Reversal of cognitive, behavioral, and language impairments after the left frontal arachnoid cyst fenestration in a pediatric patient.

BACKGROUND: Arachnoid cysts (ACs) are cerebrospinal fluid-containing cysts located between the surface of the brain or spinal cord and arachnoid layer of the leptomeninges. ACs have been known to cause cognitive, language, and behavioral deficits and currently there is no standard treatment paradigm. Surgical indications include papilledema, increasing growth with mass effect causing neurological deficit, or rapid head growth, however, cognitive symptoms related to mass effect may not always be considered. CASE DESCRIPTION: We present a 3-year-old male with an AC of the left anterior fossa causing frontal lobe compression with resultant behavioral, language, and cognitive deficits. CONCLUSION: Surgical intervention for AC decompression may be indicated when there are cognitive, behavioral, or language delays related to the mass effect and location of the AC. Neuropsychiatric testing or more advanced imaging studies may further support surgical treatment. After craniotomy for fenestration of the left frontal AC, there was drastic improvement in cognitive, language, and behavioral symptoms in our pediatric patient.

The Use of Antiplatelet Agents and Heparin in the 24-Hour Postintravenous Alteplase Window for Neurointervention.

BACKGROUND: Intravenous (IV) alteplase with mechanical thrombectomy has been found to be superior to alteplase alone in select patients with intracranial large vessel occlusion. Current guidelines discourage the use of antiplatelet agents or heparin for 24 h following alteplase. However, their use is often necessary in certain circumstances during thrombectomy procedures. OBJECTIVE: To study the safety and outcomes in patients who received blood thinning medications for thrombectomy after IV Tissue-Type plasminogen activator (tPA). METHODS: This is a multicenter retrospective review of the use of antiplatelet agents and/or heparin in patients within 24 h following tPA administration. Patient demographics, comorbidities, bleeding complications, and discharge outcomes were collected. RESULTS: A series of 88 patients at 9 centers received antiplatelet medications and/or heparin anticoagulation following IV alteplase for revascularization procedures requiring stenting. The mean National Institutes of Health Stroke Scale (NIHSS) on admission was 14.6. Reasons for use of a stent included internal carotid artery occlusion in 74% of patients. Thrombolysis in cerebral infarction (TICI) 2b-3 revascularization was accomplished in 90% of patients. The rate of symptomatic intracranial hemorrhage (sICH) was 8%; this was not significantly different than the sICH rate for a matched group of patients not receiving antiplatelets or heparin during the same time frame. Functional independence at 90 d (modified Rankin Scale 0-2) was seen in 57.8% of patients. All-cause mortality was 12%. CONCLUSION: The use of antiplatelet agents and heparin for stroke interventions following IV alteplase appears to be safe without significant increased risk of hemorrhagic complications in this group of patients when compared to control data and randomized controlled trials.

Investigation of a Valve-Agnostic Cranial Implant for Adult Hydrocephalus Patients Requiring Ventriculoperitoneal Shunting.

INTRODUCTION: Currently, the most effective treatment strategy for adults with hydrocephalus involves cerebrospinal fluid diversion by means of a shunt system, most commonly ventriculoperitoneal shunts (VPS). Ventriculoperitoneal shunting is associated with high complication and/or revision rates, in part due to the high-profile programmable valve designs. Thus, the valve-agnostic cranial implant (VACI) was designed and investigated as a safe and effective method of reducing the valve's high profile and is currently undergoing clinical trials. As such, the objective of this study was to collate preliminary, multi-institutional data of early outcomes using a VACI approach for patients requiring VPS by way of an Institutional Review Board approved registry. METHODS: A total of 25 adult patients across 4 institutions and 6 surgeons underwent VACI placement for VPS based on preoperative evaluation and perceived benefit. Patient demographics, operative details, and preliminary outcomes are presented here. RESULTS: Valve-agnostic cranial implant placement via a limited size craniectomy at time of shunt revision was performed with no adverse events. Over an average follow-up period of 1 year (394 ±â€Š178 days), 92% of patients experienced no major shunt-related or scalp-related complications. There were 2 cases with a major complication requiring reoperation: 1 shunt tubing extrusion and 1 case of meningitis. The most frequent postsurgical intervention seen in this study was related to adjustment of drainage: a non-invasively performed valve reprogramming after initial shunt placement when proper flow rate is being established. Of the 8 cases of drainage adjustment, all but 1 (88%) were receiving a VPS for the first time, with the exception undergoing a fourth shunt revision. All instances of improper flow were treated non-surgically and remediated effectively via shunt reprogramming in clinic. Removal of the VACI was not indicated in any treatment course. In this way, all complications as they relate to the shunt valve were minor and required nonsurgical intervention, and no complications reported were directly or indirectly caused by using the VACI. CONCLUSION: Preliminary findings from this multicenter trial suggest promising outcomes with a low complication rate for patients with hydrocephalus undergoing VACI placement during VPS. Ongoing research will continue to provide a more robust clinical picture of VACI in hydrocephalus management as more data becomes available.

