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1.  Trophic factors therapy in Parkinson’s disease 
Progress in brain research  2009;175:201-216.
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.
doi:10.1016/S0079-6123(09)17514-3
PMCID: PMC3430519  PMID: 19660658
neurotrophic factors; Parkinson’s disease; glial cell line-derived neurotrophic factor family ligands; GDNF; neurturin; gene therapy; clinical trials
2.  Cell transplantation strategies for retinal repair 
Progress in brain research  2009;175:3-21.
Cell transplantation is a novel therapeutic strategy to restore visual responses to the degenerate adult neural retina and represents an exciting area of regenerative neurotherapy. So far, it has been shown that transplanted postmitotic photoreceptor precursors are able to functionally integrate into the adult mouse neural retina. In this review, we discuss the differentiation of photoreceptor cells from both adult and embryonic-derived stem cells and their potential for retinal cell transplantation. We also discuss the strategies used to overcome barriers present in the degenerate neural retina and improve retinal cell integration. Finally, we consider the future translation of retinal cell therapy as a therapeutic strategy to treat retinal degeneration.
doi:10.1016/S0079-6123(09)17501-5
PMCID: PMC3272389  PMID: 19660645
stem cell; progenitor cell; photoreceptor; retina; transplantation; degeneration
3.  Primate models of schizophrenia: future possibilities 
Progress in brain research  2009;179:117-125.
Schizophrenia is a disorder of the association cortices, with especially prominent structural and functional deficiencies in the dorsolateral prefrontal cortex (PFC). True dorsolateral PFC is found only in higher primates, and is characterized by highly elaborate pyramidal cells with extensive recurrent connections. The development of the primate PFC also involves distinct developmental and genetic pathways. Thus, primate models may be particularly important in determining the functional impact of genetic changes in patients with schizophrenia. Genes involved with pyramidal cell network connectivity may be especially important to study in primates, as their effects may be magnified in the extensively connected primate neurons. Adeno-associated virus technology appears particularly promising for studying the impact of genetic insults on the structure and function of the primate association cortex.
doi:10.1016/S0079-6123(09)17913-X
PMCID: PMC2929764  PMID: 20302824
Primate; prefrontal cortex; DISC1; evolution; working memory
4.  Recovery of control of posture and locomotion after a spinal cord injury: solutions staring us in the face 
Progress in brain research  2009;175:393-418.
Over the past 20 years, tremendous advances have been made in the field of spinal cord injury research. Yet, consumed with individual pieces of the puzzle, we have failed as a community to grasp the magnitude of the sum of our findings. Our current knowledge should allow us to improve the lives of patients suffering from spinal cord injury. Advances in multiple areas have provided tools for pursuing effective combination of strategies for recovering stepping and standing after a severe spinal cord injury. Muscle physiology research has provided insight into how to maintain functional muscle properties after a spinal cord injury.
Understanding the role of the spinal networks in processing sensory information that is important for the generation of motor functions has focused research on developing treatments that sharpen the sensitivity of the locomotor circuitry and that carefully manage the presentation of proprioceptive and cutaneous stimuli to favor recovery. Pharmacological facilitation or inhibition of neurotransmitter systems, spinal cord stimulation, and rehabilitative motor training, which all function by modulating the physiological state of the spinal circuitry, have emerged as promising approaches. Early technological developments, such as robotic training systems and high-density electrode arrays for stimulating the spinal cord, can significantly enhance the precision and minimize the invasiveness of treatment after an injury.
Strategies that seek out the complementary effects of combination treatments and that efficiently integrate relevant technical advances in bioengineering represent an untapped potential and are likely to have an immediate impact. Herein, we review key findings in each of these areas of research and present a unified vision for moving forward. Much work remains, but we already have the capability, and more importantly, the responsibility, to help spinal cord injury patients now.
doi:10.1016/S0079-6123(09)17526-X
PMCID: PMC2904312  PMID: 19660669
spinal cord injury; rehabilitation; robotic motor training; pharmacological intervention; skeletal muscle adaptation; proprioception; epidural stimulation; locomotion
5.  Consciousness and epilepsy: why are complex-partial seizures complex? 
Progress in brain research  2009;177:147-170.
Why do complex-partial seizures in temporal lobe epilepsy (TLE) cause a loss of consciousness? Abnormal function of the medial temporal lobe is expected to cause memory loss, but it is unclear why profoundly impaired consciousness is so common in temporal lobe seizures. Recent exciting advances in behavioral, electrophysiological, and neuroimaging techniques spanning both human patients and animal models may allow new insights into this old question. While behavioral automatisms are often associated with diminished consciousness during temporal lobe seizures, impaired consciousness without ictal motor activity has also been described. Some have argued that electrographic lateralization of seizure activity to the left temporal lobe is most likely to cause impaired consciousness, but the evidence remains equivocal. Other data correlates ictal consciousness in TLE with bilateral temporal lobe involvement of seizure spiking. Nevertheless, it remains unclear why bilateral temporal seizures should impair responsiveness. Recent evidence has shown that impaired consciousness during temporal lobe seizures is correlated with large-amplitude slow EEG activity and neuroimaging signal decreases in the frontal and parietal association cortices. This abnormal decreased function in the neocortex contrasts with fast polyspike activity and elevated cerebral blood flow in limbic and other subcortical structures ictally. Our laboratory has thus proposed the “network inhibition hypothesis,” in which seizure activity propagates to subcortical regions necessary for cortical activation, allowing the cortex to descend into an inhibited state of unconsciousness during complex-partial temporal lobe seizures. Supporting this hypothesis, recent rat studies during partial limbic seizures have shown that behavioral arrest is associated with frontal cortical slow waves, decreased neuronal firing, and hypometabolism. Animal studies further demonstrate that cortical deactivation and behavioral changes depend on seizure spread to subcortical structures including the lateral septum. Understanding the contributions of network inhibition to impaired consciousness in TLE is an important goal, as recurrent limbic seizures often result in cortical dysfunction during and between epileptic events that adversely affects patients’ quality of life.
