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1.  New directions in behavioral treatment of autism spectrum disorders 
Current opinion in neurology  2010;23(2):137-143.
Purpose of review
The review explores current trends in the behavioral intervention literature for children with an autism spectrum disorder (ASD) during 2008 and 2009. Noteworthy findings and intervention strategies are highlighted. Additionally, the quality of all reviewed studies is systematically evaluated.
Recent findings
During 2008 and 2009, there was nearly a quarter increase in the number of behavioral intervention studies, as well as more randomized controlled trials and approaches other than applied behavior analysis. Many of the studies investigated commonly used ASD intervention practices or novel treatments. A few were conducted with underserved populations, such as toddlers and adults with ASD. Social impairment was the focus of the largest number of intervention studies. A small percentage of studies were rated as high-quality.
Overall, the reviewed studies suggest that ASD-specific deficits can be improved through behavioral intervention. However, whereas progress continues to be made in our understanding of effective treatments for children with ASD, confidence in these findings would be improved with higher-quality studies.
PMCID: PMC4324974  PMID: 20160648
autism; behavior; intervention
2.  Myotonic dystrophy: is a narrow focus obscuring the rest of the field? 
Current opinion in neurology  2012;25(5):609-613.
Purpose of review
The myotonic dystrophies (DM1 and DM2) are the paradigm for RNA toxicity in disease pathogenesis. The emphasis of this review will be on recent developments and issues in understanding the pathogenesis of DM1 and how this is driving the accelerated pace of translational and therapeutic developments.
Recent findings
RNA toxicity in myotonic dystrophy is now associated with bi-directional antisense transcription, dysregulation of microRNAs and potentially non-ATG-mediated translation of homopolymeric toxic proteins. The role of other RNA-binding proteins beyond MBNL1 and CUGBP1, such as Staufen 1 and DDX5, are being identified and studied with respect to their role in myotonic dystrophy. New functions for MBNL1 in miR-1 biogenesis might have a clinically relevant role in myotonic dystrophy cardiac conduction defects and pathology. Advances are being made in identifying and characterizing small molecules with the potential to disrupt CUG–MBNL1 interactions.
Mechanisms of RNA toxicity are moving beyond a simplistic ‘foci-centric’ view of DM1 pathogenesis as a spliceopathy due to MBNL1 sequestration. Therapeutic development for myotonic dystrophy is moving rapidly with the development of antisense and small molecule therapies. Clinically, significant emphasis is being placed on biomarker discovery and outcome measures as an essential prelude to clinical trials.
PMCID: PMC4275308  PMID: 22892953
MBNL1; myotonic dystrophy; RNA foci; RNA toxicity; therapeutic development
3.  The interaction between training and plasticity in the post-stroke brain 
Current opinion in neurology  2013;26(6):609-616.
Purpose of review
Recovery after stroke can occur either via reductions in impairment or through compensation. Studies in humans and non-human animal models show that most recovery from impairment occurs in the first 1 to 3 months after stroke as a result of both spontaneous reorganization and increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived sensitive period of post-ischemic plasticity defined by unique genetic, molecular, physiological and structural events. In contrast, compensation can occur at any time after stroke. Here we address both the biology of the brain's post-ischemic sensitive period and the difficult question of what kind of training (task-specific vs. a stimulating environment for self-initiated exploration of various natural behaviors) best exploits this period.
Recent findings
Data suggest that three important variables determine the degree of motor recovery from impairment: (i) the timing, intensity, and approach to training with respect to stroke onset, (ii) the unique post-ischemic plasticity milieu, and (iii) the extent of cortical reorganization.
Future work will need to further characterize the unique interaction between types of training and post-ischemic plasticity, and find ways to augment and prolong the sensitive period using pharmacological agents or non-invasive brain stimulation.
PMCID: PMC4012223  PMID: 24136129
Motor recovery; spontaneous recovery; motor learning; ischemia; neurological rehabilitation
4.  The Evolving Landscape of Brain Tumor Cancer Stem Cells 
Current opinion in neurology  2013;26(6):701-707.
Purpose of review
Recent advances in the role of cancer stem cells (CSC) in glioblastoma (GBM) will be reviewed.
