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26.  Cortical morphology in children with alcohol-related neurodevelopmental disorder 
Brain and Behavior  2013;4(1):41-50.
Introduction
It is well established that individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the candidate determinants of these reductions, cortical thickness (CT) and surface area (SA), have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND), the most prevalent fetal alcohol spectrum disorder subgroup that lacks the characteristic facial dysmorphology.
Methods
T1-weighted magnetic resonance imaging scans were obtained from 88 participants (8–16 years), 36 diagnosed with ARND and 52 typically developing controls. Scans were submitted to the CIVET pipeline (version 1.1.10). Deformable models were used to construct the inner white matter surfaces and pial surfaces from which CT and SA measures were derived. Group differences in cortical volume, CT, and SA were computed using a general linear model covaried for age, sex, and handedness.
Results
Global cortical volume reductions in ARND did not reflect CT, which did not differ between groups. Instead, volume decreases were consistent with global SA reductions in bilateral frontal and temporal as well as right occipital regions. Local reductions in SA were observed in the right superior temporal gyrus and the right occipital-temporal region.
Conclusion
Results suggest that in ARND, prenatal alcohol exposure perturbs global SA to a greater degree than CT, particularly in the right temporal lobe.
doi:10.1002/brb3.191
PMCID: PMC3937705  PMID: 24653953
ARND; cortical thickness; MRI; surface area
27.  GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice 
Brain and Behavior  2013;4(1):51-59.
The GPR30 is a novel estrogen receptor (ER) that is a candidate membrane ER based on its binding to 17β estradiol and its rapid signaling properties such as activation of the extracellular-regulated kinase (ERK) pathway. Its distribution in the mouse limbic system predicts a role for this receptor in the estrogenic modulation of anxiety behaviors in the mouse. A previous study showed that chronic administration of a selective agonist to the GPR30 receptor, G-1, in the female rat can improve spatial memory, suggesting that GPR30 plays a role in hippocampal-dependent cognition. In this study, we investigated the effect of a similar chronic administration of G-1 on behaviors that denote anxiety in adult ovariectomized female mice, using the elevated plus maze (EPM) and the open field test as well as the activation of the ERK pathway in the hippocampus. Although estradiol benzoate had no effect on behaviors in the EPM or the open field, G-1 had an anxiolytic effect solely in the open field that was independent of ERK signaling in either the ventral or dorsal hippocampus. Such an anxiolytic effect may underlie the ability of G-1 to increase spatial memory, by acting on the hippocampus.
doi:10.1002/brb3.197
PMCID: PMC3937706  PMID: 24653954
Elevated plus maze; ERK; G-1; open field; rapid estrogen signaling
28.  The ipsilateral motor cortex does not contribute to long-latency stretch reflex amplitude at the wrist 
Brain and Behavior  2013;4(1):60-69.
Background
A capacity for modulating the amplitude of the long-latency stretch reflex (LLSR) allows us to successfully interact with a physical world with a wide range of different mechanical properties. It has recently been demonstrated that stretch reflex modulation is impaired in both arms following monohemispheric stroke, suggesting that reflex regulation may involve structures on both sides of the motor system.
Methods
We examined the involvement of both primary motor cortices in healthy reflex regulation by eliciting stretch reflexes during periods of suppression of the motor cortices contra-and ipsilateral to the extensor carpi radialis in the nondominant arm.
Results
LLSRs were significantly attenuated during suppression of the contralateral, but not ipsilateral, motor cortex. Modulation of the LLSR was not affected by suppression of either primary motor cortex.
Conclusion
Our results confirm the involvement of the contralateral motor cortex in the transmission of the LLSR, but suggest that the ipsilateral motor cortex plays no role in reflex transmission and that neither motor cortex is involved in stability-dependent modulation of the LLSR. The implications of these results for reflex impairments following stroke are discussed.
doi:10.1002/brb3.189
PMCID: PMC3937707  PMID: 24653955
Flexor; posture; pyramidal tracts; stroke; upper extremity
29.  Superficial radial nerve–lateral antebrachial cutaneous nerve anatomic variation 
Brain and Behavior  2013;4(1):70-74.