Initial experiences of US neurologists in practice during the COVID-19 pandemic via survey.

OBJECTIVE: To test the hypothesis that US neurologists were experiencing significant challenges with lack of personal protective equipment (PPE), rapid changes in practice, and varying institutional protocols, we conducted this survey study. The current coronavirus disease of 2019 (COVID-19) pandemic has caused widespread disease and death. Rapid increases in patient volumes have exposed weaknesses in health care systems and challenged our ability to provide optimal patient care and adequate safety measures to health care workers (HCWs). METHODS: A 36-item survey was distributed to neurologists around the United States through various media platforms. RESULTS: Over a 1-week period, 567 responses were received. Of these, 56% practiced in academia. A total of 87% had access to PPE, with 45% being asked to reuse PPE due to shortages. The pandemic caused rapid changes in practice, most notably a shift toward providing care by teleneurology, although a third experienced challenges in transitioning to this model. Wide variations were noted both in testing and in the guidance provided for the exposed, sick, or vulnerable HCWs. Notably, 59% of respondents felt that their practices were doing what they could, although 56% did not feel safe taking care of patients. CONCLUSIONS: Results from our survey demonstrate significant variability in preparedness and responsiveness to the COVID-19 pandemic in neurology, affected by region, health care setting, and practice model. Practice guidelines from professional societies and other national entities are needed to improve protection for physicians and their patients, promote recommended practice changes during a pandemic, and optimize future preparedness for public health emergencies.

Case report: vertebral osteomyelitis secondary to a dental abscess.

BACKGROUND: Vertebral osteomyelitis can be attributed to many factors including immunosuppression, diabetes, malignancy, collagen disease, periodontal disease, open fractures, and endoscopic procedures. Anaerobic bacteria, such as Veillonella species, are found in the oral cavity and are rarely implicated in the infection. This report describes vertebral osteomyelitis secondary to a dental abscess with positive Veillonella cultures. CASE DESCRIPTION: A 76-year-old man presented to the hospital due to back pain with a four-day history of fever and chills. CT scans revealed several abscesses in the lumbar region as well as indications of vertebral osteomyelitis. After a psoas drain, the patient began antibiotics with a combination of ampicillin-sulbactam, metronidazole, and levofloxacin, but due to the patient's penicillin allergy, he was initially desensitized to this antibiotic for a significant period of time. Laminectomies, foraminotomies, and facetectomies were performed, but the infection spread to vertebral levels. The patient was then switched to a combination of vancomycin, metronidazole, and levofloxacin which eliminated the infection. Final laminectomy was performed with posterior segmental instrumentation and arthrodesis. Post-operatively, there were no signs of infection. The patient recovered well and regained mobility. Deeper examination of the patient's medical history revealed a severe tooth abscess immediately before the onset of bacteremia. CONCLUSION: We believe that a delay in the onset of antibiotic treatment is what led to the initial bacteremia that ultimately took root in the lower lumbar vertebrae. To the best of our ability, we could identify only one other case that linked vertebral osteomyelitis to the oral cavity.

Treating refractory depression in Parkinson's disease: a meta-analysis of transcranial magnetic stimulation.