Recent findings
In the decade since the description of brain tumor CSCs, the potential significance of these cells in tumor growth, therapeutic resistance and spread has become evident. Most recently, the interplay between CSCs, tumor genetics and the microenvironment has offered potential nodes of fragility under therapeutic development. The CSC phenotype is informed by specific receptor signaling, and the regulation of stem cell genes by transcription factors and miRNAs has identified a number of new targets amenable to treatment. Like normal stem cells, CSC display specific epigenetic landscapes and metabolic profiles.
Brain cancers activate core stem cell regulatory pathways to empower self-renewal, maintenance of an organ system (albeit an aberrant one), and survival under stress that collectively permits tumor growth, therapeutic resistance, invasion and angiogenesis. These properties have implicated CSC as contributors in GBM progression and recurrence, spurring a search for anti-CSC therapies that do not disrupt normal stem cell maintenance. The past year has witnessed a rapid evolution in the understanding of CSC biology to inform preclinical targeting.
PMCID: PMC4031658  PMID: 24152818
Glioblastoma; glioma stem cells; cancer stem cells
5.  Wearable motion sensors to continuously measure real-world physical activities 
Current opinion in neurology  2013;26(6):602-608.
Purpose of review
Rehabilitation for sensorimotor impairments aims to improve daily activities, walking, exercise, and motor skills. Monitoring of practice and measuring outcomes, however, is usually restricted to laboratory-based procedures and self-reports. Mobile health devices may reverse these confounders of daily care and research trials.
Recent findings
Wearable, wireless motion sensor data, analyzed by activity pattern-recognition algorithms, can describe the type, quantity, and quality of mobility-related activities in the community. Data transmission from sensors to the cell phone and Internet enable continuous monitoring. Remote access to laboratory-quality data about walking speed, duration and distance, gait asymmetry and smoothness of movements, as well as cycling, exercise, and skills practice, opens new opportunities to engage patients in progressive, personalized therapies with feedback about performance. Clinical trial designs will be able to include remote verification of the integrity of complex physical interventions and compliance with practice, as well as capture repeated, ecologically sound, ratio-scale outcome measures.
Given the progressively falling cost of miniaturized wearable gyroscopes, accelerometers, and other physiologic sensors, as well as inexpensive data transmission, sensing systems may become as ubiquitous as cell phones for health care. Neurorehabilitation can develop these mobile health platforms for daily care and clinical trials to improve exercise and fitness, skills learning, and physical functioning.
PMCID: PMC4035103  PMID: 24136126
mobile health; stroke rehabilitation; outcome assessment; physical activity; accelerometer; gyroscope; activity monitor; signal processing; telemedicine
6.  Genetics in glioma- lessons learned from genome wide association studies 
Current opinion in neurology  2013;26(6):688-692.
Purpose of review
The purpose of this review is to describe the recent knowledge gathered from the identification of seven genomic regions that have been linked to the risk of developing malignant glioma.
Recent findings
The recent novel discoveries in fine mapping and genotype-phenotype studies will be highlighted. Through imputation and next generation sequencing a novel genetic variant, rs55705857 with a strong association at 8q24 has been discovered and validated in two studies. This locus is specifically associated with IDH1 and IDH2 mutated tumors and oligodendroglial tumors, albeit the specific mechanism of tumor development is not understood. The genetic variants associated with risk of glioma in the EGFR gene have also been associated with specific somatic aberrations, including loss at the CDKN2A/B locus and allele specific loss of EGFR in the tumors. A specific TP53 low frequency variant has also been associated with glioma risk and validated in a separate data set. The genetic risk in the telomere regulating genes TERT and RTEL appear to be associated with higher grade tumors without IDH mutations.
The link of genetic loci to specific tumor subtypes may have relevance for understanding glioma biology, for developing new diagnostic tools and targeted therapy for glioma.
PMCID: PMC4075044  PMID: 24184969
glioma etiology; genotype; phenotype; glioblastoma; oligodendroglioma
7.  Diabetic Neuropathy: One disease or two? 
Current opinion in neurology  2012;25(5):536-541.
Purpose of review
To compare and contrast the evidence for the effect of glucose control on the prevention of neuropathy in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus.
