Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice.

Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.

Transcranial direct current stimulation (tDCS) and robotic practice in chronic stroke: the dimension of timing.

BACKGROUND: Combining tDCS with robotic therapy is a new and promising form of neurorehabilitation after stroke, however the effectiveness of this approach is likely to be influenced by the relative timing of the brain stimulation and the therapy. OBJECTIVE: To measure the kinematic and neurophysiological effects of delivering tDCS before, during and after a single session of robotic motor practice (wrist extension). METHODS: We used a within-subjects repeated-measurement design in 12 chronic (>6 months) stroke survivors. Twenty minutes of anodal tDCS was delivered to the affected hemisphere before, during, or after a 20-minute session of robotic practice. Sham tDCS was also applied during motor practice. Robotic motor performance and corticomotor excitability, assessed through transcranial magnetic stimulation (TMS), were evaluated pre- and post-intervention. RESULTS: Movement speed was increased after motor training (sham tDCS) by ∼20%. Movement smoothness was improved when tDCS was delivered before motor practice (∼15%). TDCS delivered during practice did not offer any benefit, whereas it reduced speed when delivered after practice (∼10%). MEPs were present in ∼50% of patients at baseline; in these subjects motor practice increased corticomotor excitability to the trained muscle. CONCLUSIONS: In a cohort of stroke survivors, motor performance kinematics improved when tDCS was delivered prior to robotic training, but not when delivered during or after training. The temporal relationship between non-invasive brain stimulation and neurorehabilitation is important in determining the efficacy and outcome of this combined therapy.

Preserved corticospinal conduction without voluntary movement after spinal cord injury.

STUDY DESIGN: Case report. OBJECTIVES: To identify preserved corticomotor connection in chronic spinal cord injury (SCI) in the absence of clinically observable movement. SETTING: Rehabilitation Hospital and Medical Research Institute, NY, USA. METHODS: The motor-evoked potential (MEP) response to transcranial magnetic stimulation (TMS) was recorded using surface electromyography from the right biceps brachii, extersor carpi radialis (ECR), flexor carpi radialis (FCR) and abductor pollicis brevis (APB) muscles in a 31-year-old male traumatic SCI chronic patient-ASIA B, injury level C5. Motor power scores were additionally obtained from a clinician blinded to the results of TMS. RESULTS: TMS could consistently elicit MEPs of normal latency, phase and amplitude, in the severely affected ECR muscle but not the similarly affected FCR muscle. The response in proximal and unaffected biceps muscle was larger than the healthy subject, whereas no response was obtained in the distal APB muscle as expected. CONCLUSION: TMS can identify residual pathways not apparent from clinical assessment alone, which may have prescriptive value for rehabilitation.

Brain-reactive antibodies and disease.

Autoimmune diseases currently affect 5-7% of the world's population; in most diseases there are circulating autoantibodies. Brain-reactive antibodies are present in approximately 2-3% of the general population but do not usually contribute to brain pathology. These antibodies penetrate brain tissue only early in development or under pathologic conditions. This restriction on their pathogenicity and the lack of correlation between serum titers and brain pathology have, no doubt, contributed to a delayed appreciation of the contribution of autoantibodies in diseases of the central nervous system. Nonetheless, it is increasingly clear that antibodies can cause damage in the brain and likely initiate or aggravate multiple neurologic conditions; brain-reactive antibodies contribute to symptomatology in autoimmune disease, infectious disease, and malignancy.

Rehabilitation robotics.

This chapter focuses on rehabilitation robotics which can be used to augment the clinician's toolbox in order to deliver meaningful restorative therapy for an aging population, as well as on advances in orthotics to augment an individual's functional abilities beyond neurorestoration potential. The interest in rehabilitation robotics and orthotics is increasing steadily with marked growth in the last 10 years. This growth is understandable in view of the increased demand for caregivers and rehabilitation services escalating apace with the graying of the population. We provide an overview on improving function in people with a weak limb due to a neurological disorder who cannot properly control it to interact with the environment (orthotics); we then focus on tools to assist the clinician in promoting rehabilitation of an individual so that s/he can interact with the environment unassisted (rehabilitation robotics). We present a few clinical results occurring immediately poststroke as well as during the chronic phase that demonstrate superior gains for the upper extremity when employing rehabilitation robotics instead of usual care. These include the landmark VA-ROBOTICS multisite, randomized clinical study which demonstrates clinical gains for chronic stroke that go beyond usual care at no additional cost.