BACKGROUND: Parkinson's disease (PD) is often accompanied by clinically identified depression. Providing effective pharmacotherapies that concomitantly treat both motor and psychological symptoms can pose a challenge to physicians. For this reason, alternatives to standard anti-depressant treatments, such as repetitive transcranial magnetic stimulation (rTMS), have been evaluated within the Parkinson's population. METHODS: A literature search was conducted on the PubMed database for all studies that evaluated rTMS as a treatment in patients with both depression and PD. A meta-analysis was performed on all studies that reported mean pre- and post-rTMS depression inventory scores. Widely used depression inventories included both self-report and clinician-administered measures. Effect size for individual study groups and across all studies was calculated. RESULTS: Six of 7 studies meeting inclusion criteria reported significantly improved depression scores, large effect sizes, and significant p-values. Total weighted average effect size was calculated at 1.32 across all study groups that applied rTMS. CONCLUSIONS: Across all but one study, rTMS appears to effectively reduce depression scores among self-reported and clinician administered inventories. The total weight average effect size showed that, when considering study sample sizes and degree of findings, this form of neurostimulation can relieve PD patients of their depressive symptoms. Further, rTMS is a promising alternative to traditional anti-depressant therapies when treating refractory depression in patients with PD.

Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia.

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

Carotid Artery Angioplasty and Stenting Without Distal Embolic Protection Devices.

BACKGROUND: Embolic protection devices are used during carotid artery stenting procedures to reduce risk of distal embolization. Although this is a standard procedural recommendation, no studies have shown superiority of these devices over unprotected stenting procedures. OBJECTIVE: To assess the periprocedural outcome and durability of carotid artery stenting without embolic protection devices and poststent angioplasty. METHODS: We performed a retrospective chart review of 174 carotid angioplasty stent procedures performed at our institution. One hundred sixty-six patients underwent angioplasty and stenting without distal protection devices or poststent angioplasty. Complications related to stenting, including procedural complications, postoperative stroke and/or myocardial infarction, and stent restenosis were analyzed. RESULTS: One hundred thirty-five stents (78%) were performed in symptomatic patients, whereas 22% of stents were placed for asymptomatic internal carotid artery stenosis. The degree of stenosis was 80% or greater in 75% of patients and 90% or greater in 55% of patients. Following the stenting procedure, the 24-hour and 30-day rate of transient ischemic attack, intracranial hemorrhage, or ischemic stroke was 0. Three (2%) patients had a perioperative, non-ST elevation myocardial infarction. Five patients (2.8%) required treatment for restenosis (>50% stenosis from baseline), 1 of which was symptomatic. CONCLUSION: Our data show that carotid artery stenting without the use of embolic protection devices and without postangioplasty stenting, in experienced hands, can be performed safely. Furthermore, this technique does not result in a higher degree of in-stent restenosis than series in which poststenting angioplasty is performed.

An Analysis of Transient Ischemic Attack Practices: Does Hospital Admission Improve Patient Outcomes?

INTRODUCTION: Immediate treatment has been shown to decrease the recurrence of cerebrovascular accidents following transient ischemic attacks (TIA), prompting the use of a specialized neurologic emergency department (Neuro ED) to triage patients. Despite these findings, there is little evidence supporting the notion that hospital admission improves post-TIA outcomes. Through the lens of a Neuro ED, this retrospective chart review of TIA patients examines whether hospital admission improves 90-day outcomes. MATERIALS AND METHODS: Two hundred sixty charts of patients discharged with TIA diagnosis were reviewed. These charts encompassed patients with TIA who presented to a main emergency department (ED) or Neuro ED from January 2014 to April 2015. Demographic information, admission ABCD(2) scores, admission National Institutes of Health Stroke Scale scores, and admission Modified Rankin Scale, and reason for any return visits within 90 days were collected. RESULTS: This review shows that patients triaged by the Neuro ED were admitted at a lower rate than those seen by the standard ED. Further, patients triaged by the Neuro ED experienced lower readmission and recurrence of stroke or TIA within 90 days. CONCLUSIONS: These results provide preliminary support for the notion that discharging appropriate TIA patients, with adequate follow-up, will not adversely affect the recurrence of TIA or stroke within 90 days.

Atypical laterality of resting gamma oscillations in autism spectrum disorders.

Abnormal brain oscillatory activity has been found in autism spectrum disorders (ASD) and proposed as a potential biomarker. While several studies have investigated gamma oscillations in ASD, none have examined resting gamma power across multiple brain regions. This study investigated resting gamma power using EEG in 15 boys with ASD and 18 age and intelligence quotient matched typically developing controls. We found a decrease in resting gamma power at right lateral electrodes in ASD. We further explored associations between gamma and ASD severity as measured by the Social Responsiveness Scale (SRS) and found a negative correlation between SRS and gamma power. We believe that our findings give further support of gamma oscillations as a potential biomarker for ASD.