Recent findings
In T1DM, multiple clinical trials have demonstrated a large benefit from enhanced glucose control, whereas the benefit in T2DM is much more modest. Epidemiologic and laboratory evidence exists to support factors other than hyperglycemia in the development of neuropathy including obesity, hypertension, dyslipidemia, inflammation, and insulin resistance.
T1DM neuropathy and T2DM neuropathy are fundamentally different. In T1DM, glucose control has a large effect on the prevention of neuropathy; therefore future efforts should continue to concentrate on this avenue of treatment. In contrast, in T2DM, glucose control has a small effect on the prevention of neuropathy; as a result, more research is needed to define the underlying mechanisms for the development of neuropathy. Understanding these mechanisms may lead to novel therapeutic approaches to prevent or treat diabetic neuropathy.
PMCID: PMC4239661  PMID: 22892951
Neuropathy; Type 1 diabetes; Type 2 diabetes; Metabolic syndrome
8.  Novel Frontiers in MRI of the brain 
Current opinion in neurology  2011;24(4):386-393.
Recent developments in the use of MRI contrast in images of the brain continue to expand the use of MRI in neuroscience. Higher magnetic field strengths and innovative ways to manipulate contrast have allowed improved visualization of the various properties of brain tissues, facilitating the anatomical definition of functional areas and their white matter fiber connections. This is bringing us closer to understanding the evolutionary blueprint of the brain, improving the detection and characterization of disease, and help guiding treatment. This review highlights some areas of recent progress, including the application of magnetic susceptibility contrast to study white matter fibers and cortical layers and the use of endogenous and exogenous contrast to study cellular events.
PMCID: PMC4217117  PMID: 21734576
9.  Recent developments in biomarkers in Parkinson disease 
Current opinion in neurology  2013;26(4):395-400.
Purpose of review
Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease, and current demographic trends indicate a life-time risk approaching 4% and predict a doubling of prevalence by 2030. Strategies are being developed to apply recent advances in our understanding of the cause of Parkinson disease to the development of biomarkers that will enable the identification of at-risk individuals, enable early diagnosis and reflect the progression of disease. The latter will be particularly important for the testing of disease-modifying therapies. This review summarizes recent advances in Parkinson disease biomarker development.
Recent findings
Recent reports continue to reflect the application of a variety of clinical, imaging or biochemical measurements, alone or in combination, to general Parkinson disease populations. Probably the most promising is the assay of alpha-synuclein in the diagnosis and evolution of Parkinson disease. At present, detection techniques are still being refined, but once accurate and reproducible assays are available, it will be important to define the relationship of these to early diagnosis and progression. Alpha-synuclein concentrations may also be modulated by certain disease-modifying agents in development and so may represent a measure of their efficacy. It has to be accepted that no single measure currently fulfils all the necessary criteria for a biomarker in Parkinson disease, but combinations of measures are more likely to deliver benefit.
The Parkinson disease biomarker field is approaching a stage when certain combinations of clinical, imaging and biochemical measures may identify a proportion of individuals at risk for developing the disease. However, their general applicability may be limited. Attention is now turning to stratification of Parkinson disease into certain at-risk groups defined by genotype. The application of multimodal screening to these populations may be more rewarding in the short term.
PMCID: PMC4196782  PMID: 23823465
alpha-synuclein; biomarker; genes; imaging; Parkinson disease
10.  Primary and secondary dystonic syndromes: an update 
Current opinion in neurology  2013;26(4):406-412.
Purpose of review
The dystonias are a common but complex group of disorders that show considerable variation in cause and clinical presentation. The purpose of this review is to highlight the most important discoveries and insights from across the field over the period of the past 18 months.
Recent findings
Five new genes for primary dystonia (PRRT2, CIZ1, ANO3, TUBB4A and GNAL) have made their appearance in the literature. New subtypes of neuronal brain iron accumulation have been delineated and linked to mutations in C19orf12 and WDR45, while a new treatable form of dystonia with brain manganese deposition related to mutations in SLC30A10 has been described. At the same time, the phenotypes of other forms of dystonic syndromes have been expanded or linked together. Finally, there has been increasing recognition of both the extramotor phenotype in dystonia and the part played by the cerebellum in its pathophysiology.