Introduction
This study focuses on an anatomic variation in which the lateral antebrachial cutaneous nerve (LACN) innervates the radial border of the dorsum of the hand and thumb in addition to, or replacing, the superficial radial nerve (RSN). Here, we propose a technique of nerve conduction that identifies this variation.
Methods
We studied nerve conduction in 200 upper limbs of two series of 50 volunteers. We sought evidence of the aforementioned variation on the dorsum of the hand and in the thumb.
Results
We found eight occurrences of this variation on the dorsum of the hand and 11 variants on the thumb within the two respective series of 100 upper limbs studied.
Discussion
The RSN–LACN anatomic variation can be studied using nerve conduction. The knowledge of this variation is particularly important for the evaluation of proximal radial nerve injury.
doi:10.1002/brb3.195
PMCID: PMC3937708  PMID: 24653956
Anatomic variation; hand dorsum; lateral antebrachial cutaneous nerve; nerve conduction; superficial radial nerve
30.  Longitudinal study of alexithymia and multiple sclerosis 
Brain and Behavior  2013;4(1):75-82.
Objective
The aim of this study was to investigate the course of alexithymia and its relation with anxiety and depression in patients with multiple sclerosis (MS), over a period of 5 years.
Methods
Sixty-two MS patients were examined at two timepoints, 5 years apart, and they answered questionnaires collecting socio-demographic, medical, and psychological data (depression, anxiety, alexithymia).
Results
Our data show that emotional disorders remain stable over time in patients with MS, particularly as regards alexithymia and anxiety. Conversely, the rate of depression decreased between the two evaluations, falling from 40% to 26%. The two dimensions of alexithymia (i.e., difficulty describing and difficulty identifying feelings) were correlated with anxiety and depression, whereas the third component of alexithymia (externally oriented thinking) was independent, and was the only component to change over time, with a significant fall observed at 5 years.
Conclusion
Alexithymia was associated with increased severity of anxiety and attack relapses.
doi:10.1002/brb3.194
PMCID: PMC3937709  PMID: 24653957
Alexithymia; anxiety; depression; longitudinal study; multiple sclerosis
31.  Mucus trail tracking in a predatory snail: olfactory processing retooled to serve a novel sensory modality 
Brain and Behavior  2013;4(1):83-94.
Introduction
The rosy wolfsnail (Euglandina rosea), a predatory land snail, finds prey snails and potential mates by following their mucus trails. Euglandina have evolved unique, mobile lip extensions that detect mucus and aid in following trails. Currently, little is known of the neural substrates of the trail-following behavior.
Methods
To investigate the neural correlates of trail following we used tract-tracing experiments in which nerves were backfilled with either nickel-lysine or Lucifer yellow, extracellular recording of spiking neurons in snail procerebra using a multielectrode array, and behavioral assays of trail following and movement toward the source of a conditioned odor.
Results
The tract-tracing experiments demonstrate that in Euglandina, the nerves carrying mucus signals innervate the same region of the central ganglia as the olfactory nerves, while the electrophysiology studies show that mucus stimulation of the sensory epithelium on the lip extensions alters the frequency and pattern of neural activity in the procerebrum in a manner similar to odor stimulation of the olfactory epithelium on the optic tentacles of another land snail species, Cantareus aspersa (previously known as Helix aspersa). While Euglandina learn to follow trails of novel chemicals that they contact with their lip extensions in one to three trials, these snails proved remarkably resistant to associative learning in the olfactory modality. Even after seven to nine pairings of odorant molecules with food, they showed no orientation toward the conditioned odor. This is in marked contrast to Cantareus snails, which reliably oriented toward conditioned odors after two to three trials.
Conclusions
The apparent inability of Euglandina to learn to associate food with odors and use odor cues to drive behavior suggests that the capability for sophisticated neural processing of nonvolatile mucus cues detected by the lip extensions has evolved at the expense of processing of odorant molecules detected by the olfactory system.
doi:10.1002/brb3.198
PMCID: PMC3937710  PMID: 24653958
Euglandina; invertebrate model; multielectrode array; olfaction; sensory learning; trail following
32.  Modulation of the perforant path-evoked potential in dentate gyrus as a function of intrahippocampal β-adrenoceptor agonist concentration in urethane-anesthetized rat 
Brain and Behavior  2013;4(1):95-103.