Improved door-to-needle times and neurologic outcomes when IV tissue plasminogen activator is administered by emergency physicians with advanced neuroscience training.

BACKGROUND: The neurologic emergency department (neuro ED) at our medical center is staffed by emergency medicine physicians who have specialized neuroscience training and give intravenous (IV) tissue plasminogen activator (tPA) independently for acute ischemic stroke patients. Door-to-needle (DTN) times, discharge location, and discharge National Institute of Health Stroke Scale (NIHSS) scores were studied between the neuro ED and main emergency department (ED) with the hypothesis that all measures would be better in the neuro ED group. METHODS: This is a retrospective study evaluating DTN time, discharge outcomes, and discharge location in acute stroke patients who received IV tPA at our comprehensive stroke center. These outcome measures were compared between patients who were evaluated and treated in our neuro ED to those treated in our main ED. RESULTS: From 2012 to 2014, 67 acute stroke patients received IV tPA in our ED. Thirty-five patients were evaluated in the neuro ED, and 32, in the main ED. Average DTN times were significantly faster in the neuro ED at 35 minutes, compared to main ED DTN times of 83 minutes. Discharge NIHSS score was significantly lower, and more patients were discharged to home in the neuro ED group compared to the main ED group. CONCLUSIONS: Trained neuro ED physicians can safely give IV tPA independently for stroke patients with improved DTN times, lower discharge NIHSS, and higher likelihood of being discharged to home compared to the main ED physicians who used teleneurology consultation. This suggests utility in training emergency medicine physicians to administer tPA independently based on clinical practice guidelines.

Early postmarket experience after US Food and Drug Administration approval with the Trevo device for thrombectomy for acute ischemic stroke.

BACKGROUND: TREVO 2 showed the Trevo stent retriever to be more successful for revascularization than Merci for acute stroke intervention in patients treated within 8 hours of symptom onset. These results led to US Food and Drug Administration approval of Trevo. OBJECTIVE: To report the first postmarket experience with Trevo since US Food and Drug Administration approval at a single high-volume comprehensive stroke center in the United States. METHODS: A retrospective analysis of prospectively collected data was conducted in patients who underwent intervention for ischemic stroke with the Trevo device. Trevo was used alone or in conjunction with other intra-arterial devices. Two groups of patients were identified: those with symptom onset within (group 1) and those with symptom onset beyond (group 2) 8 hours. Recanalization, outcome, symptomatic intracranial hemorrhage, and in-hospital and 90-day mortality were assessed. RESULTS: Fifty-two patients were identified, 27 in group 1 and 25 in group 2. Thrombolysis in Cerebral Infarction grade 2 to 3 revascularization was achieved in 93% of group 1 and 84% of group 2 patients. In-hospital mortality and symptomatic intracranial hemorrhage rates were 3.8% and 12% for groups 1 and 2, respectively. Ninety-day mortality was 15% and 24% for groups 1 and 2, respectively. In groups 1 and 2, 48% and 42% of patients, respectively, had good outcomes (modified Rankin Scale score, 0-2), and 50% in both groups of patients achieved Thrombolysis in Cerebral Infarction grade 3 revascularization. Group 2 had longer revascularization times and required adjuvant devices more frequently. CONCLUSION: Our postmarket experience shows that in highly selected patients Trevo is safe and effective, even beyond 8 hours, despite longer procedure times and the need for adjuvant devices.

The broad autism phenotype predicts child functioning in autism spectrum disorders.