Recently, there has been unprecedented change in the scientific landscape with respect to the cause of various dystonic syndromes that is likely to make a direct impact on clinical practice in the near future. Understanding the genetic cause of these syndromes and the often wide phenotypic variation in their presentations will improve diagnosis and treatment. With time, these discoveries may also lead to much-needed progress in elucidating the underlying pathophysiology of dystonia.
PMCID: PMC4196839  PMID: 23757263
cerebellum; dystonia; genetics; nonmotor; phenotype
11.  The Pallidopyramidal Syndromes: nosology, aetiology and pathogenesis 
Current opinion in neurology  2013;26(4):381-394.
Purpose of review
The aims of this review are to suggest a new nomenclature and classification system for the diseases currently categorised as NBIA or dystonia-parkinsonism, and to discuss the mechanisms implicated in the pathogenesis of these diseases.
Recent findings
Neurodegeneration with brain iron accumulation (NBIA) is a disease category encompassing syndromes with iron accumulation and prominent dystonia-parkinsonism. However, as there are many diseases with similar clinical presentations but without iron accumulation and/or known genetic cause, the current classification system and nomenclature remain confusing. The pathogenetic mechanisms of these diseases and the causes of gross iron accumulation and significant burden of neuroaxonal spheroids are also elusive. Recent genetic and functional studies have identified surprising links between PPS, Parkinson’s disease (PD) and Lysosomal storage disorders (LSD) with the common theme being a combined lysosomal-mitochondrial dysfunction. We hypothesise that mitochondria and lysosomes form a functional continuum with a predominance of mitochondrial and lysosomal pathways in PPS and LSD respectively and with PD representing an intermediate form of disease.
During the past 18 months important advances have been made towards understanding the genetic and pathological underpinnings of the Pallidopyramidal syndromes with important implications for clinical practice and future treatment developments.
PMCID: PMC4196641  PMID: 23817214
Neurodegeneration with brain iron accumulation; Hallervordern-Spatz disease; Parkinson’s disease; lysosomal storage disorders
12.  Sex differences in autism spectrum disorders 
Current opinion in neurology  2013;26(2):146-153.
Purpose of review
A strong male bias in autism spectrum disorder (ASD) prevalence has been observed with striking consistency, but no mechanism has yet to definitively account for this sex difference. Toward the pursuit of a more complete understanding of the biological basis for sex-differential risk, this review explores the current status of epidemiological, genetic, and neuroendocrinological work addressing ASD prevalence and liability in males and females.
Recent findings
Recent studies continue to report a male bias in ASD prevalence, but also suggest that sex differences in phenotypic presentation, including fewer restricted and repetitive behaviors and externalizing behavioral problems in females, may contribute to this bias. Genetic studies demonstrate that females are protected from the effects of heritable and de novo ASD risk variants, and compelling work suggests that sex chromosomal genes and/or sex hormones, especially testosterone, may modulate the effects of genetic variation on the presentation of an autistic phenotype.
ASDs affect females less frequently than males, and several sex-differential genetic and hormonal factors may contribute. Future work to determine the mechanisms by which these factors confer risk and protection to males and females is essential.
PMCID: PMC4164392  PMID: 23406909
autism spectrum disorders; sex differences; hormones; sex chromosomes; genetic liability
Current opinion in neurology  2008;21(5):585-589.
Purpose of review
The aim of this communication is to provide an up-to-date overview of myofibrillar myopathies (MFMs).
Recent findings
The most important recent advance in the MFMs has been the identification of mutation Bag3 (Bcl-2-associated athanogene-3) as a new cause of MFM. Although, the typical clinical manifestations of MFMs are slowly progressive weakness, the patients with Bag3opathy may have had a rapidly progressive and more severe phenotype.
Several MFM disease genes have recently been recognized. The identified disease proteins (desmin, αB-crystallin, myotilin, Zasp, filamin C, and Bag3) interact with components or with chaperones of the Z-disk. In each case the molecular defect leads to a largely stereotyped cascade of structural perturbation of the muscle fiber architecture.