Background
β-adrenoceptor activation in the hippocampus is sufficient to induce heterosynaptic long-term potentiation of perforant path input to the dentate gyrus. However, in vitro and in vivo studies suggest the plasticity effects of β-adrenoceptor activation may vary depending on the level of receptor activation.
Methods
The present experiments use an in vivo model concurrently infusing differing concentrations of the β-adrenoceptor agonist, isoproterenol (ISO; 0, 0.1, 1, 10, and 100 μmol/L in aCSF; 1 μL over 12.5 min) in the dentate gyrus, while monitoring changes in the perforant path-evoked potential at the same site.
Results
Long-term depression (LTD) of fEPSP slope was elicited by 0.1 μmol/L ISO. Higher doses did not alter fEPSP slope. Maximal long-term potentiation of the perforant path-evoked population spike (183% >3 h) occurred at 10 μmol/L ISO. Transient depression of spike amplitude occurred at 0.1 μmol/L ISO.
Conclusions
These data demonstrate concentration-dependent effects of β-adrenoceptor activation on the perforant path-evoked potential. Long-term depression and long-term potentiation of perforant path-evoked responses are variably elicited as a function of the degree of receptor activation.
doi:10.1002/brb3.199
PMCID: PMC3937711  PMID: 24653959
Long-term depression; LTP; NE-LTP; noradrenaline; norepinephrine
33.  Issue Information 
Brain and Behavior  2013;3(6):i-ii.
doi:10.1002/brb3.193
PMCID: PMC3868164  PMID: 24363978
34.  Creating one problem to try and fix another: the saga of ischemic preconditioning 
Brain and Behavior  2013;3(6):603-605.
doi:10.1002/brb3.170
PMCID: PMC3868165  PMID: 24363963
35.  The role of remote ischemic preconditioning in the treatment of atherosclerotic diseases 
Brain and Behavior  2013;3(6):606-616.
Background
Remote ischemic preconditioning (RIPC) is the application of a transient and brief ischemic stimulus to a distant site from the organ or tissue that is afterward exposed to injury ischemia, and has been found to reduce ischemia–reperfusion injury (IRI) in various animal models. RIPC appears to offer two distinct phases of endothelial IRI protection, which are presumably mediated through neuronal and humoral pathways.
Methods
We conducted a comprehensive literature review on the available published data about the potential effect of RIPC in patients undergoing IRI in one or more vital organs.
Results
Our search highlighted 24 randomized clinical trials about the effect of RIPC on variable clinical settings (abdominal aortic aneurysm repair, open heart surgery, percutaneous coronary intervention, living donor renal transplantation, coronary angiography, elective decompression surgery, carotid endarterectomy, recent stroke, or transient ischemic attack combined with intracranial carotid artery stenosis). Most of the trials focused on postoperative cardiac or renal function after RIPC with conflicting results. Preconditioning protocols, age limits, comorbidities, and concomitant drug use varied significantly across trials, and therefore no firm conclusions can be drawn using the available data. However, no severe local adverse events were observed in any patient undergoing limb or arm preconditioning.
Conclusions
RIPC is a safe and well-tolerated procedure that may constitute a potentially promising innovative treatment in atherosclerotic diseases. Large, multicenter, randomized clinical trials are required to determine an optimal protocol for the RIPC procedure, and to evaluate further the potential benefits of RIPC in human ischemic injury.
doi:10.1002/brb3.161
PMCID: PMC3868166  PMID: 24363964
Aortic aneurysm; atherosclerosis; coronary artery disease; ischemic stroke; peripheral arterial disease; remote ischemic preconditioning
36.  Environmental and behavioral modulation of the number of substantia nigra dopamine neurons in adult mice 
Brain and Behavior  2013;3(6):617-625.
Background
Recent evidence indicates that hypothalamic neurons acquire or lose the capacity to synthesize and release dopamine (DA) in response to environmental stimuli, and this has functional and behavioral consequences for adult rats. We have evidence that neuronal activity, including that driven by afferent input, regulates acquisition and loss of the DA phenotype by substantia nigra pars compacta (SNc) neurons in adult mice.
