Protocadherin 10 alters γ oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits.

Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10+/-) has been investigated as a proxy for ASD. Male Pcdh10+/- mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10+/- mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10+/- mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10+/- mice, male Pcdh10+/- mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10+/- mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABAB agonist remediated these electrophysiological alterations among male Pcdh10+/-mice. Pcdh10+/- mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10+/- mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD.

Prospective MEG biomarkers in ASD: pre-clinical evidence and clinical promise of electrophysiological signatures.

Autism spectrum disorders (ASD) are characterized by social impairments and restricted/stereotyped behaviors and currently affect an estimated 1 in 68 children aged 8 years old. While there has been substantial recent focus on ASD in research, both the biological pathology and, perhaps consequently, a fully effective treatment have yet to be realized. What has remained throughout is the hypothesis that ASD has neurobiological underpinnings and the observation that both the phenotypic expression and likely the underlying etiology is highly heterogeneous. Given the neurodevelopmental basis of ASD, a biologically based marker (biomarker) could prove useful not only for diagnostic and prognostic purposes, but also for stratification and response indices for pharmaceutical development. In this review, we examine the current state of the field for MEG-related biomarkers in ASD. We describe several potential biomarkers (middle latency delays [M50/M100], mismatch negativity latency, gamma-band oscillatory activity), and investigate their relation to symptomology, core domains of dysfunction (e.g., language impairment), and putative biological underpinnings.

High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice.

Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3ß with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.

Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.

Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 µM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia.

Anterior thoracolumbar spine exposure: critical review and analysis.

BACKGROUND: Indications for anterior thoracolumbar spine interbody fusion have expanded because of safe and expeditious surgical exposure that can be provided by the approach surgeon. In our practice, previous anterior interbody instrumentation, multiple disc level exposure, patient age, and body habitus are not surgical deterrents despite the potential for increased complications. The arterial and venous complications of anterior spine exposure have been well documented; however, the purpose of this study is to document the incidence of other complications, such as deep vein thrombosis (DVT), lymphedema, seroma/hematoma, wound infection, and hospital readmission and to determine whether outcome is influenced by the factors mentioned above. METHODS: Six hundred seventeen consecutive patients had anterior thoracolumbar spine exposure performed by a single vascular surgeon between January 2007 and June 2012. Office and hospital records were reviewed with institutional review board approval. RESULTS: The mean patient age was 56 years, and 16% were >69 years of age. The mean body mass index (BMI) was 29.27 kg/m(2) (range: 16-53 kg/m(2)); 39% were considered obese, with BMI measurements of >30 kg/m(2). The overwhelming majority of cases were performed for varying grades of spondylolisthesis and/or degenerative disc disease; in 8 cases (1.3%), the indication for disc exposure was diskitis/osteomyelitis. One disc level was exposed in 36% of cases, 2 in 43%, and ≥3 in 21%. Six percent of patients had previous anterior spine exposure, 42% had previous posterior laminectomy and/or diskectomy, and 3% required anterior disc reexposure to remove hardware or an artificial disc. There was 1 major arterial dissection and 3 major venous injuries. Other complications included extensive DVT (2%), debilitating lymphedema (0.5%), wound seroma/hematoma requiring treatment (2%), wound infection (3%), and readmission within 60 days (8%). Multilevel (>2 levels) disc exposure was associated with an increased rate of lymphedema, posterior lumbar wound infection, and hospital readmission (all P values ≤ 0.01; chi-squared analysis). A BMI >30 kg/m(2) was associated with an increased rate of DVT, posterior lumbar wound infection, and hospital readmission (all P values ≤ 0.018; chi-squared analysis). Age >69 years was associated with an increased rate of wound hematoma (P = 0.002; chi-squared analysis). Logistic regression analysis revealed that BMI >30, multilevel disc exposure, and removal of an artificial disc or hardware were all associated with an increased rate of any nonvessel complication (P values < 0.001); however, no specific variable was associated with an increased rate of a major vessel complication, including those cases where the surgical indication was diskitis/osteomyelitis. CONCLUSIONS: The overall incidence of nonvessel injury complications after anterior thoracolumbar spine exposure is low. Redo anterior spine exposure and redo disc exposure cases, including those that require hardware or artificial disc removal, can be performed safely. Multidisc level exposure is, however, associated with an increased incidence of lymphedema, wound infection, and hospital readmission. Patients with BMI >30 kg/m(2) should be approached with caution because there is a significantly increased rate of DVT, wound infection, and hospital readmission.

