Postsurgical morbidity and mortality favorably informs deep brain stimulation for new indications including schizophrenia and schizoaffective disorder.

Background: Deep brain stimulation (DBS) shows promise for new indications like treatment-refractory schizophrenia in early clinical trials. In the first DBS clinical trial for treatment refractory schizophrenia, despite promising results in treating psychosis, one of the eight subjects experienced both a symptomatic hemorrhage and an infection requiring device removal. Now, ethical concerns about higher surgical risk in schizophrenia/schizoaffective disorder (SZ/SAD) are impacting clinical trial progress.

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

Introduction: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison.

Review of serum prolactin levels as an antipsychotic-response biomarker.

Antipsychotics acting as antagonists at dopamine D2 receptors concentrated in the striatum are the cornerstone of effective treatment of psychosis. Substantial progress in treating persons with schizophrenia could be achieved by the identification of biomarkers which reliably determine the lowest efficacious dose of antipsychotics. Prolactin levels have been considered a promising treatment-response biomarker due to dopamine's regulation of serum prolactin levels through D2 receptors in the hypothalamic-pituitary pathway.

Approaches to neuromodulation for schizophrenia.

Based on the success of deep brain stimulation (DBS) for treating movement disorders, there is growing interest in using DBS to treat schizophrenia (SZ). We review the unmet needs of patients with SZ and the scientific rationale behind the DBS targets proposed in the literature in order to guide future development of DBS to treat this vulnerable patient population. SZ remains a devastating disorder despite treatment.

Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System.

Background: Deep brain stimulation (DBS) is the most commonly performed surgery for the debilitating symptoms of Parkinson disease (PD). However, DBS systems remain largely unaffordable to patients in developing countries, warranting the development of a safe, economically viable, and functionally comparable alternative.

Objective: To investigate the efficacy and safety of wirelessly programmed DBS of bilateral subthalamic nucleus (STN) in patients with primary PD.

Correlated expression analysis of genes implicated in schizophrenia: identification of putative disease-related pathways.

Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population.[1] When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality.

Elevated DISC1 transcript levels in PBMCs during acute psychosis in patients with schizophrenia.

BACKGROUND: Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges.

A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia.

Multiple genetic linkage studies support the hypothesis that the 15q13-14 chromosomal region contributes to the etiology of schizophrenia. Among the putative candidate genes in this area are the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) and its partial duplication, CHRFAM7A. A large chromosomal segment including the CHRFAM7A gene locus, but not the CHRNA7 locus, is deleted in some individuals.

Cerebral cavernous malformations: somatic mutations in vascular endothelial cells.

Objective: Germline mutations in 3 genes have been found in familial cases of cerebral cavernous malformations (CCMs). We previously discovered somatic and germline truncating mutations in the KRIT1 gene, supporting the "2-hit" mechanism of CCM lesion formation in a single lesion. The purpose of this study was to screen for somatic, nonheritable mutations in 3 more lesions from different patients and identify the cell type(s) in which somatic mutations occur.

Familial cerebral cavernous malformations: Rio de Janeiro study and review of the recommendations for management.

Objective: Multiple cerebral cavernous malformation (CCM) is the hallmark of familial presentation of cavernous malformation in the brain. We describe an ongoing Familial Cerebral Cavernous Malformation Project in the Rio de Janeiro state showing genetic profile and the pattern of emergent neuroimaging findings of this particular population besides a review of the updated recommendations for management of familial CCM versus patients harboring sporadic lesions.

Method: Four families of our cohort of 9 families were genetically mapped showing mutational profile linked to CCM1.

Spinal root arteriovenous malformations and same-segment cord cavernous malformation in familial cerebral cavernous malformation. Case report.

Spinal vascular malformations are uncommon lesions, and controversy persists regarding optimal investigation, classification, and treatment strategies. The authors report on a patient with a spinal root arteriovenous malformation (AVM) associated with a parenchymal cavernous malformation (CM) in the same spinal cord segment and describe a complete familial and molecular investigation. This 35-year-old woman presented with symptoms of progressive clinical spastic paraparesis.

Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.

Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in hemorrhagic stroke and seizures. Familial forms of CCM are inherited in an autosomal-dominant fashion, and three CCM genes have been identified. We recently determined that large genomic deletions in the CCM2 gene represent 22% of mutations in a large CCM cohort from the USA.

Spectrum of genotype and clinical manifestations in cerebral cavernous malformations.

Objective: Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies predisposing individuals to hemorrhagic stroke and epilepsy. CCMs are sporadic or inherited as autosomal dominant disease with three known genes. The hypothesis that genetic heterogeneity would account for the remarkable variability in CCM manifestations was tested.

An adult case of leukoencephalopathy with intracranial calcifications and cysts.

We describe a 44-year-old woman with progressive headache, ataxia, and seizures in association with multifocal cerebral and cerebellar leukoencephalopathy, intracranial calcifications, and cysts. The cause of death was intracerebellar hemorrhage while taking warfarin. Pathologic features on biopsy included angiomatous-like blood vessels, intense gliosis, and Rosenthal fiber formation in the white matter.

Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion.

Background And Purpose: Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies that predispose patients to hemorrhagic stroke and epilepsy. CCMs are sporadic or inherited and 3 genes (CCM1, CCM2, and CCM3) have been identified. However, the role of somatic mutation in CCM genesis has been disputed.

Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations.

Objective: Cerebral cavernous malformations (CCMs) are associated with hemorrhagic proliferation of endothelial-lined vascular caverns, resulting in hemorrhagic stroke, epilepsy, and other neurological manifestations. We hypothesize that structural protein expression and endothelial cell proliferation markers within CCM lesions are different in the setting of various clinical manifestations.

Methods: The percentage of immunohistochemically stained caverns positive for collagen IV, fibronectin, laminin, alpha-smooth muscle actin, myosin, and smoothelin and the percentage of dividing endothelial cells within caverns were determined in 36 excised CCM surgical specimens.

Multiple spinal cavernous malformations with atypical phenotype after prior irradiation: case report.

Objective And Importance: This is the first reported case of histologically proven multiple spinal cavernous malformations (CMs) associated with previous irradiation. There are only two cases reported in the literature of solitary spinal CM after irradiation. In addition, the lesions in our patient had an atypical magnetic resonance imaging appearance mimicking intraspinal drop metastasis.

Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance.

Cerebrovascular malformations affect more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features.

Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects.

The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects.

Differential gene expression in human cerebrovascular malformations.

Objective: We sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions.

Methods: Total ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis.

Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.

Background: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects.