Differences in Interfacility Transfer from Emergency Department and Inpatient Services for Inpatient Neurologic Care.

Introduction: Interhospital transfer is an important mechanism for improving access to specialized neurologic care but there are large gaps in our understanding of interhospital transfer for the management of non-stroke-related neurologic disease. Methods: This observational study included consecutive patients admitted to an adult academic general neurology service via interhospital transfer from July 1, 2015 to July 1, 2017. Characteristics of the referring hospital and transferred patients were obtained through the American Hospital Association Directory, a hospital transfer database maintained by the accepting hospital, and the electronic medical record. The analyses used descriptive statistics to examine the cohort overall and compare characteristics of patients transferred from an emergency department and inpatient service. Results: 504 patients were admitted via interhospital transfer during the study period. Of these, 395 patients (78.4%) were transferred because the referring hospital lacked capability, and 139 patients (27.6%) were transferred from an emergency department as opposed to inpatient service. Seizures was the most common diagnosis (23.8%). Patients who were transferred from an emergency department had a higher proportion covered by Medicaid (44.6%) than those transferred from an inpatient service (28.8%) and had a shorter median length of stay (3 days; IQR 2-7 vs 7 days; IQR 4-12). Conclusions: The majority of observed interhospital non-stroke neurologic transfers occurred to improve access to specialized neurological care for patients, though patients transferred from the ED, as opposed to an inpatient service, had lower health care utilization, and this will be important to consider when developing systems of care and in future research.

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

Amyloid-ß related angiitis presenting as eosinophilic meningitis: a case report.

BACKGROUND: Eosinophilic meningitis is uncommon and often attributed to infectious causes. CASE PRESENTATION: We describe a case of a 72-year-old man who presented with subacute onset eosinophilic meningitis, vasculitis, and intracranial hypertension with progressive and severe neurologic symptoms. Brain MRI demonstrated multifocal strokes and co-localized right temporo-parieto-occipital vasogenic edema, cortical superficial siderosis, and diffuse leptomeningeal enhancement. He ultimately underwent brain biopsy with immunohistochemical stains for amyloid-ß and Congo red that were extensively positive in the blood vessel walls and in numerous diffuse and neuritic parenchymal confirming a diagnosis of amyloid-ß related angiitis. He was treated with immunosuppression with clinical stabilization. CONCLUSIONS: Amyloid-ß related angiitis is an underrecognized cause of eosinophilic meningitis that can present fulminantly and is typically responsive to immunosuppression. The presence of eosinophils may provide additional clues to the underlying pathophysiology of amyloid-ß related angiitis.

Approach to Myelopathy and Myelitis.

Myelopathy can present acutely or more insidiously and has a broad differential diagnosis. In addition to the clinical history and neurologic examination, diagnostic testing, including MRI and cerebrospinal fluid analysis, as well as thorough review of patient comorbidities, risk factors, and potential toxic exposures, can help neurohospitalists distinguish between various causes and potentially start appropriate empiric therapy while awaiting definitive testing. This article focuses on how imaging can help in determining the most likely cause of myelopathy and highlights a range of causes, including compressive, vascular, metabolic and toxic, infectious, autoimmune, neoplastic, and paraneoplastic causes of spinal cord dysfunction.

An Elusive Seizure.

We present a case of a healthy 62-year-old woman who developed recurrent seizures preceded by subacute cognitive slowing, ataxia, night sweats, and weight loss. She was found to have cytopenias, multifocal T2/FLAIR hyperintensities on magnetic resonance imaging (MRI), and magnetic susceptibility artifact lesions on susceptibility weighted imaging (SWI). Her symptoms, imaging and laboratory abnormalities all improved with high-doses of steroids and intravenous immunoglobulin (IVIG). But recurred several weeks after completing treatment. Despite extensive work-up, she required multiple hospitalizations and repeat diagnostic studies to arrive at a diagnosis. With an expert discussant in hematology and oncology, we review the differential diagnosis and stepwise approach of unexplained neuro-inflammatory syndromes with cytopenias and systemic symptoms. Our case highlights how time, empiric treatment response, and repeated diagnostic studies refine differential diagnoses and subsequent evaluation. After revealing the diagnosis, we discuss the heterogenous clinical manifestations of this disease process.

Detection of Neoplasms by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid.

Importance: Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis. Objective: To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm. Design, Setting, and Participants: Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed. Main Outcomes and Measures: The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance. Results: Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%. Conclusions and Relevance: This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.

Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing.

Importance: Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective: To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants: In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures: Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results: The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance: Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

National characteristics and predictors of neurologic 30-day readmissions.

OBJECTIVE: To examine national 30-day readmission rates for patients hospitalized with neurologic disorders. METHODS: Using the University HealthSystem Consortium (UHC) database, we identified 554,399 index neurologic admissions from October 2011 through January 2015. We collected information regarding age, race, insurance payer, Medicare severity diagnosis-related group, and severity of illness. We examined readmission by diagnosis and performed multivariable logistic regression to determine predictors of readmission. RESULTS: The unplanned readmission rate was 11.0%. Rates of unplanned readmission were highest for patients with peripheral nerve disorders (21.9%), CNS neoplasms (21.0%), nonhypertensive encephalopathy (15.5%), arterial stenosis (15.4%), and bacterial CNS infections (14.5%). In multivariable analysis, higher severity of illness and public health insurance coverage predicted higher rates of 30-day readmission. CONCLUSION: We found significant variation in readmission rates for different neurologic disorders. These data provide insight into management of neurologic disease nationally, offering policymakers realistic goals for standards of care and challenging health care providers to develop systems-based solutions that will improve transitions of care for those at highest risk of readmission with neurologic disease.

Time from onset of SIRS to antibiotic administration and outcomes after subarachnoid hemorrhage.

INTRODUCTION: The interval from presentation with systemic inflammatory response syndrome (SIRS) to the start of antibiotic administration affects mortality in patients with sepsis. However, patients with subarachnoid hemorrhage (SAH) often develop SIRS directly from their brain injury, making it a less useful indicator of infection. We therefore hypothesized that SIRS would not be a suitable trigger for antibiotics in this population. METHODS: We examined the time from the development of SIRS until antibiotic initiation and its relationship to long-term neurological outcomes in patients with nontraumatic SAH. Patients' baseline characteristics, time of antibiotic administration, and hospital course were collected from retrospective chart review. The primary outcome, 6-month functional status, was prospectively determined using blinded, structured interviews incorporating the modified Rankin Scale (mRS). RESULTS: Sixty-six of 70 patients with SAH during the study period had 6-month follow-up and were included in this analysis. SIRS developed in 57 patients (86%, 95% CI 78-95%). In ordinal logistic regression models controlling for age and illness severity, the time from SIRS onset until antibiotic initiation was not associated with 6-month mRS scores (OR per hour, 0.994; 95% CI 0.987-1.001). CONCLUSIONS: In this cohort of patients with SAH, time from SIRS onset until antibiotic administration was not related to functional outcomes. Our results indicate that SIRS is nonspecific in patients with SAH, and support the safety of withholding antibiotics in those who lack additional evidence of infection or hemodynamic deterioration.

The use of neuroimaging studies and neurological consultation to evaluate dizzy patients in the emergency department.

BACKGROUND AND PURPOSE: Dizziness is a frequent reason for neuroimaging and neurological consultation, but little is known about the utility of either practice. We sought to characterize the patterns and yield of neuroimaging and neurological consultation for dizziness in the emergency department (ED). METHODS: We retrospectively identified consecutive adults presenting to an academic ED from 2007 to 2009, with a primary complaint of dizziness, vertigo, or imbalance. Neurologists reviewed medical records to determine clinical characteristics, whether a neuroimaging study (head computed tomography [CT] or brain magnetic resonance imaging [MRI]) or neurology consultation was obtained in the ED, and to identify relevant findings on neuroimaging studies. Two neurologists assigned a final diagnosis for the cause of dizziness. Logistic regression was used to evaluate bivariate and multivariate predictors of neuroimaging and consultation. RESULTS: Of 907 dizzy patients (mean age 59 years; 58% women), 321 (35%) had a neuroimaging study (28% CT, 11% MRI, and 4% both) and 180 (20%) had neurological consultation. Serious neurological disease was ultimately diagnosed in 13% of patients with neuroimaging and 21% of patients with neurological consultation, compared to 5% of the overall cohort. Headache and focal neurological deficits were associated with both neuroimaging and neurological consultation, while age ≥60 years and prior stroke predicted neuroimaging but not consultation, and positional symptoms predicted consultation but not neuroimaging. CONCLUSION: In a tertiary care ED, neuroimaging and neurological consultation were frequently utilized to evaluate dizzy patients, and their diagnostic yield was substantial.

Rate and predictors of serious neurologic causes of dizziness in the emergency department.

OBJECTIVE: To describe the rate and predictors of central nervous system (CNS) disease in emergency department (ED) patients with dizziness in the modern era of neuroimaging. PATIENTS AND METHODS: We retrospectively reviewed the medical records of all adults presenting between January 1, 2007, and December 31, 2009, to an academic ED for a primary triage complaint of dizziness, vertigo, or imbalance. The final diagnosis for the cause of dizziness was independently assigned by 2 neurologists, with a third neurologist resolving any disagreements. The primary outcome was a composite of ischemic stroke, intracranial hemorrhage, transient ischemic attack, seizure, brain tumor, demyelinating disease, and CNS infection. Univariate and multivariate logistic regression were used to assess the association between clinical variables and serious CNS causes of dizziness. RESULTS: Of 907 patients experiencing dizziness (mean age, 59 years; 58% women [n=529]), 49 (5%) had a serious neurologic diagnosis, including 37 cerebrovascular events. Dizziness was often caused by benign conditions, such as peripheral vertigo (294 patients [32%]) or orthostatic hypotension (121 patients [13%]). Age 60 years or older (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.5-11.2), a chief complaint of imbalance (OR, 5.9; 95% CI, 2.3-15.2), and any focal examination abnormality (OR, 5.9; 95% CI, 3.1-11.2) were independently associated with serious neurologic diagnoses, whereas isolated dizziness symptoms were inversely associated (OR, 0.2; 95% CI, 0.0-0.7). CONCLUSION: Dizziness in the ED is generally benign, although a substantial fraction of patients harbor serious neurologic disease. Clinical suspicion should be heightened for patients with advanced age, imbalance, or focal deficits.

Application of the ABCD2 score to identify cerebrovascular causes of dizziness in the emergency department.

BACKGROUND AND PURPOSE: Dizziness can herald a cerebrovascular event. The ABCD(2) score predicts the risk of stroke after transient ischemic attack partly by distinguishing transient ischemic attack from mimics. We evaluated whether this score would also identify cerebrovascular events among emergency department patients with dizziness. METHODS: We retrospectively identified consecutive adults presenting to a university emergency department with a primary symptom of dizziness, vertigo, or imbalance. Two neurologists independently reviewed medical records to determine whether the presenting symptom was caused by a cerebrovascular event (ischemic stroke, transient ischemic attack, or intracranial hemorrhage). ABCD(2) scores were then assigned using clinical information from the medical record. The ability of the score to discriminate between patients with cerebrovascular events and those with other diagnoses was quantified using the c statistic. RESULTS: Among 907 dizzy patients (mean age, 59 years; 58% female), 37 (4.1%) had a cerebrovascular cause, the majority of which were ischemic strokes (n=24). The median ABCD(2) score was 3 (interquartile range, 3-4). The ABCD(2) score predicted ultimate diagnosis of a cerebrovascular event (c statistic, 0.79; 95% CI, 0.73-0.85). Only 5 of 512 (1.0%) patients with a score of ≤ 3 had a cerebrovascular event compared to 25 of 369 patients (6.8%) with a score of 4 or 5 and 7 of 26 patients (27.0%) with a score of 6 or 7. CONCLUSIONS: The ABCD(2) score may provide useful information on dizzy emergency department patients at low-risk for having a cerebrovascular diagnosis and may aid frontline providers in acute management if validated prospectively.

Therapeutic hypothermia after cardiac arrest: experience at an academically affiliated community-based veterans affairs medical center.

At laboratory and clinical levels, therapeutic hypothermia has been shown to improve neurologic outcomes and mortality following cardiac arrest. We reviewed each cardiac arrest in our community-based Veterans Affairs Medical Center over a three-year period. The majority of cases were in-hospital arrests associated with initial pulseless electrical activity or asystole. Of a total of 100 patients suffering 118 cardiac arrests, 29 arrests involved comatose survivors, with eight patients completing therapeutic cooling. Cerebral performance category scores at discharge and six months were significantly better in the cooled cohort versus the noncooled cohort, and, in every case except for one, cooling was offered for appropriate reasons. Mean time to initiation of cooling protocol was 3.7 hours and mean time to goal temperature of 33°C was 8.8 hours, and few complications clearly related to cooling were noted in our case series. While in-patient hospital mortality of cardiac arrest was high at 65% mortality during hospital admission, therapeutic hypothermia was safe and feasible at our center. Our cooling times and incidence of favorable outcomes are comparable to previously published reports. This study demonstrates the feasibility of implementing, a cooling protocol a community setting, and the role of neurologists in ensuring effective hospital-wide implementation.

Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder.

OBJECTIVE: Abnormalities in the morphology and function of two gray matter structures central to emotional processing, the perigenual anterior cingulate cortex (pACC) and amygdala, have consistently been reported in bipolar disorder (BD). Evidence implicates abnormalities in their connectivity in BD. This study investigates the potential disruptions in pACC-amygdala functional connectivity and associated abnormalities in white matter that provides structural connections between the two brain regions in BD. METHODS: Thirty-three individuals with BD and 31 healthy comparison subjects (HC) participated in a scanning session during which functional magnetic resonance imaging (fMRI) during processing of face stimuli and diffusion tensor imaging (DTI) were performed. The strength of pACC-amygdala functional connections was compared between BD and HC groups, and associations between these functional connectivity measures from the fMRI scans and regional fractional anisotropy (FA) from the DTI scans were assessed. RESULTS: Functional connectivity was decreased between the pACC and amygdala in the BD group compared with HC group, during the processing of fearful and happy faces (p < .005). Moreover, a significant positive association between pACC-amygdala functional coupling and FA in ventrofrontal white matter, including the region of the uncinate fasciculus, was identified (p < .005). CONCLUSION: This study provides evidence for abnormalities in pACC-amygdala functional connectivity during emotional processing in BD. The significant association between pACC-amygdala functional connectivity and the structural integrity of white matter that contains pACC-amygdala connections suggest that disruptions in white matter connectivity may contribute to disturbances in the coordinated responses of the pACC and amygdala during emotional processing in BD.

Relation between amygdala structure and function in adolescents with bipolar disorder.

OBJECTIVE: Previous study supports the presence of reduced volume and elevated response to emotional stimuli in amygdala in adolescents with bipolar disorder (BD). In the present study, structural and functional magnetic resonance imaging scans were obtained during the same neuroimaging session to examine amygdala structure-function relations in adolescents with BD. We hypothesized that amygdala volume would be inversely associated with amygdala response to emotional stimuli, such that BD participants with the smallest amygdala volumes would exhibit the highest amygdala response. METHOD: Fifty-one adolescents (21 with BD I and 30 control adolescents, ages 10-18 years) underwent structural and functional magnetic resonance imaging scans. Amygdala volume (n = 49) and signal change (n = 44) during emotional face processing were compared between groups, and structure-function correlations were examined within the BD group (n = 16). RESULTS: Adolescents with BD showed decreased amygdala volume (p =.009) and increased amygdala response to emotional faces (p =.043). There was no significant interaction between diagnosis and emotion type. A significant inverse association between amygdala volume and activation during emotional face processing was observed (r = -0.54, p =.029). CONCLUSIONS: Decreased volume and increased response to emotional stimuli in the amygdala in adolescents with BD are consistent with previous reports. This study represents the first report, to our knowledge, of the two findings in the same adolescent BD sample and supports an amygdala structure-function relation characterized by an inverse association between volume and response to emotional stimuli. This preliminary finding requires replication and suggests a possible pathophysiological link between abnormalities in amygdala structure and response to emotional stimuli in BD.

Role of variation in the serotonin transporter protein gene (SLC6A4) in trait disturbances in the ventral anterior cingulate in bipolar disorder.

Bipolar disorder (BD) is associated with abnormalities of the ventral anterior cingulate cortex (vACC) and its connection sites, including the amygdala, which are key components of a corticolimbic neural system that subserves emotional regulation. Decreased functional connectivity from the vACC to the amygdala in healthy individuals is associated with the short 's' allele--as opposed to the long 'l' allele--of a well-known serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4), as are features of BD. This study tests the hypothesis that the s allele influences dysfunction in the vACC-amygdala neural system in BD. A total of 30 euthymic individuals with BD (20 s carriers, 10 ll) and 48 healthy comparison (HC) participants (34 s, 14 ll) participated in an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, vACC activation was significantly lower in the BD compared to the HC group, and in s carriers compared to ll individuals within both the HC and BD groups, such that BD s carriers exhibited the greatest magnitude of vACC dysfunction. No significant differences were detected in amygdala activation. The findings suggest that the 5-HTTLPR s allele may contribute to a trait-related, genetically derived, neurobiological subgroup within BD characterized by prominent vACC dysfunction. Future treatment may be optimized for this BD subgroup by targeting the serotonergic system and the vACC.