Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons

Acute Amnesia due to Isolated Mammillary Body Infarct

BACKGROUND: There are limited reports describing acute amnesia after mammillothalamic tract infarction. Furthermore, acute infarction isolated to the mammillary body has never been reported. We present the first case of anterograde amnesia after isolated acute infarction of the mammillary body in a patient without concurrent or prior thalamic or mammillothalamic tract injury. METHODS: A retrospective review of the patient\u27s electronic medical record including inpatient notes and all radiological examinations was performed. RESULTS: A 50-year-old woman presented with acute onset of confusion and constant repetition of the same questions. Magnetic resonance (MR) imaging of the brain showed isolated acute infarct of the left mammillary body without concurrent abnormality of the thalamus or mammillothalamic tract. MR angiography showed severe stenosis of the proximal posterior cerebral artery at the origin of the perforating mammillary artery. CONCLUSIONS: Isolated injury to the mammillary body is rare. In addition to recognized memory-related structures such as the thalamus and mammillothalamic tract, mammillary body injury may also play a role in memory dysfunction. Knowledge of the vascular supply of memory-related structures is important in diagnosing and understanding memory dysfunction

Chronic, Painful Abducens Palsy May Require Angiography

"Posteriorly-draining cavernous-carotid fistulas (CCFs) ("white-eyed shunts") can present with painful cranial nerve palsies. We report a case of posteriorly-draining CCF presenting as a persistently painful, chronic left abducens palsy.

Purtscher's Retinopathy as a Manifestation of Hemophagocytic Lymphohistiocytosis (.pdf)

Hemophagocytic Lymphohistiocytosis (HLH) is an inflammatory disease whose diagnostic criteria include fever, cytopenia, and hemophagocytosis in the bone marrow. Often incited by viral infections, it leads to uncontrolled activation of macrophages and a subsequent cytokine storm. We describe the case of a 52-year-old previously healthy Hispanic woman who presented with bilateral vision loss and purtschers retinopathy secondary to HLH

Glioblastoma Induces Vascular Dysregulation in Nonenhancing Peritumoral Regions in Humans.

ObjectiveGlioblastoma is an invasive primary brain malignancy that typically infiltrates the surrounding tissue with malignant cells. It disrupts cerebral blood flow through a variety of biomechanical and biochemical mechanisms. Thus, neuroimaging focused on identifying regions of vascular dysregulation may reveal a marker of tumor spread. The purpose of this study was to use blood oxygenation level-dependent (BOLD) functional MRI (fMRI) to compare the temporal dynamics of the enhancing portion of a tumor with those of brain regions without apparent tumors.Materials and methodsPatients with pathologically proven glioblastoma underwent preoperative resting-state BOLD fMRI, T1-weighted contrast-enhanced MRI, and FLAIR MRI. The contralesional control hemisphere, contrast-enhancing tumor, and peritu-moral edema were segmented by use of structural images and were used to extract the time series of these respective regions. The parameter estimates (beta values) for the two regressors and resulting z-statistic images were used as a metric to compare the similarity of the tumor dynamics to those of other brain regions.ResultsThe time course of the contrast-enhancing tumor was significantly different from that of the rest of the brain (p < 0.05). Similarly, the control signal intensity was significantly different from the tumor signal intensity (p < 0.05). Notably, the temporal dynamics in the peritumoral edema, which did not contain enhancing tumor, were most similar to the those of enhancing tumor than to those of control regions.ConclusionThe findings show that the disruption in vascular regulation induced by a glioblastoma can be detected with BOLD fMRI and that the spatial distribution of these disruptions is localized to the immediate vicinity of the tumor and peritumoral edema

Local Glioma Cells Are Associated with Vascular Dysregulation.

BACKGROUND AND PURPOSE: Malignant glioma is a highly infiltrative malignancy that causes variable disruptions to the structure and function of the cerebrovasculature. While many of these structural disruptions have known correlative histopathologic alterations, the mechanisms underlying vascular dysfunction identified by resting-state blood oxygen level-dependent imaging are not yet known. The purpose of this study was to characterize the alterations that correlate with a blood oxygen level-dependent biomarker of vascular dysregulation. MATERIALS AND METHODS: Thirty-two stereotactically localized biopsies were obtained from contrast-enhancing (n = 16) and nonenhancing (n = 16) regions during open surgical resection of malignant glioma in 17 patients. Preoperative resting-state blood oxygen level-dependent fMRI was used to evaluate the relationships between radiographic and histopathologic characteristics. Signal intensity for a blood oxygen level-dependent biomarker was compared with scores of tumor infiltration and microvascular proliferation as well as total cell and neuronal density. RESULTS: Biopsies corresponded to a range of blood oxygen level-dependent signals, ranging from relatively normal (z = -4.79) to markedly abnormal (z = 8.84). Total cell density was directly related to blood oxygen level-dependent signal abnormality (P = .013, R2 = 0.19), while the neuronal labeling index was inversely related to blood oxygen level-dependent signal abnormality (P = .016, R2 = 0.21). The blood oxygen level-dependent signal abnormality was also related to tumor infiltration (P = .014) and microvascular proliferation (P = .045). CONCLUSIONS: The relationship between local, neoplastic characteristics and a blood oxygen level-dependent biomarker of vascular function suggests that local effects of glioma cell infiltration contribute to vascular dysregulation

