A Systematic Review and Meta-Analysis of Cognitive Training in Adults with Major Depressive Disorder.

Major Depressive Disorder (MDD) is common and disabling, and is linked to functional impairment and increased mortality. While current treatments for MDD are moderately effective, ultimately, up to one third of patients do not achieve full remission. Interestingly, while affective symptoms of major depression typically resolve with the depressive episode, cognitive impairment frequently persists, and has been identified as one of the most prominent predictors of illness recurrence. Additionally, MDD is well-recognised as a key risk factor for further cognitive decline and dementia. Yet, available treatments for MDD do not typically address cognitive impairment. Cognitive training, represents a promising and novel therapeutic intervention in this regard. This review systematically identified and evaluated the evidence for cognitive training in adults with MDD. Following PRISMA guidelines, eligible studies were selected according to pre-defined criteria delineating our target population (adults with clinically defined MDD), parameters for cognitive training interventions (computer-or strategy-based, clinician-facilitated), and study design (controlled trials including pre-post cognitive and psychological or functional outcome data). Of 448 studies identified, nine studies met inclusion criteria. These studies were evaluated for methodological quality and risk of bias. Despite heterogeneity, qualitative and meta-analytic synthesis of study findings revealed significant improvements in cognitive and affective outcomes following cognitive training, with moderate pooled effect sizes. Unfortunately, very few studies investigated 'far transfer' to broader domains of everyday functioning. Overall, given the strong evidence for the efficacy and value of cognitive training in this context, cognitive training should be considered as a primary therapeutic intervention in the treatment of MDD.

Overexpression of human HSP27 protects sensory neurons from diabetes.

OBJECTIVES: To evaluate whether augmenting neuronal protective mechanisms might slow or arrest experimental diabetic peripheral neuropathy (DPN). DPN is one of the most common neurodegenerative disorders and is rising in prevalence. How it targets sensory neurons is uncertain; the disorder is irreversible and untreatable. We explored the intrinsic protective properties of overexpressed human HSP27 on experimental DPN. HSP27 is a small pro-survival heat shock protein that also increases axonal regeneration. METHODS: Experimental diabetes was superimposed on mice overexpressing a human HSP27 transgene and its impact was evaluated on epidermal innervation, behavioral tests of sensation and electrophysiological indices of DPN. RESULTS: Mice that overexpress human HSP27 in their sensory and motor neurons and that were made diabetic for 6 months by streptozotocin treatment were protected from a range of neuropathic abnormalities, including loss of footpad thermal sensation, mechanical allodynia, loss of epidermal innervation, and slowing of sensory conduction velocity. The protection was selective for sensory neurons in comparison to motor neurons and at 6 months provided better protection in female than male mice. Markers of RAGE-NFκB activation were attenuated by the transgene. CONCLUSIONS: The findings support the idea that diabetic polyneuropathy involves a unique, sensory-centric neurodegenerative process which can be reduced by overexpressing a single gene, an important starting point for new disease-modifying therapeutic approaches.

Neuronal plasticity: increasing the gain in pain.

We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.

Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.

Regeneration is abortive following adult mammalian CNS injury. We have investigated whether increasing the intrinsic growth state of primary sensory neurons by a conditioning peripheral nerve lesion increases regrowth of their central axons. After dorsal column lesions, all fibers stop at the injury site. Animals with a peripheral axotomy concomitant with the central lesion show axonal growth into the lesion but not into the spinal cord above the lesion. A preconditioning lesion 1 or 2 weeks prior to the dorsal column injury results in growth into the spinal cord above the lesion. In vitro, the growth capacity of DRG neurite is also increased following preconditioning lesions. The intrinsic growth state of injured neurons is, therefore, a key determinant for central regeneration.

The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord.