PMCID: PMC4151125  PMID: 18769253
Myofibrillar myopathy; desmin; αB-crystallin; myotilin; Zasp; filamin C; Bag3; FHL1
14.  Advances in Auditory Prostheses 
Current opinion in neurology  2012;25(1):61-66.
Purpose of the Review
Auditory prostheses use electric currents on multiple electrodes to stimulate auditory neurons and recreate auditory sensations in deaf people. Cochlear implants have restored hearing in more than 200,000 deaf adults and children to a level that allows most to understand speech. Here we review the reasons underlying these results and describe new directions in restoring hearing to additional patient populations and the design of new devices.
Recent findings
From their early development about 50 years ago, cochlear implants (CIs) have been well received and beneficial to people who had lost their hearing. Although those first implants did not allow high levels of speech understanding, they provided auditory information that worked synergistically with lip reading to improve communication. Present day CIs provide excellent speech understanding in children and in postlingually deafened adults. Research is focused on improved signal processing and new electrode designs. Electric stimulation of the auditory brainstem can also produce excellent hearing in some children and adults.
Auditory prostheses, both at the level of the sensory nerve and at the brainstem, can restore patterns of neural activation that are sufficient for high levels of speech understanding. These prostheses are not only clinically successful but also are important tools for understanding sensory processing in the brain.
PMCID: PMC4123811  PMID: 22157109
cochlear implants; auditory brainstem implants; speech recognition; hearing
15.  Novel brain imaging approaches to understand acquired and congenital neuro-ophthalmological conditions 
Current opinion in neurology  2014;27(1):92-97.
Purpose of review
The arrival of large datasets and the on-going refinement of neuroimaging technology have led to a number of recent advances in our understanding of visual pathway disorders. This work can broadly be classified into two areas, both of which are important when considering optimal management strategies. The first looks at delineation of damage, teasing out subtle changes to (specific components of) the visual pathway, which may help evaluate severity and extent of pathology. The second uses neuroimaging to investigate neuroplasticity, via changes in connectivity, cortical thickness, and retinotopic maps within the visual cortex.
Recent findings
Here we give consideration to both acquired and congenital patients with damage to the visual pathway, and how they differ. Congenital disorders of the peripheral visual system can provide insight into the large-scale reorganisation of the visual cortex: these are investigated with reference to disorders of the optic chiasm and anophthalmia (absence of the eyes). In acquired conditions, we consider recent work describing patterns of degeneration, both following single insult and in neurodegenerative conditions. We also discuss developments in functional neuroimaging, with particular reference to work on hemianopia and the controversial suggestion of cortical reorganisation following acquired retinal injury.
Techniques for comparing neuro-ophthalmological conditions with healthy visual systems provide sensitive metrics to uncover subtle differences in gray and white matter structure of the brain. It is now possible to compare the massive reorganisation present in congenital conditions with the apparent lack of plasticity following acquired damage.
PMCID: PMC3983755  PMID: 24300791
hemianopia; optic chiasm; neuroimaging; fMRI; blindness
16.  Migraine and estrogen 
Current opinion in neurology  2014;27(3):315-324.
Purpose of review
The aim is to systematically and critically review the relationship between migraine and estrogen, the predominant female sex hormone, with a focus on studies published in the last 18 months.
Recent findings
Recent functional MRI (fMRI) studies of the brain support the existence of anatomical and functional differences between men and women, as well as between participants with migraine and healthy controls. In addition to the naturally occurring changes in endogenous sex hormones over the lifespan (e.g. puberty and menopause), exogenous sex hormones (e.g. hormonal contraception or hormone therapy) also may modulate migraine. Recent data support the historical view of an elevated risk of migraine with significant drops in estrogen levels. In addition, several lines of research support that reducing the magnitude of decline in estrogen concentrations prevents menstrually related migraine (MRM) and migraine aura frequency.
Current literature has consistently demonstrated that headache, in particular migraine, is more prevalent in women as compared with men, specifically during reproductive years. Recent studies have found differences in headache characteristics, central nervous system anatomy, as well as functional activation by fMRI between the sexes in migraine patients. Although the cause underlying these differences is likely multifactorial, considerable evidence supports an important role for sex hormones. Recent studies continue to support that MRM is precipitated by drops in estrogen concentrations, and minimizing this decline may prevent these headaches. Limited data also suggest that specific regimens of combined hormone contraceptive use in MRM and migraine with aura may decrease both headache frequency and aura.
PMCID: PMC4102139  PMID: 24792340
estradiol; estrogen; headache; migraine; sex hormone
17.  Motor rehabilitation after stroke, traumatic brain, and spinal cord injury: common denominators within recent clinical trials 
Current opinion in neurology  2009;22(6):563-569.
Purpose of review
Experimental studies and clinical trials that aim to improve motor function for use of the upper extremity and walking are traditionally separated by the category of neurological disease. This boundary may deter investigators from finding common denominators in the conceptual basis and deployment of rehabilitation interventions, especially across nonprogressive diseases in adults, such as stroke, brain trauma, and spinal cord injury.
Recent findings
The results of recent randomized clinical trials for walking by treadmill training and robotic devices and for the upper extremity by constraint-induced therapy, robotics, and brain stimulation suggest that more efficient strategies are needed to devise and prove the value of new therapies.
Investigators should consider working across disease platforms to develop and test the most optimal methods for training patients, the most practical trial designs, the best dose–response characteristics of interventions, the most meaningful outcome measures, and the likelihood of transfer of trained performance to real-world settings. Clinicians in the community may be more likely to adopt evidence-based practices drawn from positive trial results if these treatment strategies focus on key motor impairments and related disabilities, rather than on diseases.
PMCID: PMC4077333  PMID: 19724226
functional electrical stimulation; gait training; robotics; spinal cord injury; stroke rehabilitation
18.  Recent Advances in Tourette Syndrome 
Current opinion in neurology  2011;24(2):119-125.
Purpose of review
The purpose of this review is to consider the recent literature pertaining to the neurobiology, genetics and treatment of Tourette syndrome (TS).
Recent findings
Over the last several years, both neuropathological and genetic findings have further focused attention on long-standing hypotheses regarding the role of the basal ganglia in the etiology of tics and TS. Moreover, while the field awaits the results the first large-scale genetic studies, recent findings have already mirrored developments in the neuropsychiatric genetics literature more broadly, highlighting the value of the study of rare variation and the overlap of risks among seemingly disparate diagnostic categories. Finally, treatment studies have underscored the importance of cognitive-behavioral as well as pharmacological interventions for the treatment of tic disorders.
Recent findings have led to novel, testable hypotheses regarding the molecular and cellular mechanisms underlying TS. These, in turn, have begun to provide new avenues to conceptualizing treatment strategies. While the development of additional medication options is a pressing need, recent data has demonstrated both the safety and efficacy of non-pharmacological approaches.
PMCID: PMC4065550  PMID: 21386676
Tourette syndrome; striatal interneurons; histaminergic neurotransmission; Habit Reversal Therapy
19.  Connectomics and epilepsy 
Current opinion in neurology  2013;26(2):186-194.
Purpose of review
Tremendous advances have occurred in recent years in elucidating basic mechanisms of epilepsy at the level of ion channels and neurotransmitters. Epilepsy, however, is ultimately a disease of functionally and/or structurally aberrant connections between neurons and groups of neurons at the systems level. Recent advances in neuroimaging and electrophysiology now make it possible to investigate structural and functional connectivity of the entire brain, and these techniques are currently being used to investigate diseases that manifest as global disturbances of brain function. Epilepsy is such a disease, and our understanding of the mechanisms underlying the development of epilepsy and the generation of epileptic seizures will undoubtedly benefit from research utilizing these connectomic approaches.
Recent findings
MRI using diffusion tensor imaging provides structural information, whereas functional MRI and electroencephalography provide functional information about connectivity at the whole brain level. Optogenetics, tracers, electrophysiological approaches, and calcium imaging provide connectivity information at the level of local circuits. These approaches are revealing important neuronal network disturbances underlying epileptic abnormalities.
An understanding of the fundamental mechanisms underlying the development of epilepsy and the generation of epileptic seizures will require delineation of the aberrant functional and structural connections of the whole brain. The field of connectomics now provides approaches to accomplish this.