Eye Tracking for Deep Learning Segmentation Using Convolutional Neural Networks.

Deep learning with convolutional neural networks (CNNs) has experienced tremendous growth in multiple healthcare applications and has been shown to have high accuracy in semantic segmentation of medical (e.g., radiology and pathology) images. However, a key barrier in the required training of CNNs is obtaining large-scale and precisely annotated imaging data. We sought to address the lack of annotated data with eye tracking technology. As a proof of principle, our hypothesis was that segmentation masks generated with the help of eye tracking (ET) would be very similar to those rendered by hand annotation (HA). Additionally, our goal was to show that a CNN trained on ET masks would be equivalent to one trained on HA masks, the latter being the current standard approach. Step 1: Screen captures of 19 publicly available radiologic images of assorted structures within various modalities were analyzed. ET and HA masks for all regions of interest (ROIs) were generated from these image datasets. Step 2: Utilizing a similar approach, ET and HA masks for 356 publicly available T1-weighted postcontrast meningioma images were generated. Three hundred six of these image + mask pairs were used to train a CNN with U-net-based architecture. The remaining 50 images were used as the independent test set. Step 1: ET and HA masks for the nonneurological images had an average Dice similarity coefficient (DSC) of 0.86 between each other. Step 2: Meningioma ET and HA masks had an average DSC of 0.85 between each other. After separate training using both approaches, the ET approach performed virtually identically to HA on the test set of 50 images. The former had an area under the curve (AUC) of 0.88, while the latter had AUC of 0.87. ET and HA predictions had trimmed mean DSCs compared to the original HA maps of 0.73 and 0.74, respectively. These trimmed DSCs between ET and HA were found to be statistically equivalent with a p value of 0.015. We have demonstrated that ET can create segmentation masks suitable for deep learning semantic segmentation. Future work will integrate ET to produce masks in a faster, more natural manner that distracts less from typical radiology clinical workflow

Semiautomated volumetric measurement on postcontrast MR imaging for analysis of recurrent and residual disease in glioblastoma multiforme

BACKGROUND AND PURPOSE: A limitation in postoperative monitoring of patients with glioblastoma is the lack of objective measures to quantify residual and recurrent disease. Automated computer-assisted volumetric analysis of contrast-enhancing tissue represents a potential tool to aid the radiologist in following these patients. In this study, we hypothesize that computer-assisted volumetry will show increased precision and speed over conventional 1D and 2D techniques in assessing residual and/or recurrent tumor. MATERIALS AND METHODS: This retrospective study included patients with native glioblastomas with MR imaging performed at 24-48 hours following resection and 2-4 months postoperatively. 1D and 2D measurements were performed by 2 neuroradiologists with Certificates of Added Qualification. Volumetry was performed by using manual segmentation and computer-assisted volumetry, which combines region-based active contours and a level set approach. Tumor response was assessed by using established 1D, 2D, and volumetric standards. Manual and computer-assisted volumetry segmentation times were compared. Interobserver correlation was determined among 1D, 2D, and volumetric techniques. RESULTS: Twenty-nine patients were analyzed. Discrepancy in disease status between 1D and 2D compared with computer-assisted volumetry was 10.3% (3/29) and 17.2% (5/29), respectively. The mean time for segmentation between manual and computer-assisted volumetry techniques was 9.7 minutes and \u3c1 \u3eminute, respectively (P \u3c .01). Interobserver correlation was highest for volumetric measurements (0.995; 95% CI, 0.990-0.997) compared with 1D (0.826; 95% CI, 0.695-0.904) and 2D (0.905; 95% CI, 0.828-0.948) measurements. CONCLUSIONS: Computer-assisted volumetry provides a reproducible and faster volumetric assessment of enhancing tumor burden, which has implications for monitoring disease progression and quantification of tumor burden in treatment trials