Hypotheses The aims of the present study were to determine whether the environment or behavior regulates the number of SNc DA neurons in adult mice, and whether this is mediated by afferent input.
Methods
Adult mice were subject to two different environments/behaviors: “mating” for 1 week or “environment enrichment” (EE) for 2 weeks; then the numbers of tyrosine hydroxylase (TH, the rate limiting enzyme in DA synthesis) immunopositive (TH+) and immunonegative (TH−) SNc neurons were counted.
Results
More TH+ neurons were present in mated males whereas less TH+ neurons were present in mated females. Also, more TH+ neurons were present in EE males, and this increase was completely abolished by concurrent local infusion of GABAA receptor antagonists.
Conclusions
The number of DA neurons in the adult SNc is not fixed, but readily increases and decreases in response to environmental stimuli and/or behaviors. These changes are mediated by afferent input relaying information about the environment or behavior to SNc neurons.
doi:10.1002/brb3.163
PMCID: PMC3868167  PMID: 24363965
Dopamine; midbrain; plasticity
37.  The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease 
Brain and Behavior  2013;3(6):626-636.
Background
It is well established that aging and vascular processes interact to disrupt cerebral hemodynamics in older adults. However, the independent effects of cerebral perfusion on neurocognitive function among older adults remain poorly understood. We examined the associations among cerebral perfusion, cognitive function, and brain structure in older adults with varying degrees of vascular disease using perfusion magnetic resonance imaging (MRI) arterial spin labeling (ASL).
Materials and methods
52 older adults underwent neuroimaging and were administered the Mini Mental State Examination (MMSE), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and measures of attention/executive function. ASL and T1-weighted MRI were used to quantify total brain perfusion, total brain volume (TBV), and cortical thickness.
Results
Regression analyses showed reduced total brain perfusion was associated with poorer performance on the MMSE, RBANS total index, immediate and delayed memory composites, and Trail Making Test B. Reduced frontal lobe perfusion was associated with worse executive and memory function. A similar pattern emerged between temporal lobe perfusion and immediate memory. Regression analyses revealed that decreased total brain perfusion was associated with smaller TBV and mean cortical thickness. Regional effects of reduced total cerebral perfusion were found on temporal and parietal lobe volumes and frontal and temporal cortical thickness.
Discussion
Reduced cerebral perfusion is independently associated with poorer cognition, smaller TBV, and reduced cortical thickness in older adults.
Conclusion
Prospective studies are needed to clarify patterns of cognitive decline and brain atrophy associated with cerebral hypoperfusion.
doi:10.1002/brb3.171
PMCID: PMC3868168  PMID: 24363966
Arterial spin labeling; cardiovascular disease; cerebral blood flow; cerebrovascular disease; cognitive function; magnetic resonance imaging; neuroimaging
38.  A reversal coarse-grained analysis with application to an altered functional circuit in depression 
Brain and Behavior  2013;3(6):637-648.
Introduction
When studying brain function using functional magnetic resonance imaging (fMRI) data containing tens of thousands of voxels, a coarse-grained approach – dividing the whole brain into regions of interest – is applied frequently to investigate the organization of the functional network on a relatively coarse scale. However, a coarse-grained scheme may average out the fine details over small spatial scales, thus rendering it difficult to identify the exact locations of functional abnormalities.
Methods
A novel and general approach to reverse the coarse-grained approach by locating the exact sources of the functional abnormalities is proposed.
Results
Thirty-nine patients with major depressive disorder (MDD) and 37 matched healthy controls are studied. A circuit comprising the left superior frontal gyrus (SFGdor), right insula (INS), and right putamen (PUT) exhibit the greatest changes between the patients with MDD and controls. A reversal coarse-grained analysis is applied to this circuit to determine the exact location of functional abnormalities.
