The Neuroscientist

Noninvasive plasticity paradigms, both physiologically induced and artificially induced, have come into their own in the study of the effects of genetic variation on human cortical plasticity. These techniques have the singular advantage that they enable one to study the effects of genetic variation in its natural and most relevant context, that of the awake intact human cortex, in both health and disease. This review aims to introduce the currently available artificially induced plasticity paradigms, their putative mechanisms—both in the traditional language of the systems neurophysiologist and in the evolving (and perhaps more relevant for the purposes of stimulation genomics) reinterpretation in terms of molecular neurochemistry, and highlights recent studies employing these techniques by way of examples of applications.

Over the last 15 years there has been a burgeoning number of publications using functional brain imaging (>40,000 articles based on an ISI/Web of Science search) to localize behavioral and cognitive processes to specific areas in the human brain that are often not confirmed by traditional, lesion-based studies. Thus, there is a need to reassess what cerebral localization of functions is and is not. Otherwise, there is no rational way to interpret the escalating claims of localization in the functional imaging literature that is taking on the appearance of neurophysiologic “phrenology”. This article will present arguments to suggest that functional localization in the brain is a robust but very dynamic, four-dimensional process. It is a learned phenomenon driven over time by large-scale, spatially distributed, neural networks seeking to efficiently maximize the processing, storage, and manipulation of information for cognitive and behavioral operations. Because of historical considerations and space limitations, the main focus will be on localization of language-related functions whose theoretical neurological basis can be generalized for any complex cognitive-behavioral function.

Neurons respond to numerous factors in their environment that influence their survival and function during development and in the mature brain. Among these factors, the neurotrophins have been shown to support neuronal survival and function, acting primarily through the Trk family of receptor tyrosine kinases. However, recent studies have established that the uncleaved neurotrophin precursors, the proneurotrophins, can be secreted and induce apoptosis via the p75 neurotrophin receptor, suggesting that the balance of secreted mature and proneurotrophins has a critical impact on neuronal survival or death. Epileptic seizures elicit increases in both proneurotrophin secretion and p75^NTR expression, shifting the balance of these factors toward signaling cell death. This review will discuss the evidence that this ligand-receptor system plays an important role in neuronal loss following seizures.

Epilepsy accounts for 0.5% of the global burden of disease, and primary prevention of epilepsy represents one of the three 2007 NINDS Epilepsy Research Benchmarks. In the past decade, efforts to understand and intervene in the process of epileptogenesis have yielded fruitful preventative strategies in animal models.This article reviews the current understanding of epileptogenesis, introduces the concept of a “critical period” for epileptogenesis, and examines strategies for epilepsy prevention in animal models of both acquired and genetic epilepsies. We discuss specific animal models, which may yield important insights into epilepsy prevention including kindling, poststatus epilepticus, prolonged febrile seizures, traumatic brain injury, hypoxia, the tuberous sclerosis mouse model, and the WAG/Rij rat model of primary generalized epilepsy. Hopefully, further investigation of antiepileptogenesis in animal models will soon enable human therapeutic trials to be initiated, leading to long-term epilepsy prevention and improved patient quality of life.

Attentional and emotional states alter the way we perceive pain. Recent findings suggest that the mechanisms underlying these two forms of pain modulation are at least partially separable. This concept is supported by the observation that attention and emotions differentially alter the sensory and affective dimensions of pain perception and apparently implicate different brain circuits. In this review, we will examine those recent findings within the broader cognitive neuroscience conceptualization of human attention and emotion and the corresponding functional neuroanatomy.

Transcranial stimulation with weak direct current (DC) has been valuable in exploring the effect of cortical modulation on various neural networks. Less attention has been given, however, to cranial stimulation with low-intensity alternating current (AC). Reviewing and discussing these methods simultaneously with special attention to what is known about their mechanisms of action may provide new insights for the field of noninvasive brain stimulation. Direct current appears to modulate spontaneous neuronal activity in a polarity-dependent fashion with site-specific effects that are perpetuated throughout the brain via networks of interneuronal circuits, inducing significant effects on high-order cortical processes implicated in decision making, language, memory, sensory perception, and pain. AC stimulation has also been associated with a significant behavioral and clinical impact, but the mechanism of AC stimulation has been underinvestigated in comparison with DC stimulation. Even so, preliminary studies show that although AC stimulation has only modest effects on cortical excitability, it has been shown to induce synchronous changes in brain activity as measured by EEG activity. Thus, cranial AC stimulation may render its effects not by polarizing brain tissue, but rather via rhythmic stimulation that synchronizes and enhances the efficacy of endogenous neurophysiologic activity. Alternatively, secondary nonspecific central and peripheral effects may explain the clinical outcomes of DC or AC stimulation. Here the authors review what is known about DC and AC stimulation, and they discuss features that remain to be investigated.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT_2a receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.