Learning, not adaptation, characterizes stroke motor recovery: evidence from kinematic changes induced by robot-assisted therapy in trained and untrained task in the same workspace.

Both the American Heart Association and the VA/DoD endorse upper-extremity robot-mediated rehabilitation therapy for stroke care. However, we do not know yet how to optimize therapy for a particular patient's needs. Here, we explore whether we must train patients for each functional task that they must perform during their activities of daily living or alternatively capacitate patients to perform a class of tasks and have therapists assist them later in translating the observed gains into activities of daily living. The former implies that motor adaptation is a better model for motor recovery. The latter implies that motor learning (which allows for generalization) is a better model for motor recovery. We quantified trained and untrained movements performed by 158 recovering stroke patients via 13 metrics, including movement smoothness and submovements. Improvements were observed both in trained and untrained movements suggesting that generalization occurred. Our findings suggest that, as motor recovery progresses, an internal representation of the task is rebuilt by the brain in a process that better resembles motor learning than motor adaptation. Our findings highlight possible improvements for therapeutic algorithms design, suggesting sparse-activity-set training should suffice over exhaustive sets of task specific training.

Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.

Raised corticomotor excitability of M1 forearm area following anodal tDCS is sustained during robotic wrist therapy in chronic stroke.

PURPOSE: Anodal transcranial direct current stimulation (tDCS) can transiently increase corticomotor excitability of intrinsic hand muscles and improve upper limb function in patients with chronic stroke. As a preliminary study, we tested whether increased corticomotor excitability would be similarly observed in muscles acting about the wrist, and remain present during robotic training involving active wrist movements, in six chronic stroke patients with residual motor deficit. METHODS: Transcranial magnetic stimulation (TMS) generated motor evoked potentials (MEP) in the flexor carpi radialis (FCR) and provided a measure of corticomotor excitability and short-interval cortical inhibition (SICI) before and immediately after a period of tDCS (1 mA, 20 min, anode and TMS applied to the lesioned hemisphere), and robotic wrist training (1hr). RESULTS: Following tDCS, the same TMS current strength evoked an increased MEP amplitude (mean 168 +/- 22%SEM; p < 0.05), that remained increased after robot training (166 +/- 23%; p < 0.05). Conditioned MEPs were of significantly lower amplitude relative to unconditioned MEPs prior to tDCS (62 +/- 6%, p < 0.05), but not after tDCS (89 +/- 14%, p = 0.40), or robot training (91 +/- 8%, p = 0.28), suggesting that the increased corticomotor excitability is associated with reduced intracortical inhibition. CONCLUSION: The persistence of these effects after robotic motor training, indicates that a motor learning and retraining program can co-exist with tDCS-induced changes in cortical motor excitability, and supports the concept of combining brain stimulation with physical therapy to promote recovery after brain injury.

Changing motor synergies in chronic stroke.

Synergies are thought to be the building blocks of vertebrate movements. The inability to execute synergies in properly timed and graded fashion precludes adequate functional motor performance. In humans with stroke, abnormal synergies are a sign of persistent neurological deficit and result in loss of independent joint control, which disrupts the kinematics of voluntary movements. This study aimed at characterizing training-related changes in synergies apparent from movement kinematics and, specifically, at assessing: 1) the extent to which they characterize recovery and 2) whether they follow a pattern of augmentation of existing abnormal synergies or, conversely, are characterized by a process of extinction of the abnormal synergies. We used a robotic therapy device to train and analyze paretic arm movements of 117 persons with chronic stroke. In a task for which they received no training, subjects were better able to draw circles by discharge. Comparison with performance at admission on kinematic robot-derived metrics showed that subjects were able to execute shoulder and elbow joint movements with significantly greater independence or, using the clinical description, with more isolated control. We argue that the changes we observed in the proposed metrics reflect changes in synergies. We show that they capture a significant portion of the recovery process, as measured by the clinical Fugl-Meyer scale. A process of "tuning" or augmentation of existing abnormal synergies, not extinction of the abnormal synergies, appears to underlie recovery.

Molecular mimicry: anti-DNA antibodies bind microbial and nonnucleic acid self-antigens.