Conclusions
The voxel-wise time series extracted from the reversal coarse-grained analysis (source) had several advantages over the original coarse-grained approach: (1) presence of a larger and detectable amplitude of fluctuations, which indicates that neuronal activities in the source are more synchronized; (2) identification of more significant differences between patients and controls in terms of the functional connectivity associated with the sources; and (3) marked improvement in performing discrimination tasks. A software package for pattern classification between controls and patients is available in Supporting Information.
doi:10.1002/brb3.173
PMCID: PMC3868169  PMID: 24363967
Reversal coarse-grained analysis; source location; voxel-wise time series
39.  Endothelial progenitor cells in acute ischemic stroke 
Brain and Behavior  2013;3(6):649-655.
Objectives
The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points.
Material and methods
We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0–2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry.
Results
We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio [OR] 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large-artery atherosclerosis and small-vessel disease etiologic subtypes.
Conclusions
After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large-artery atherosclerosis and small-vessel disease subtypes, higher counts were related to better outcome at 3 months.
doi:10.1002/brb3.175
PMCID: PMC3868170  PMID: 24363968
Endothelial progenitor cells; ischemic stroke; statin
40.  Comparison of diabetes patients with “demyelinating” diabetic sensorimotor polyneuropathy to those diagnosed with CIDP 
Brain and Behavior  2013;3(6):656-663.
Background
We have previously identified a subset of diabetic sensorimotor polyneuropathy (DSP) patients with probable demyelination related to poor glycemic control. We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury in diabetes patients with “demyelinating” DSP (D-DSP) differed from those diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) (CIDP + diabetes mellitus [DM]).
Methods
D-DSP (56) and CIDP + DM (67) subjects underwent clinical examination and nerve conduction studies (NCS), and were compared using analysis of variance, contingency tables, and Kruskal–Wallis analyses.
Results
Of the 123 subjects with a mean age of 60.5 ± 15.6 years and mean hemoglobin A1c (HbA1c) of 8.2 ± 2.2%, 54% had CIDP + DM and 46% had D-DSP. CIDP + DM subjects were older (P = 0.0003), had shorter duration of diabetes (P = 0.005), and more severe neuropathy as indicated by Toronto Clinical Neuropathy Score (TCNS) (P = 0.003), deep tendon reflexes (P = 0.02), and vibration perception thresholds (VPT) (P = 0.01, P = 0.02). The mean HbA1c value for D-DSP subjects (8.9 ± 2.3%) was higher than in CIDP + DM subjects (7.7 ± 2.0%, P = 0.02).
Conclusions
The clinical phenotype and electrophysiological profile of CIDP + DM patients is marked by more severe neuropathy and better glycemic control than in patients with D-DSP. These findings indicate that these two conditions – despite similarities in their electrophysiological pattern of demyelination – likely differ in etiology.
doi:10.1002/brb3.177
PMCID: PMC3868171  PMID: 24363969
CIDP; diabetic neuropathy; type 1 diabetes; type 2 diabetes
41.  Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis 
Brain and Behavior  2013;3(6):664-682.
Background
Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.
Aims
We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.
Materials and methods
Active EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.
Results
Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.
Discussion
Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.
Conclusions
Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.
doi:10.1002/brb3.174
PMCID: PMC3868172  PMID: 24363970
Axon conduction; demyelination; experimental autoimmune encephalomyelitis; laquinimod; multiple sclerosis; myelination; neuroprotective drug; oligodendrocytes; peripheral cytokines; rotorod motor performance; therapeutic treatment
42.  Prediction processes during multiple object tracking (MOT): involvement of dorsal and ventral premotor cortices 
Brain and Behavior  2013;3(6):683-700.
Background
The multiple object tracking (MOT) paradigm is a cognitive task that requires parallel tracking of several identical, moving objects following nongoal-directed, arbitrary motion trajectories.
Aims
The current study aimed to investigate the employment of prediction processes during MOT. As an indicator for the involvement of prediction processes, we targeted the human premotor cortex (PM). The PM has been repeatedly implicated to serve the internal modeling of future actions and action effects, as well as purely perceptual events, by means of predictive feedforward functions.
Materials and methods
Using functional magnetic resonance imaging (fMRI), BOLD activations recorded during MOT were contrasted with those recorded during the execution of a cognitive control task that used an identical stimulus display and demanded similar attentional load. A particular effort was made to identify and exclude previously found activation in the PM-adjacent frontal eye fields (FEF).
Results
We replicated prior results, revealing occipitotemporal, parietal, and frontal areas to be engaged in MOT.