BACKGROUND: Broad autism phenotype (BAP) is a milder expression of the social and communication impairments seen in autism spectrum disorders (ASD). While prior studies characterized the BAP in unaffected family members of probands with ASD, the relationship between parental BAP traits and proband symptomatology remains poorly understood. This study utilizes the Broad Autism Phenotype Questionnaire (BAPQ) in parents and the Social Responsiveness Scale (SRS) in children to examine this connection. We hypothesized that in families affected by ASD, elevated maternal and paternal BAPQ scores would correlate with greater autism symptomatology in diagnosed children. In an extension of prior research, we also explored this relationship in families with typically developing children (TDC). METHODS: Two hundred and forty-five children with ASD, 129 TDC and all parents were recruited as part of a larger study investigating relationships between genes, brain and behavior. The Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and expert clinical judgment confirmed ASD diagnoses in children. SRS was collected for all children. Parents completed a self-report BAPQ and an informant report BAPQ for their spouse; an average of self-report and informant report for each parent was used in all analyses. RESULTS: Mothers and fathers of children with ASD had significantly higher rates of BAP traits as compared to parents of TDC. Maternal and paternal BAPQ total scores were not correlated with child IQ in either group. In the ASD group, 10% of mothers and 21% of fathers scored above the established BAP threshold compared to 4% of TDC parents. Crude regression analyses showed that maternal and paternal BAPQ total scores accounted for significant variance in child SRS scores in both ASD (17.1%) and TDC (19.8%) families. CONCLUSIONS: Our results suggest that broad autism symptomatology in parents is moderately associated with their child's autism symptomatology. This result extended to TDC families, suggesting that the BAPQ and SRS capture subtle, subclinical social variation in both children and adults. These findings could help define multi-generational social impairments in future phenotypic and genetic studies.

Spontaneous trigeminal allodynia in rats: a model of primary headache.

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

Blood-brain barrier abnormalities caused by exposure to HIV-1 gp120--protection by gene delivery of antioxidant enzymes.

HIV-1 effects on the blood-brain barrier (BBB) structure and function are still poorly understood in animal models based on direct administration of recombinant HIV proteins. We therefore injected HIV-1 envelope glycoprotein, gp120, into rat caudate-putamens (CPs) and examined vascular integrity and function. Gp120 coimmunostained with endothelial cell marker, CD31. It induced apoptosis of endothelial cells in vitro and in vivo. BBB function was assessed by administering Evans Blue (EB) intravenously before injecting gp120. EB leaked near the site of gp120 administration. Within 1h after intra-CP gp120 injection, structures positive for endothelial markers ICAM-1 and RECA-1 were greatly decreased. Vascular density assessed by laminin immunostaining remained decreased 1 month after gp120 injection. RECA-1-positive cells expressed hydroxynonenal, a marker of lipid peroxidation and rSV40-mediated gene delivery of antioxidant enzymes protected the BBB from gp120-related injury. Extravasated IgG accumulated following intra-CP SV(gp120) injection, an experimental model of continuing gp120 exposure. Thus: acute and chronic exposure to gp120 disrupts the BBB; gp120-mediated BBB abnormalities are related to lesions of brain microvessels; and gp120 is directly toxic to brain endothelial cells.

Ketamine modulates theta and gamma oscillations.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.

Acetate causes alcohol hangover headache in rats.

BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache. METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats. RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity. DISCUSSION: Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction.

Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia.

CCR3 has been implicated as a co-receptor for human immunodeficiency virus type 1 (HIV-1), particularly in brain microglia cells. We sought to clarify the comparative roles of CCR3 and CCR5 in the central nervous system (CNS) HIV-1 infection and the potential utility of CCR3 as a target for manipulation via gene transfer. To target CCR3, we developed a single-chain antibody (SFv) and an interfering RNA (RNAi), R3-526. Coding sequences for both were cloned into Tag-deleted SV40-dervied vectors, as these vectors transduce brain microglia and monocyte-derived macrophages (MDM) highly efficiently. These anti-CCR3 transgenes were compared to SFv-CCR5, an SFv against CCR5, and RNAi-R5, an RNAi that targets CCR5, for the ability to protect primary human brain microglia and MDM from infection with peripheral and neurotropic strains of HIV-1. Downregulation of CCR3 and CCR5 by these transgenes was independent from one another. Confocal microscopy showed that CCR3 and CCR5 co-localized at the plasma membrane with each other and with CD4. Targeting either CCR5 or CCR3 largely protected both microglia and MDM from infection by many strains of HIV-1. That is, some HIV-1 strains, isolated from either the CNS or periphery, required both CCR3 and CCR5 for optimal productive infection of microglia and MDM. Some HIV-1 strains were relatively purely CCR5-tropic. None was purely CCR3-tropic. Thus, some CNS-tropic strains of HIV-1 utilize CCR5 as a co-receptor but do not need CCR3, while for other isolates both CCR3 and CCR5 may be required.

Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.

BACKGROUND: People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine. METHODS: ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN. RESULTS: Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike. CONCLUSIONS: The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.

RATIONALE: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. OBJECTIVES: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. MATERIALS AND METHODS: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. RESULTS: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. CONCLUSIONS: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.