Although cells of the innate immune response have a variety of pattern recognition receptors that are triggered by blood classes of markers, a critical feature of the adaptive immune response is antigenic specificity. Yet it is becoming increasingly clear that the specificity of lymphocyte receptors admits of some laxity. Cross-reactivity may, in fact, be necessary for lymphocyte survival as antigen receptor signaling maintains cellular viability in the absence of antigen activation. Studies of molecular mimicry have revealed many instances in which antibodies to microbial antigens bind also to self-antigens; in some cases, this cross-reactivity has pathogenic potential. In this chapter, we describe cross-reactivity between two self-antigens, DNA and NMDA receptors, and how antibodies with specificity for DNA in patients with splenic lupus may cause central nervous system damage by virtue of binding also to neuronal receptors. This example serves as a reminder that cross-reactivity may exist among self-antigens as well as between foreign and self-antigens.

Ibuprofen protects ischemia-induced neuronal injury via up-regulating interleukin-1 receptor antagonist expression.

The inflammatory response accompanies and exacerbates the developing injury after cerebral ischemia. Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to attenuate injuries in animal models of various neurological diseases. In the present study, we investigated ibuprofen's neuroprotective effects in rats exposed to transient forebrain ischemia and in cultures exposed to oxygen glucose deprivation (OGD). Rats treated with ibuprofen after transient forebrain ischemia displayed long-lasting protection of CA1 hippocampal neurons. There were selective increases in interleukin-1 receptor antagonist gene and protein expression in ibuprofen-treated OGD microglia. Furthermore, treatment with ibuprofen in neuron/microglia co-cultures increased the number of surviving HC2S2 neurons against OGD whereas IL-1ra neutralizing antibody reversed the ibuprofen-induced neuroprotection. The data indicate that ibuprofen-induced IL-1ra secretion is involved in neuroprotection against ischemic conditions.

A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia.

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.

Robot-aided sensorimotor arm training improves outcome in patients with chronic stroke.

Thirty patients with chronic stroke received 6 weeks of sensorimotor robotic training in a pilot study that targeted motor function of the affected shoulder and elbow. The impairment and disability scores were stable during a 2-month observation/measurement period, improved significantly by program completion, and remained robust in the 3-month follow-up. Task-specific motor training attenuated a chronic neurologic deficit well beyond the expected period for improvement after stroke.

Temporal and sequential analysis of microglia in the substantia nigra following medial forebrain bundle axotomy in rat.

Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis after transection of the medial forebrain bundle. We have assessed the temporal and sequential activities of microglia in these events by examining the complement-3 (OX-42), major histocompatibility complex class II antigen presentation (OX-6) and phagocytic activity (ED1), and correlating these indicators with dopaminergic neuronal loss. Microglia in the ipsilateral substantia nigra pars reticulata evinced activation morphology at 12 h postaxotomy. Phagocytic microglia apposed dying dopaminergic neurons in the pars compacta starting at 3 days postlesion; their number increased through 14 days and slowly decreased. Nuclear chromatin condensation and significant loss of tyrosine hydroxylase-positive dopaminergic neurons occurred around 7 days postlesion. In contrast to microglial expression of interleukin-1beta and inducible nitric oxide synthase at the axotomy site, nigral microglia were interleukin-1beta and inducible nitric oxide synthase-negative. Consistently, RNase protection assays showed that interleukin-1beta and inducible nitric oxide synthase transcripts in nigra were equivocal. The present data support the idea that phagocytosis of axotomized neurons by activated microglia is not limited to dead neurons but includes dying neurons probably without cytotoxic effects of inflammatory substances, such as interleukin-1beta or nitric oxide.

Robot-aided neurorehabilitation: from evidence-based to science-based rehabilitation.

There is no "magic bullet" in rehabilitation. In the absence of direct neural transplants, neurological rehabilitation is an arduous process. We have pioneered the clinical application of robotics in stroke rehabilitation and have shown evidence of the positive impact of targeted exercise on stroke recovery. In this article, we will review results obtained in the initial clinical trials with 96 stroke patients at the Burke Rehabilitation Hospital. We will provide evidence that robot-aided training enhances recovery, that this enhanced recovery is sustained in the long term, and that this recovery is not due to a general physiological improvement--in fact, it appears to be limb and muscle group specific. An evidence-based approach must now segue into a more scientific approach to stroke rehabilitation. Given the length of the required protocols and patients' variability and limited census, the practical limitations of the evidence-based approach are self-evident and extend trials for years. Each patient and lesion is unique in stroke rehabilitation, so there is no reason to believe that a "one-size-fits-all" optimal treatment exists. To optimize therapy for individual patients, we need science-based models. In this article, we will summarize the scientific tools and models that we are investigating and present some of the results to date.