Cutaneous sensory neurons that detect noxious stimuli project to the dorsal horn of the spinal cord, while those innervating muscle stretch receptors project to the ventral horn. DRG11, a paired homeodomain transcription factor, is expressed in both the developing dorsal horn and in sensory neurons, but not in the ventral spinal cord. Mouse embryos deficient in DRG11 display abnormalities in the spatio-temporal patterning of cutaneous sensory afferent fiber projections to the dorsal, but not the ventral spinal cord, as well as defects in dorsal horn morphogenesis. These early developmental abnormalities lead, in adults, to significantly attenuated sensitivity to noxious stimuli. In contrast, locomotion and sensori-motor functions appear normal. Drg11 is thus required for the formation of spatio-temporally appropriate projections from nociceptive sensory neurons to their central targets in the dorsal horn of the spinal cord.

Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.

We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.

Alterations in the mechanical properties of the lung during dyspnea in chronic obstructive pulmonary disease.

The mechanical properties of the lungs in seven patients with chronic obstructive pulmonary disease (COPD) were measured before and during dyspnea on exertion, as well as when relief with added oxygen was obtained. Mean pulmonary dynamic compliance was 0.091 liters/cm of H(2)O before dyspnea, 0.057 during dyspnea, and 0.101 liters/cm H(2)O during relief. During dyspnea there was an increase in the total respiratory work (both elastic and nonelastic work) and this fell during relief with oxygen. Nonelastic resistance and respiratory rate were not significantly different during the three periods. In five similar patients a progressive increase in the instantaneous rate of change of transpulmonary pressure (dP/dt) was observed during exercise and this was markedly increased during dyspnea. These changes in dP/dt during exercise could explain the observed fall of pulmonary dynamic compliance.

Common patterns of plasticity contributing to nociceptive sensitization in mammals and Aplysia.

In contrast to innocuous stimuli, which only have transient effects when applied to the body surface, noxious stimuli generate persistent changes in the nervous system. This nociceptive memory manifests itself most prominently as a post-injury sensitization where, after tissue damage, the avoidance reaction and pain that result from subsequent stimuli are exaggerated and prolonged and can be initiated by low intensity stimuli. Similarities between nociceptive sensitization in mammals (including humans) and the mollusc Aplysia californica suggest that fundamental mechanisms contributing to injury-induced behavioral modifications might be widespread in the animal kingdom.

The pathophysiology of chronic pain--increased sensitivity to low threshold A beta-fibre inputs.

Chronic pain is characterized by abnormal sensitivity, which is due to the generation of pain in response to the activation of the low-threshold mechanoreceptive A beta fibres that normally generate innocuous sensations. Three different processes in the spinal cord can account for this dramatic alteration in sensory processing in the somatosensory system: increased excitability, decreased inhibition and structural reorganization. All have been shown to occur and each may contribute separately or together to the wide range of chronic inflammatory and neuropathic pain disorders. The unravelling of the cellular mechanisms involved both offers the potential for developing novel therapeutic strategies, which reduce functional synaptic plasticity and prevent central atrophic and regenerative responses in injured neurones, and illustrates the capacity of the adult nervous system for maladaptive modification.

Reciprocal Schwann cell-axon interactions.

This article describes the reciprocal interactions between neurones and Schwann cells with particular reference to the role of growth factors and neurokines as signalling molecules between these cells and of the extracellular matrix as a conduit for such signalling. Major recent advances have identified molecules produced by neurones that are responsible for Schwann cell proliferation, as well as some of the Schwann cell factors regulating the expression of molecules shown to play an important role in neuronal survival and differentiation.

Direct activation of rat spinal dorsal horn neurons by prostaglandin E2.