doi:10.1016/S0079-6123(09)17711-7
PMCID: PMC2901990  PMID: 19818900
cortex; EEG; fMRI; septal nuclei; slow waves; attention; temporal lobe epilepsy; thalamus
6.  Cultural neurolinguistics 
As the only species that evolved to possess a language faculty, humans have been surprisingly generative in creating a diverse array of language systems. These systems vary in phonology, morphology, syntax, and written forms. Before the advent of modern brain-imaging techniques, little was known about how differences across languages are reflected in the brain. This chapter aims to provide an overview of an emerging area of research — cultural neurolinguistics — that examines systematic cross-cultural/crosslinguistic variations in the neural networks of languages. We first briefly describe general brain networks for written and spoken languages. We then discuss language-specific brain regions by highlighting differences in neural bases of different scripts (logographic vs. alphabetic scripts), orthographies (transparent vs. nontransparent orthographies), and tonality (tonal vs. atonal languages). We also discuss neural basis of second language and the role of native language experience in second-language acquisition. In the last section, we outline a general model that integrates culture and neural bases of language and discuss future directions of research in this area.
doi:10.1016/S0079-6123(09)17811-1
PMCID: PMC2821076  PMID: 19874968
cross-cultural; neurolinguistics; language; brain
7.  Developing novel immunogens for a safe and effective Alzheimer’s disease vaccine 
Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Aβ) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is elevated in brains of early onset AD patients in a small number of families that bear certain genetic mutations, further implicating its role in this devastating neurological disease. In addition, soluble Aβ oligomers have been shown to be detrimental to neuronal function. Therapeutic strategies aimed at lowering cerebral Aβ levels are currently under development. One strategy is to immunize AD patients with Aβ peptides so that they will generate antibodies that bind to Aβ protein and enhance its clearance. As of 1999, Aβ immunotherapy, either through active immunization with Aβ peptides or through passive transfer of Aβ-specific antibodies, has been shown to reduce cerebral Aβ levels and improve cognitive deficits in AD mouse models and lower plaque load in nonhuman primates. However, a Phase II clinical trial of active immunization using full-length human Aβ1-42 peptide and a strong Th1-biased adjuvant, QS-21, ended prematurely in 2002 because of the onset of meningoencephalitis in ~6% of the AD patients enrolled in the study. It is possible that T cell recognition of the human full-length Aβ peptide as a self-protein may have induced an adverse autoimmune response in these patients. Although only ~20% of immunized patients generated anti-Aβ titers, responders showed some general slowing of cognitive decline. Focal cortical regions devoid of Aβ plaques were observed in brain tissues of several immunized patients who have since come to autopsy. In order to avoid a deleterious immune response, passive Aβ immunotherapy is under investigation by administering monthly intravenous injections of humanized Aβ monoclonal antibodies to AD patients. However, a safe and effective active Aβ vaccine would be more cost-effective and more readily available to a larger AD population. We have developed several novel short Aβ immunogens that target the Aβ N-terminus containing a strong B cell epitope while avoiding the Aβ mid-region and C-terminus containing T cell epitopes. These immunogens include dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine antigen tree), 2xAβ1-15 (a tandem repeat of two lysine-linked Aβ1-15 peptides), and 2xAβ1-15 with the addition of a three amino acid RGD motif (R-2xAβ1-15). Intranasal immunization with our short Aβ fragment immunogens and a mucosal adjuvant, mutant Escherichia coli heat-labile enterotoxin LT(R192G), resulted in reduced cerebral Aβ levels, plaque deposition, and gliosis, as well as increased plasma Aβ levels and improved cognition in a transgenic mouse model of AD. Preclinical trials in nonhuman primates, and human clinical trials using similar Aβ immunogens, are now underway. Aβ immunotherapy looks promising but must be made safer and more effective at generating antibody titers in the elderly. It is hoped that these novel immunogens will enhance Aβ antibody generation across a broad population and avoid the adverse events seen in the earlier clinical trial.
doi:10.1016/S0079-6123(09)17506-4
PMCID: PMC2814339  PMID: 19660650
amyloid-beta; vaccine; Alzheimer’s disease; immunotherapy; T cells; B cells; adjuvant; nonhuman primates; transgenic mice
8.  Estrogen and Testosterone Therapies in Multiple Sclerosis 
Progress in brain research  2009;175:239-251.
It has been known for decades that females are more susceptible to inflammatory autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis, and psoriasis. In addition, female patients with these diseases experience clinical improvements during pregnancy with a temporary ‘rebound’ exacerbation post partum. These clinical observations suggest an effect of sex hormones on disease suggest potential use of the male hormone testosterone and the pregnancy hormone estriol, respectively, for treatment of MS. A growing number of studies using the MS animal model experimental autoimmune encephalomyelitis (EAE) support a therapeutic effect of these hormones. Both testosterone and estriol have been found to induce anti-inflammatory as well as neuroprotective effects. Findings from two recent pilot studies of transdermal testosterone in male MS patients and oral estriol in female MS patients support the therapeutic potential of these hormones. In this paper, we review the pre-clinical and clinical evidence for sex hormone treatments in MS and discuss potential mechanisms of action.
doi:10.1016/S0079-6123(09)17516-7
PMCID: PMC2724009  PMID: 19660660

Results 1-8 (8)