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia.

DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.

Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function.

Genetic studies have associated deficient function of the serine/threonine kinase Akt1 with schizophrenia. This disorder is associated with developmental, structural, and functional abnormalities of the hippocampus that could be traced to abnormal Akt1 function. To establish a closer connection between Akt1 and hippocampal function, mice with a selective deletion of Akt1 (Akt1(-/-) mice) were examined for physiological and behavioral outcomes dependent on the hippocampus and associated with schizophrenia. Genetic deletion of Akt1 was associated with both impaired proliferative capacity of adult-born hippocampal progenitors and hippocampal long-term potentiation, indicating deficient functions of this brain region associated with neuroplasticity. Moreover, Akt1(-/-) mice demonstrated impairments in contextual fear conditioning and recall of spatial learning, behaviors known to selectively involve the hippocampus. Akt1(-/-) mice also showed reduced prepulse inhibition of the acoustic startle response, a sensorimotor gating response that is perturbed in schizophrenia. Postmortem tissue samples from patients with schizophrenia showed significant reductions of phosphorylated Akt levels in hilar neurons of the dentate gyrus, the neurogenic zone of the hippocampus. Taken together, these results implicate the Akt1 isoform in regulating hippocampal neuroplasticity and cognition and in contributing to the etiology of schizophrenia.

Revision Proximal Tibiofibular Joint Reconstruction for the Treatment of Chronic Instability Secondary to Suture Button Construct Failure.

Recurrent proximal tibiofibular joint (PTFJ) instability can result from nonanatomic repair using a suture button construct. During initial reconstruction, proper identification of anatomic landmarks is critical for proper placement of suture button construct components and successful patient outcomes. In cases of symptomatic recurrent instability, a PTFJ reconstruction revision is warranted to alleviate symptoms of pain and instability. This Technical Note describes a technique for performing an anatomic PTFJ reconstruction revision and fibular collateral ligament reconstruction in which the semitendinosus is used as a graft for both the FCL and posterior ligamentous complex of the PTFJ. The biceps femoris is also repaired following a tear that resulted from a misplaced suture button.

Hippocampal microcircuit dynamics probed using optical imaging approaches.

Mammalian cortical structures are endowed with the capacity for plasticity, which emerges from a combination of the dynamics of circuit connectivity and function, and the intrinsic function of the neurons within the circuit. However, this capacity is accompanied by a significant risk: the capability to generate seizure discharges is also a property of all mammalian cortices. How do cortical circuits reconcile the requirement to maintain plasticity, but at the same time control seizure initiation? These issues come into particular focus in the hippocampus. The hippocampus is one of the main plasticity engines in the brain, and is also a structure frequently implicated in the generation of epileptic seizures, with temporal lobe epilepsy constituting the most prevalent form of epilepsy in the adult population. One aspect of hippocampal circuitry that is particularly prominent is its intimate interconnections with the entorhinal cortex. These interconnections create a number of excitatory synaptic loops within the limbic system, which, in addition to being important in cognitive function, can support reentrant activation and seizure generation. In the present review, using optical imaging approaches to elucidate circuit processing at high temporal and spatial resolution, we examine how two targets of entorhinal cortical input within the hippocampus, the dentate gyrus and area CA1, regulate these synaptic pathways in ways that can maintain functions important in generation of normal activity patterns, but that dampen the ability of these inputs to generate seizure discharges.

The Oblique Meniscomeniscal Ligament: A Case Report of a Rare Obstruction to Meniscal Root Repair.

CASE: The authors present a case of a 41-year-old woman who was treated for a chronic type 2 posterior horn tear of the medial meniscal root. During an arthroscopic repair, a broad, thick ligament coursing through the intercondylar notch caused difficulty in visualizing the posterior joint space and necessitated creation of an accessory portal. Given its course and attachments, this structure was an example of a rare variant of anatomy, an oblique meniscomeniscal ligament. CONCLUSION: An oblique meniscomeniscal ligament may complicate surgery in the posterior knee by presenting a visual and physical impediment to the surgeon.

Multiple Ligament Reconstructions of the Knee and Posterolateral Corner.