PMCID: PMC4064674  PMID: 23406911
epilepsy; functional connectivity; local circuits; structural connectivity; whole brain
20.  High-frequency oscillations in epileptic brain 
Current opinion in neurology  2010;23(2):151-156.
Purpose of review
It has been 10 years since pathological high-frequency oscillations (pHFOs) were described in the brain of epileptic animals and patients. This review summarizes progress in research on mechanisms of their generation and potential clinical applications over that period.
Recent findings
Initially, pHFOs were recorded with microelectrodes in the hippocampus of rodents and patients with mesial temporal lobe epilepsy (MTLE), but recently pHFOs have also been recorded with clinical depth and grid electrodes in multiple brain areas including the hippocampus and neocortex of patients with different types of epilepsy. One hypothesis is that pHFOs reflect fields of hypersynchronized action potentials (bursts of population spikes) within small discrete neuronal clusters responsible for seizure generation. Studies suggest that pHFOs can be used as a reliable biomarker for epileptogenesis, epileptogenicity, and the delineation of the epileptogenic region.
Recording of pHFOs with clinical electrodes provides a means for further investigation of their functional role in the epileptic brain and as a potential biomarker of epileptogenesis and epileptogenicity and for presurgical mapping.
PMCID: PMC4063284  PMID: 20160649
biomarkers; epilepsy; fast ripples; high-frequency oscillations
21.  Multisensory Integration in Migraine 
Current opinion in neurology  2013;26(3):248-253.
Purpose of Review
Migraine attacks consist of head pain and hypersensitivities to somatosensory, visual, auditory and olfactory stimuli. Investigating how the migraine brain simultaneously processes and responds to multiple incoming stimuli may yield insights into migraine pathophysiology and migraine symptoms.
Recent Findings
The presence and intensity of hypersensitivity to one stimulus type are positively associated with the presence and intensity of hypersensitivities to other stimuli and to headache intensity. Furthermore, exposure to visual, auditory and olfactory stimuli can trigger migraine attacks. These relationships suggest a role for multisensory integration in migraine.
Multisensory integration of somatosensory, visual, auditory and olfactory stimuli by the migraine brain may be an important concept for understanding migraine.
PMCID: PMC4038337  PMID: 23591684
Migraine; Multisensory Integration; Sensitization; Cutaneous Allodynia; Migraine Pathophysiology
22.  Ketogenic Diets: New Advances for Metabolism-Based Therapies 
Current opinion in neurology  2012;25(2):173-178.
Purpose of review
Despite myriad anticonvulsants available and in various stages of development, there are thousands of children and adults with epilepsy worldwide still refractory to treatment and not candidates for epilepsy surgery. Many of these patients will now turn to dietary therapies such as the ketogenic diet, medium-chain triglyceride (MCT) diet, modified Atkins diet, and low glycemic index treatment.
Recent Findings
In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome). Adults are also one of the most rapidly growing populations being treated nowadays; a group of patients previously not typically offered these treatments. In 2009, two controlled trials of the ketogenic diet were published as well as an International Expert Consensus Statement on dietary treatment of epilepsy. Ketogenic diets are also now being increasingly studied for neurologic conditions other than epilepsy, including Alzheimer disease and cancer. Insights from basic science research have helped elucidate the mechanisms by which metabolism-based therapy may be helpful, both in terms of an anticonvulsant and possibly neuroprotective effect.
Dietary therapy for epilepsy continues to grow in popularity worldwide, with expanding use for adults and conditions other than epilepsy.
PMCID: PMC4002181  PMID: 22322415
Ketogenic; diet; epilepsy; modified Atkins; metabolism; ketosis
23.  Cilia in the nervous system: linking cilia function and neurodevelopmental disorders 
Current opinion in neurology  2011;24(2):98-105.
Purpose of review
Ciliopathies are genetic disorders caused by defects of primary ciliary structure and/or function and are characterized by pleiotropic clinical features. The ciliopathies include several partially overlapping syndromes such as Joubert syndrome, Bardet–Biedl syndrome and Meckel–Gruber syndrome, all of which have pronounced neurodevelopmental features. Here we focus on potential roles of cilia in central nervous system function, to explore how impairments may cause brain malformation and neurodevelopmental disease.