Discussion
The activation in frontal areas is interpreted to originate from dorsal and ventral premotor cortices. The results are discussed in light of our assumption that MOT engages prediction processes.
Conclusion
We propose that our results provide first clues that MOT does not only involve visuospatial perception and attention processes, but prediction processes as well.
doi:10.1002/brb3.180
PMCID: PMC3868173  PMID: 24363971
Action prediction; dorsal premotor cortex; fMRI; multiple object tracking; perceptual event prediction; predictive forward models; ventral premotor cortex
43.  Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies 
Brain and Behavior  2013;3(6):701-709.
Background
Diabetic neuropathy and idiopathic neuropathy are among the most prevalent neuropathies in human patients. The molecular mechanism underlying pathological changes observed in the affected nerve remains unclear but one candidate molecule, the receptor for advanced glycation end-products (RAGE), has recently gained attention as a potential contributor to neuropathy. Our previous studies revealed that RAGE expression is higher in porcine and murine diabetic nerve, contributing to the inflammatory mechanisms leading to diabetic neuropathy. Here, for the first time, we focused on the expression of RAGE in human peripheral nerve.
Methods
Our study utilized de-identified human sural nerve surplus obtained from 5 non-neuropathic patients (control group), 6 patients with long-term mild-to-moderate diabetic neuropathy (diabetic group) and 5 patients with mild-to-moderate peripheral neuropathy of unknown etiology (idiopathic group). By using immunofluorescent staining and protein immunoblotting we studied the expression and colocalization patterns of RAGE and its ligands: carboxymethyllysine (CML), high mobility group box 1 (HMBG1) and mammalian Diaphanous 1 (mDia1) in control and neuropathic nerves.
Results
We found that in a normal, healthy human nerve, RAGE is expressed in almost 30% of all nerve fibers and that number is higher in pathological states such as peripheral neuropathy. We established that the levels of RAGE and its pro-inflammatory ligands, CML and HMBG1, are higher in both idiopathic and diabetic nerve, while the expression of the RAGE cytoplasmic domain-binding partner, mDia1 is similar among control, diabetic, and idiopathic nerve. The highest number of double stained nerve fibers was noted for RAGE and CML: ∼76% (control), ∼91% (idiopathic) and ∼82% (diabetic) respectively.
Conclusions
Our data suggest roles for RAGE and its inflammatory ligands in human peripheral neuropathies and lay the foundation for further, more detailed and clinically oriented investigation involving these proteins and their roles in disorders of the human peripheral nerve.
doi:10.1002/brb3.176
PMCID: PMC3868174  PMID: 24363972
Diabetes; human; peripheral neuropathy; RAGE; RAGE ligands
44.  Blood pressure fluctuation and hypertension in patients with Parkinson's disease 
Brain and Behavior  2013;3(6):710-714.
Objectives
Blood pressure (BP) abnormalities have been known in Parkinson's disease (PD) patients. The present study aimed at determining how the BPs of PD patients fluctuate in a day.
Methods
A total of 37 PD patients and 44 OD (other disease) patients, all of who were inpatients, were monitored every 30 min by 24-h ambulatory blood pressure monitoring (ABPM).
Results
The average systolic BP and the number of patients who showed postprandial hypotension were not different between the two groups. However, occurrence of nocturnal hypertension, BP fluctuation of over 100 mmHg in a day and BP of over 200 mmHg were significantly more frequently observed in the PD patients than in the OD patients. In the PD patients, these parameters were not different between those who were suffering from the disease for less than 10 years and those with the disease for 10 years or longer, as well as between those who had a Hoehn–Yahr staging scale of 2–3 and those with a scale of 4–5.
Conclusion
Twenty-four-hour ABPM, not BP measurement once a day, enables us to determine the actual BP in PD patients. Although hypotension is a severe risk factor for falling and syncope, we emphasize the importance of monitoring rather hypertension and fluctuating BP in PD patients that may lead to a variety of other undesirable conditions. Management of hypotension, hypertension, and BP fluctuation is an important issue in the future.
doi:10.1002/brb3.179
PMCID: PMC3868175  PMID: 24363973
24-h ABPM; autonomic dysfunction; fluctuating blood pressure; hypertension; Parkinson's disease
45.  Thalamo-striato-cortical determinants to fatigue in multiple sclerosis 
Brain and Behavior  2013;3(6):715-728.