Injuries to the knee involving multiple ligaments occur in a variety of circumstances and require careful assessment and planning. A wide constellation of injuries can occur with causes sufficiently traumatic to produce bicruciate ligament deficiency, and this technical report will describe diagnosis, treatment and rehabilitation for a knee dislocation with lateral injury (KD-III-L on the Schenk classification). Reconstruction in the acute setting is preferred, with anatomic-based, single-bundle anterior cruciate ligament reconstruction, double-bundle posterior cruciate ligament reconstruction, and anatomic reconstruction of the posterolateral corner using two grafts for the 3 primary posterolateral corner stabilizers. Tunnel orientation to prevent convergence and sequence of graft tensioning and fixation are discussed as well. Successful outcomes have been achieved using these anatomic-based reconstruction techniques along with appropriate rehabilitation and bracing.

Proximal Tibial Opening Wedge Osteotomy for the Treatment of Posterior Knee Instability and Genu Recurvatum Secondary to Increased Anterior Tibial Slope.

Decreased posterior tibial slope has been associated with increased risk of graft failure and knee instability after posterior cruciate ligament (PCL) reconstruction. Premature physeal arrest at the tibial tubercle is a common cause of osseous genu recurvatum. Surgical management is recommended to correct the tibial slope and prolong the integrity of the PCL graft. This article discusses our preferred treatment using a proximal tibial opening wedge osteotomy for surgical management of posterior knee instability and genu recurvatum secondary to significant anterior tibial slope.

Tibial Tubercle Preserving Anterior Closing Wedge Proximal Tibial Osteotomy and ACL Tunnel Bone Grafting for Increased Posterior Tibial Slope in Failed ACL Reconstructions.

Anterior cruciate ligament reconstruction (ACLR) failure is multifactorial, but it is known that increased posterior tibial slope (PTS) leads to a greater likelihood of ACLR failure. This technical note describes the senior author's technique for performing an anterior closing wedge proximal tibial osteotomy, in which the osteotomy is made proximal to the tibial tubercle. This procedure is the first part of a staged surgery for patients with multiple failed ACLRs and increased sagittal plane PTS. Debridement of osteolytic reconstruction tunnels with bone grafting is also undertaken in preparation for a second-stage revision ACLR.

Patellar Tendon Revision Reconstruction With Hamstring Tendon Autografts.

Patellar tendon rupture is an infrequent cause of disability in patients younger than 40 years, with chronic injury and repeat procedures creating difficulty in facilitating healing. Use of hamstring autograft to reinforce the repair has been reported to strengthen the repair construct in patients with previous failure or chronic injury. This technique describes utilization of gracilis and semitendinosus tendon autografts to reconstruct the patellar tendon in a case of primary repair failure.

Arthroscopic-Assisted Lateral Meniscal Allograft Transplantation With Open Ligamentous Extra-Articular Tenodesis.

Lateral meniscus allograft transplantation is performed in predominantly young, active patients and is an option to stabilize the joint in lateral meniscus-deficient patients after anterior cruciate ligament reconstruction. The lateral meniscus functions as an important restraint to anterior tibial translation, and meniscal transplant in such a patient may improve survivability of the graft in addition to preserving the patient's articular cartilage in the long term. A ligamentous extra-articular tenodesis procedure may be performed simultaneously to augment rotational stability of the joint, particularly in a patient with underlying ligamentous hyperlaxity.

Medial Patellofemoral Reconstruction Using Quadriceps Tendon Autograft, Tibial Tubercle Osteotomy, and Sulcus-Deepening Trochleoplasty for Patellar Instability.

Recurrent patellar dislocations have been correlated with an elevated risk of further patellar dislocations, often requiring surgical treatment. Risk factors include medial patellofemoral ligament (MPFL) tears, patella alta, trochlear dysplasia, and an increased tibial tubercle-trochlear groove distance. Surgical management must be based on a patient's unique joint pathoanatomy and may require MPFL reconstruction with tibial tubercle osteotomy or trochleoplasty either alone or in combination. This article discusses our preferred technique for surgical treatment of recurrent patellar instability with MPFL reconstruction using a quadriceps tendon autograft, an open trochleoplasty, and a tibial tubercle osteotomy for patients with patella alta, trochlear dysplasia, and an increased tibial tubercle-trochlear groove distance.

Arthroscopic Excision of Bipartite Patella.

A bipartite patella usually presents as an incidental finding on radiographs because most cases are asymptomatic. However, some patients may present with pain and functional limitations. Conservative treatment is sufficient to resolve symptoms in most cases; however, a small minority of patients may require surgical management. Recent studies have reported excellent results with an arthroscopic approach. This Technical Note details our procedure for treating a symptomatic bipartite patella that has not resolved with conservative care.

