Volume 3, Issue 1

Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822–829 (2011)]. Rodents administered CBD3 intraperitoneally, fused to the HIV TAT protein cell penetrating domain, exhibited antinociception lasting ∼4 hours highlighting potential instability, limited oral bioavailability, and/or rapid elimination of peptide. This report focuses on improving upon the parental CBD3 peptide. Using SPOTScan analysis of synthetic versions of the parental CBD3 peptide, we identified peptides harboring single amino acid mutations that bound with greater affinity to CaV2.2. One such peptide, harboring a phenylalanine instead of glycine (G14F), was tested in rodent models of migraine and neuropathic pain. In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2′-3′-didehydro-2′-3′-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.

Diffuse axonal injury is a common pathological consequence of Traumatic Brain Injury (TBI). Diffusion Tensor Imaging is an ideal technique to study white matter integrity using the Fractional Anisotropy (FA) index which is a measure of axonal integrity and coherence. There have been several reports showing reduced FA in individuals with TBI, which suggest demyelination or reduced fiber density in white matter tracts secondary to injury. Individuals with TBI are usually diagnosed with cognitive deficits such as reduced attention span, memory and executive function. In this study we sought to investigate correlations between brain functional networks, white matter integrity, and TBI severity in individuals with TBI ranging from mild to severe. A resting state functional magnetic resonance imaging protocol was used to study the default mode network in subjects at rest. FA values were decreased throughout all white matter tracts in the mild to severe TBI subjects. FA values were also negatively correlated with TBI injury severity ratings. The default mode network showed several brain regions in which connectivity measures were higher among individuals with TBI relative to control subjects. These findings suggest that, subsequent to TBI, the brain may undergo adaptation responses at the cellular level to compensate for functional impairment due to axonal injury.

This review summarizes the most recent studies on synaesthesia, particularly studies on grapheme-colour synaesthesia, time-space synaesthesia, and coloured-hearing synaesthesia. Based on behavioural as well as neuroimaging studies, there is emerging evidence that synaesthesia is not only caused by the cross activation of two sensory areas but that it may require additional binding processes, which are assumed to take place in the parietal lobe. However, divergent results exist with respect to the lateralization of this effect, i.e. whether it is the left or right parietal lobe most responsible. Studies also indicate that attention modulates the synaesthetic experience. Furthermore, it has been shown that synaesthetes demonstrate a higher level of connectivity, thus supporting the view of a genetic pre-disposition of synaesthesia.

One of the main problems in understanding synaesthesia is determining whether it is a sensory or semantic phenomenon-a problem also known as the distinction between ‘low-’ vs. ‘high-level’ synaesthesia. Recently, it has been reported that in grapheme-colour synaesthesia, the colour associated to a letter is chosen by similarity to other letters. Letters of similar shapes tend to elicit similar colours. The authors explained this result by low-level cross-wiring between grapheme and colour brain areas. In the present study we show that when new graphemes are learned, they also associate synaesthetic colours based on shape- and colour similarity. Importantly, these novel associations between graphemes and colors are created within minutes, which is too rapid to be accounted for by cross-wiring. In addition, the dimensions of similarity used to create these associations were more abstract than what would be expected from elementary features processed in the grapheme area. Therefore, we conclude that the result is better explained by high-level conceptual mechanisms that guide the choices and creation of synaesthetic concurrents.

Alterations in gyral form and complexity have been consistently noted in both autism and dyslexia. In this present study, we apply spherical harmonics, an established technique which we have exapted to estimate surface complexity of the brain, in order to identify abnormalities in gyrification between autistics, dyslexics, and controls. On the order of absolute surface complexity, autism exhibits the most extreme phenotype, controls occupy the intermediate ranges, and dyslexics exhibit lesser surface complexity. Here, we synthesize our findings which demarcate these three groups and review how factors controlling neocortical proliferation and neuronal migration may lead to these distinctive phenotypes.

Professional military training makes tough demands on soldiers’ perceptual and motor skills, as well as on their physical fitness and cognitive capabilities in the course of preparation for stressful operational environments. In this pilot study we attempted to identify difference in pattern of neural responses between extensively trained, professional mission-ready soldiers and novice soldiers during audiovisual simulation of mission conditions. We performed fMRI scanning on a few volunteers during presentation of semantically relevant video-clips of real combat from Afghanistan to evaluate influence of military training on mental responses of soldiers. We showed that for professional mission-ready soldiers a week before their deployment to Afghanistan, videoclips with deadly ambush combat induce greater overall brain activation compared to novice soldiers. Missionready soldiers showed greater activation in premotor/prefrontal cortex, posterior parietal cortex, and posterior temporal cortex. These results imply that fMRI technique could be used as challenging step forward in the multidimensional evaluation of military training influence on neural responses and operational capabilities of professional soldiers. This is extremely important not only for potential failure prevention and mere success of the mission, but even more for the survival and the well-being of the servicemen and servicewomen.

Negative and positive symptoms are defining features of schizophrenia. This illness is commonly associated with a number of cognitive and affective deficits as well as with some more specific sleep abnormalities. It has been previously proposed that psychosis and positive symptoms in schizophrenia could be understood as disorders of internal brain dynamics. This proposed disordered network interplay might be particularly displayed during sleep when modulation by the senses is at the minimum. It is argued here that sleep abnormalities in schizophrenia inform our understanding of the pathomechanisms involved in psychosis. More specifically, sleep spindle initiation in NREM sleep and the preparation of sensory pathways for upcoming motor actions during wakefulness may share a common mechanism, and this shared mechanism is suggested to be impaired in schizophrenia.

Lithium is one of the most widely used drugs in neuropsychopharmacology. Preclinical scientists have made several advances in ascertaining the molecular mechanisms of action of this cation; such as its ability to stabilize monoamine levels, to interact with second messengers, and its neuroprotective effects, possibly over suicidal behaviors. Nevertheless, there remains a gap of knowledge between the pharmacological advances and the number of reliable clinical trials, creating a lack of evidence-based medicine to support medical prescriptions. In this review we examine lithium’s molecular mechanisms of action and evaluate their relevance in clinical applications.

The cytoarchitectonic map of the adult human cerebral cortex prepared by Korbinian Brodmann is probably the most widely used and reproduced cortical map. However, few people today realize that in the period between 1908 and 1914 (the first and last date of maps publication by Brodmann himself) that map was gradually developed, extended and subjected to some significant modifications. The aim of this article is to reproduce and briefly describe all versions of Brodmann’s map, trace its changes and highlight the importance of these changes — especially with respect to the speech and language related cortical regions of the left cerebral hemisphere.