Background
The aim was to explore the thalamo-striato-cortical theory of central fatigue in multiple sclerosis (MS) patients with self-reported fatigue. If the theory correctly predicted fatigue based on disruptions of the thalamo-striato-cortical network, we expected altered brain activation in this network in MS participants while performing a complex cognitive task that challenged fatigue.
Methods
MS participants with self-reported fatigue were examined by functional magnetic resonance imaging (fMRI) during the performance of a complex working memory task. In this task, cognitive effort was challenged by a parametric design, which modeled the cerebral responses at increasing cognitive demands. In order to explore the theory of central fatigue in MS we also analyzed the cerebral responses by adding perceived fatigue scores as covariates in the analysis and by calculating the functional connectivity between regions in the thalamo-striatocortical network. The main findings were that MS participants elicited altered brain responses in the thalamo-striato-cortical network, and that brain activation in the left posterior parietal cortex and the right substantia nigra was positively correlated to perceived fatigue ratings. MS participants had stronger cortical-to-cortical and subcortical-to-subcortical connections, whereas they had weaker cortical-to-subcortical connections.
Conclusions
The findings of the present study indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS, and provide support for the theory of central fatigue. However, due to the limited number of participants and the somewhat heterogeneous sample of MS participants, these results have to be regarded as tentative, though they might serve as a basis for future studies.
doi:10.1002/brb3.181
PMCID: PMC3868176  PMID: 24363974
Basal ganglia; functional magnetic resonance imaging; parietal cortex; substantia nigra; working memory
46.  Infants' object location and identity processing in spatial scenes: an ERP study 
Brain and Behavior  2013;3(6):729-737.
Background
Fast detection and identification of objects in an environment is important for using objects as landmarks during navigation. While adults rapidly process objects within an environment and use landmarks during navigation, infants do not routinely use distal landmarks below the age of 18 months. In the current event-related potential (ERP) study we adopted an oddball paradigm to examine whether infants are capable of processing objects in environments, which is a prerequisite for using objects as landmarks.
Methods
We measured the electrophysiological correlates and time courses related to the processing of changes in object location, object identity, and a switch of two objects.
Results
Twelve-month-old infants showed an Nc (negative central) effect reflecting increased attention likely caused by initial change detection within 300 msec for all three manipulations. In addition, they showed conscious processing of an object change and a location change as evidenced by a positive slow wave (PSW).
Conclusion
This study is the first to show that infants are capable of rapidly detecting changes in single objects when these are presented in an environment, but lack conscious detection of a switch. These results indicate that 12-month-old infants as yet lack the ability to rapidly bind the identity and location of multiple objects within an environment.
doi:10.1002/brb3.184
PMCID: PMC3868177  PMID: 24363975
ERP; infants; object processing; spatial cognition
47.  A factor analysis of posttraumatic stress disorder symptoms using data pooled from two venlafaxine extended-release clinical trials 
Brain and Behavior  2013;3(6):738-746.
Background
Confirmatory factor analysis (CFA) of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) three-factor posttraumatic stress disorder (PTSD) diagnostic criteria was conducted to determine fit for this patient population. An exploratory factor analysis (EFA) of alternate symptom structures was planned to identify symptoms that cluster in this population. The response of symptom factors to treatment with venlafaxine extended release (ER) was explored.
Methods
Baseline 17-item Clinician-Administered PTSD Scale (CAPS-SX17) data were pooled from patients enrolled in two double-blind, randomized, placebo-controlled trials. The CFA was conducted using maximum likelihood and weighted, least-squares factor extraction methods. The EFA was performed using a polychoric correlation covariance matrix and Pearson correlation matrix.
Results
Data from a pooled population of 685 patients (venlafaxine ER: n = 339; placebo: n = 346) were analyzed. CFA rejected the DSM-IV three-factor structure. The EFA identified a different three-factor structure as the best fit: factor 1 included reexperiencing symptoms, factor 2 included symptoms of altered mood and cognition, whereas factor 3 comprised avoidance and arousal symptoms. All DSM-IV symptom factors and all factors in the identified three-factor model responded positively to venlafaxine ER treatment.
Conclusions
Data are consistent with literature failing to confirm the three-factor structure of DSM-IV PTSD, and they support the DSM-5 inclusion of a symptom cluster addressing altered mood and cognition in PTSD. The efficacy of venlafaxine ER in reducing a range of symptom clusters in PTSD is consistent with its multiple mechanisms of action.
doi:10.1002/brb3.183
PMCID: PMC3868178  PMID: 24363976
CAPS-SX17; DSM; factor analysis; posttraumatic stress disorder; venlafaxine
48.  Reappraisal of field dynamics of motor cortex during self-paced finger movements 
Brain and Behavior  2013;3(6):747-762.
Background
The exact origin of neuronal responses in the human sensorimotor cortex subserving the generation of voluntary movements remains unclear, despite the presence of characteristic but robust waveforms in the records of electroencephalography or magnetoencephalography (MEG).
Aims
To clarify this fundamental and important problem, we analyzed MEG in more detail using a multidipole model during pulsatile extension of the index finger, and made some important new findings.
Results
Movement-related cerebral fields (MRCFs) were confirmed over the sensorimotor region contralateral to the movement, consisting of a temporal succession of the first premovement component termed motor field, followed by two or three postmovement components termed movement evoked fields. A source analysis was applied to separately model each of these field components. Equivalent current diploes of all components of MRCFs were estimated to be located in the same precentral motor region, and did not differ with respect to their locations and orientations. The somatosensory evoked fields following median nerve stimulation were used to validate these findings through comparisons of the location and orientation of composite sources with those specified in MRCFs. The sources for the earliest components were evoked in Brodmann's area 3b located lateral to the sources of MRCFs, and those for subsequent components in area 5 and the secondary somatosensory area were located posterior to and inferior to the sources of MRCFs, respectively. Another component peaking at a comparable latency with the area 3b source was identified in the precentral motor region where all sources of MRCFs were located.
Conclusion
These results suggest that the MRCF waveform reflects a series of responses originating in the precentral motor area.
doi:10.1002/brb3.186
PMCID: PMC3868179  PMID: 24363977
Diploe sources; magnetoencephalography; motor cortex; movement-related cerebral fields; somatosensory evoked fields
49.  Issue Information 
Brain and Behavior  2013;3(5):i-ii.
doi:10.1002/brb3.178
PMCID: PMC3869976  PMID: 24392280
50.  The role of rs2237781 within GRM8 in eating behavior 
Brain and Behavior  2013;3(5):495-502.
Introduction:The glutamate receptor, metabotropic 8 gene (GRM8) encodes a G-protein-coupled glutamate receptor and has been associated with smoking behavior and liability to alcoholism implying a role in addiction vulnerability. Data from animal studies suggest that GRM8 may be involved in the regulation of the neuropeptide Y and melanocortin pathways and might influence food intake and metabolism. This study aimed to investigate the effects of the genetic variant rs2237781 within GRM8 on human eating behavior. Methods:The initial analysis included 548 Sorbs from Germany who have been extensively phenotyped for metabolic traits and who completed the German version of the three-factor eating questionnaire. In addition, we analyzed two independent sample sets comprising 293 subjects from another German cohort and 430 Old Order Amish individuals. Genetic associations with restraint, disinhibition, and hunger were assessed in an additive linear regression model. Results:Among the Sorbs the major G allele of rs2237781 was significantly associated with increased restraint scores in eating behavior (P = 1.9 × 10−4; β = +1.936). The German cohort and the Old Order Amish population revealed a trend in the same direction for restraint (P = 0.242; β = +0.874; P = 0.908; β = +0.096; respectively). A meta-analysis resulted in a combined P = 3.1 × 10−3 (Z-score 2.948). Conclusion:Our data suggest that rs2237781 within GRM8 may influence human eating behavior factors probably via pathways involved in addictive behavior.
doi:10.1002/brb3.151
PMCID: PMC3869977  PMID: 24392270
Addiction; alcohol intake; food intake; human eating behavior; smoking behavior

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