Medial Patellofemoral Ligament Reconstruction Using a Quadriceps Tendon Autograft in a Patient with Open Physes.

Recurrent patellar dislocations are correlated with an elevated risk for further patellar dislocations. Chronic patellar instability is a disabling issue for some patients and may require surgical intervention for proper treatment. Risk factors for recurrent dislocations include medial patellofemoral ligament (MPFL) tears, patella alta, trochlear dysplasia, and increased tibial tubercle to trochlear groove distance. Surgical management must be based on a patient's unique joint pathoanatomy and typically requires medial patellofemoral ligament reconstruction, with or without accompanying procedures such as tibial tubercle osteotomy or sulcus-deepening trochleoplasty. Chronic patellar instability in minors with open growth plates, requires alternative MPFL reconstruction techniques to prevent physeal injury, because of the close proximity of the femoral physis to the MPFL insertion. This article discusses the authors' preferred technique for surgical treatment of recurrent patellar instability with a medial patellofemoral ligament reconstruction using a quadriceps tendon autograft.

The Natural History of Medial Meniscal Root Tears: A Biomechanical and Clinical Case Perspective.

Posterior medial meniscus root tears (PMMRTs) make up a relatively notable proportion of all meniscus pathology and have been definitively linked to the progression of osteoarthritis (OA). While known risk factors for development of OA in the knee include abnormal tibial coronal alignment, obesity and female gender, PMMRTs have emerged in recent years as another significant driver of degenerative disease. These injuries lead to an increase in average contact pressure in the medial compartment, along with increases in peak contact pressure and a decrease in contact area relative to the intact state. Loss of the root attachment impairs the function of the entire meniscus and leads to meniscal extrusion, thus impairing the force-dissipating role of the meniscus. Anatomic meniscus root repairs with a transtibial pullout technique have been shown biomechanically to restore mean and peak contact pressures in the medial compartment. However, nonanatomic root repairs have been reported to be ineffective at restoring joint pressures back to normal. Meniscal extrusion is often a consequence of nonanatomic repair and is correlated with progression of OA. In this study, the authors will describe the biomechanical basis of the natural history of medial meniscal root tears and will support the biomechanical studies with a case series including patients that either underwent non-operative treatment (5 patients) or non-anatomic repair of their medial meniscal root tears (6 patients). Using measurements derived from axial MRI, the authors will detail the distance from native root attachment center of the non-anatomic tunnels and discuss the ongoing symptoms of those patients. Imaging and OA progression among patients who were treated nonoperatively before presentation to the authors will be discussed as well. The case series thus presented will illustrate the natural history of meniscal root tears, the consequences of non-anatomic repair, and the findings of symptomatic meniscal extrusion associated with a non-anatomic repair position of the meniscus.

Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy.

GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl- concentration ([Cl-]in) at low levels. In neurons in the developing CNS, [Cl-]in is elevated, E(GABA) is depolarizing, and GABA consequently is excitatory. Depolarizing GABAergic synaptic responses may be recapitulated in various neuropathological conditions, including epilepsy. In the present study, rat hippocampal dentate granule cells were recorded using gramicidin perforated patch techniques at varying times (1-60 d) after an epileptogenic injury, pilocarpine-induced status epilepticus (STEP). In normal, non-epileptic animals, these strongly inhibited dentate granule cells act as a gate, regulating hippocampal excitation, controlling seizure initiation and/or propagation. For 2 weeks after STEP, we found that E(GABA) was positively shifted in granule cells. This shift in E(GABA) altered synaptic integration, increased granule cell excitability, and resulted in compromised "gate" function of the dentate gyrus. E(GABA) recovered to control values at longer latencies post-STEP (2-8 weeks), when animals had developed epilepsy. During this period of shifted E(GABA), expression of the Cl- extruding K+/Cl- cotransporter, KCC2 was decreased. Application of the KCC2 blocker, furosemide, to control neurons mimicked E(GABA) shifts evident in granule cells post-STEP. Furthermore, post-STEP and furosemide effects interacted occlusively, both on E(GABA) in granule cells, and on gatekeeper function of the dentate gyrus. This suggests a shared mechanism, reduced KCC2 function. These findings demonstrate that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability. This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy.