli can be attributed to a dysfunction in the strategic component of memory process.

YY1 Over-expression in human brain gliomas and meningiomas correlates with TGF-beta1, IGF-1 and FGF-2 mRNA levels.

In this study we examined by QRT-PCR the mRNA expression of TGF-beta 1, IGF-1, EGF, FGF-2 and YY1 in human brain tumors. Our findings introduce YY1, for the first time, as a novel gene implicated in brain gliomatogenesis and meningioma establishment. We present a positive correlation between the autocrine expression of YY1 and TGF-beta 1, IGF-1 and FGF-2, known to be involved in the progression of gliomas and meningiomas. We suggest that mRNA profiling of the above genes in the early stages of disease development could be useful for prognostic purposes, and these genes can be considered as potential targets for therapeutic approaches against brain tumors.

Down-regulation of K-ras and H-ras in human brain gliomas.

Ras genes, a class of nucleotide-binding proteins that regulate normal and transformed cell growth, have been scarcely investigated in human brain tumours. We evaluated the mutational, mRNA and protein expression profile of the ras genes in 21 glioblastomas multiforme (grade IV), four fibrillary astrocytoma (grade II), four anaplastic astrocytoma (grade III) and 15 normal specimens. K-, H- and N-ras transcript levels were determined by real-time RT-PCR and mutational status by PCR-restriction fragment length polymorphism (RFLP) and direct sequencing. p21 protein was evaluated by Western blot analysis. Two K-ras mutations were found in codons 16 and 26 in one pathological and one normal sample, respectively. Glioblastoma multiforme cases exhibited significantly lower K- and H-ras mRNA levels compared to controls (P < 10(-4)). K- and H-ras mRNA down-regulation was not associated with patient outcome or survival. K-ras was positively correlated with H-ras in glioblastomas (P = 0.005), but not in normal specimens. p21 protein was absent in all samples. Our findings provide evidence of K- and H-ras involvement in brain malignant transformation through transcriptional down-regulation, while N-ras seems to contribute less to brain carcinogenesis.

Transient acute obstructive hydrocephalus of unknown origin in a 13-month-old infant.

We report on a case of a 13-month-old female infant who was admitted to our department with the chief complaints of drowsiness and vomiting. A history of an unspecified viral infection was reported. Clinical examination was negative for focal neurological signs or signs of central nervous system infection. Initial CT scan revealed obstructive hydrocephalus, and shunting was scheduled. Dexamethasone treatment was started. Eight hours after admission the child almost restored his baseline mental status and the operation was postponed. The dexamethasone treatment was discontinued 3 days later. Follow up CT and MRI scans were normal. We discuss the case and the possible causes of transient hydrocephalus in children.