Is robot-aided sensorimotor training in stroke rehabilitation a realistic option?

Stroke is the leading cause of disability, despite continued advances in prevention and treatment techniques based on novel delivery of new fibrinolytic drugs. Improved medical treatment of the complications caused by acute stroke has contributed to decreased mortality, but 90% of the survivors have significant neurological deficits. Reducing the degree of permanent disability remains the goal of poststroke neuro-rehabilitation programs, and new approaches to impairment reduction through managing sensorimotor experience may contribute further to altering disability. Recent reports from a number of laboratories using enhanced sensorimotor training protocols, particularly those with robotic devices, have indicated modest success in reducing impairment and increasing motor power in the exercised limb of patients with stroke when compared with control individuals. Whether arming the therapist with new tools, especially robotic devices, to treat impairment is a realistic approach to modern interdisciplinary rehabilitation raises questions regarding the added value of impairment reduction, and under what conditions should scientific and clinical development of robotic studies continue.

A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus.

In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.

Early c-Fos induction after cerebral ischemia: a possible neuroprotective role.

The role of c-Fos in neurodegeneration or neuroprotection after cerebral ischemia is controversial. To investigate whether early c-Fos induction after ischemia is associated with neuroprotection, rats were subjected to 10 minutes of transient forebrain ischemia and c-Fos expression was examined. Resistant dentate granule cells and neurons in CA2-4 displayed more robust immunoreactivity than vulnerable neurons in the CA1 region of hippocampus during early hours of reperfusion. By 6 hours after reperfusion, c-Fos immunoreactivity was greatly diminished in all areas of the hippocampus. Administration of N-acetyl-O-methyldopamine (NAMDA), a compound previously shown to protect CA1 neurons against ischemia, increased c-Fos immunoreactivity in the CA1 vulnerable region at 6 hours after ischemia and protected SK-N-BE(2)C neurons from oxygen glucose deprivation. Further in vitro study showed that NAMDA potentiated phorbol-12 myristate-13 acetate (PMA)-induced c-Fos expression, AP1 binding activity, and late gene expression determined by chloramphenicol acetyltransferase (CAT) activity from AP1 containing tyrosine hydroxylase promoter-CAT fusion gene in SK-N-BE(2)C neurons. In vivo and in vitro results showed that a neuroprotectant, NAMDA, in concert with another stimulus (for example, ischemia or PMA) up-regulates c-Fos expression and suggested that the early rise of NAMDA-induced c-Fos expression in vulnerable CA1 neurons may account for neuroprotection by means of up-regulating late gene expression for survival.

Patients with capsular infarct and Wallerian degeneration show persistent regional premotor cortex activation on functional magnetic resonance imaging.

BACKGROUND AND PURPOSE: By using neurorehabilitation outcome measures and functional magnetic resonance imaging (fMRI), we attempted to elucidate the effect of Wallerian degeneration (WD) in the pyramidal tract distal to a posterior capsular stroke on functional recovery. METHODS: In 18 patients with pure motor hemiparesis caused by capsular infarct, we identified the presence of WD and then tested whether it affected the rate of motor improvement and the final motor outcome. The discharge T2-weighted MRI (139 +/- 5 days on average after stroke) showed WD in 10 of 18 patients (WD-positive, n = 10; WD-negative, n = 8). All patients performed mass grasping of paretic fingers before and after inpatient neurorehabilitation for the fMRI. RESULTS: Demographic characteristics, rate of disability change, final motor status, and volume of lesion were comparable between the groups. On the first fMRI, patterns of fMRI activation in the sensorimotor cortex, premotor cortex (PMC), and supplementary motor area were comparable. However, on the second fMRI, considerably more patients in the WD-positive group (8 out of 10) exhibited persistent contralateral activation in PMC than in the WD-negative group (1 out of 8; P = .0044, chi-square test). Ipsilateral PMC was also more frequently activated (P = .04) in WD-positive patients than in WD-negative patients. CONCLUSIONS: Persistent WD had no effect on the impairment or disability outcome; however, it was associated with novel regional activation on repeat fMRI after recovery. To determine whether persistent PMC activation resulted from effort or represents a general effect of WD on motor recovery will require a longer follow-up time and more precise control of functional measurement during imaging.