Recent findings
Cilia have long been considered as ‘sensory cellular antennae’, responding as chemo-sensors, mechano-sensors and thermo-sensors, although their roles in development were not well understood until recently. The surprising finding that disparate syndromes are all due to defects of the primary cilia, along with the recent advances in genetics, has helped elucidate further roles of primary cilia beyond sensory functions. Several molecules that are associated with key signaling pathways have been discovered in primary cilia. These include sonic hedgehog, wingless, planar cell polarity and fibroblast growth factor, which are essential for many cellular processes. Additionally, mutations in ‘ciliome’ genes have largely shown developmental defects such as abnormal body axis and brain malformation, implying disrupted cilia-related signaling pathways. Accordingly, the emerging theme is that primary cilia may play roles as modulators of signal transduction to help shape cellular responses within the environmental context during both development and homeostasis.
The link between cilia and signal pathways has become a framework for understanding the pathogenesis of ciliopathies. Despite recent progress in ciliary biology, fundamental questions remain about how cilia regulate neuronal function in the central nervous system. Therefore, investigation of ciliary function in the nervous system may reveal cilia-modulating mechanisms in neurodevelopmental processes, as well as suggest new treatments for disease.
PMCID: PMC3984876  PMID: 21386674
brain; central nervous system; cilia; ciliopathy; Joubert syndrome; neuron; signaling pathways
24.  Issues for new antiepilepsy drug development 
Current opinion in neurology  2013;26(2):195-200.
Purpose of review
Preclinical research in epileptology has been very successful in producing effective drugs. Unfortunately, however, seizures are still not adequately controlled in a third of the affected individuals, and comorbidities still impose a major burden on quality of life. New preclinical and clinical drug development strategies are needed to identify drugs that target these unmet medical needs.
Recent findings
Even in recent years, the antiseizure approach based on screenings has contributed to the identification of new drugs. Thus, it should not be abandoned. However, we propose that a radically new approach, specifically designed to tackle the existing gaps in care, should be developed to complement the traditional screening. This new approach will require integrated strategies for preclinical screening and experimental trial design. In this review, we will attempt to address some of the issues that must be resolved to engage this effort. Are there suitable models to tackle the unmet therapeutic needs in epilepsy? Are there ways de-risk the transition from pre-clinical to clinical studies? Are there ways to improve the efficiency of clinical trials and to design ad hoc trials for the unmet therapeutic needs?
Development and validation of a new, integrated strategy for anti-epilepsy drug development is needed to identify truly innovative drugs.
PMCID: PMC3770466  PMID: 23406913
Anti-seizure drug; Anti-epileptogenesis; Disease modification; Co-morbidity; Biomarker
25.  Genetics of the epilepsies: where are we and where are we going? 
Current opinion in neurology  2013;26(2):179-185.
Purpose of the review
We aim to review the most recent advances in the field of epilepsy genetics with particular focus on the progress in gene discovery in monogenic epilepsies, identification of risk genes in complex genetic epilepsies and recent findings in the field of epilepsy pharmacogenomics.
Recent findings
During the last 12 months, the use of massive parallel sequencing technologies has allowed for the discovery of several genes for monogenic epilepsies. Most importantly, PRRT2 was identified as the long-sought gene for Benign Familial Infantile Seizures (BFIS). Mutations in KCNT1 were found in two seemingly unrelated monogenic epilepsies including Malignant Migrating Partial Seizures of Infancy (MMPSI) and severe Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). A genome-wide association study in Idiopathic Generalized Epilepsy (IGE) revealed the first common risk variants for human seizure disorders including variants in VRK2, PNPO and SCN1A. Furthermore, a landmark study provided evidence that screening for the HLAB*1502 variant may prevent carbamazepine-induced side effects in the Taiwanese population. Also, HLA-A*3101 variants were identified as a risk factor for carbamazepine side effects in Europeans.
Novel technologies and an unprecedented level of international collaboration has resulted in novel genes for monogenic and complex genetic epilepsies as well as risk factors for side effects of antiepileptic drugs. This review provides an overview of the most relevant studies in the last year and highlights the future direction of the field.
PMCID: PMC3781236  PMID: 23429546
Epilepsy; genetics; pharmacogenomics; epileptic encephalopathies

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