Whole-cell patch-clamp and intracellular recording techniques have been used to study the action of prostaglandin E2 (PGE2) on neurons in adult rat transverse spinal cord slices. Bath-applied PGE2 (1-20 microm) induced an inward current or membrane depolarization in the majority of deep dorsal horn neurons (laminas III-VI; 83 of 139 cells), but only in a minority of lamina II neurons (6 of 53 cells). PGE2 alone never elicited spontaneous action potentials; however, it did convert subthreshold EPSPs to suprathreshold, leading to action potential generation. PGE2-induced inward currents were unaffected by perfusion with either a Ca(2+)-free/high Mg(2+) (5 mm) solution or tetrodotoxin (1 microm), indicating a direct postsynaptic action. Both 17-phenyl trinor prostaglandin E2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect on membrane current, whereas butaprost methyl ester (an EP2 agonist) mimicked the effect of PGE2. Depolarizing responses to PGE2 were associated with a decrease in input resistance, and the amplitude of inward current was decreased as the holding potential was depolarized. PGE2-induced inward currents were reduced by substitution of extracellular Na(+) with N-methyl-d-glucamine and inhibited by flufenamic acid (50-200 microm), which is compatible with activation of a nonselective cation channel. These results suggest that PGE2, acting via an EP2-like receptor, directly depolarizes spinal neurons. Moreover, these findings imply an involvement of spinal cord-generated prostanoids in modulating sensory processing through an alteration in dorsal horn neuronal excitability.

Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons.

The development of neuronal excitability involves the coordinated expression of different voltage-gated ion channels. We have characterized the expression of two sensory neuron-specific tetrodotoxin-resistant sodium channel alpha subunits, Na(v)1. (SNS/PN3) and Na(v)1.9 (SNS2/NaN), in developing rat lumbar dorsal root ganglia (DRGs). Expression of both Na(v)1.8 and Na(v)1.9 increases with age, beginning at embryonic day (E) 15 and E17, respectively, and reaching adult levels by postnatal day 7. Their distribution is restricted mainly to those subpopulations of primary sensory neurons in developing and adult DRGs that give rise to unmyelinated C-fibers (neurofilament 200 negative). Na(v)1.8 is expressed in a higher proportion of neuronal profiles than Na(v)1.9 at all stages during development, as in the adult. At E17, almost all Na(v)1.8-expressing neurons also express the high-affinity NGF receptor TrkA, and only a small proportion bind to IB4, a marker for c-ret-expressing (glial-derived neurotrophic factor-responsive) neurons. Because IB4 binding neurons differentiate from TrkA neurons in the postnatal period, the proportion of Na(v)1.8 cells that bind to IB4 increases, in parallel with a decrease in the proportion of Na(v)1.8-TrkA co-expressing cells. In contrast, an equal number of Na(v)1.9 cells bind IB4 and TrkA in embryonic life. The differential expression of Na(v)1.8 and Na(v)1.9 in late embryonic development, with their distinctive kinetic properties, may contribute to the development of spontaneous and stimulus-evoked excitability in small diameter primary sensory neurons in the perinatal period and the activity-dependent changes in differentiation they produce.

Transport and localization of the DEG/ENaC ion channel BNaC1alpha to peripheral mechanosensory terminals of dorsal root ganglia neurons.

Mammalian brain sodium channel (BNaC, also known as BNC/ASIC) proteins form acid-sensitive and amiloride-blockable sodium channels that are related to putative mechanosensory channels. Certain BNaC isoforms are expressed exclusively in dorsal root ganglia (DRG) and have been proposed to form the ion channels mediating tissue acidosis-induced pain. With antibody labeling, we find that the BNaC1alpha isoform is expressed by most large DRG neurons (low-threshold mechanosensors not involved in acid-induced nociception) and few small nociceptor neurons (which include high-threshold mechanoreceptors). BNaC1alpha is transported from DRG cell bodies to sensory terminals in the periphery, but not to the spinal cord, and is located specifically at specialized cutaneous mechanosensory terminals, including Meissner, Merkel, penicillate, reticular, lanceolate, and hair follicle palisades as well as some intraepidermal and free myelinated nerve endings. Accordingly, BNaC1alpha channels might participate in the transduction of touch and painful mechanical stimuli.

A role for HSP27 in sensory neuron survival.

Peripheral nerve injury in neonatal rats results in the death of the majority of the axotomized sensory neurons by 7 d after injury. In adult animals, however, all sensory neurons survive for at least 4 months after axotomy. How sensory neurons acquire the capacity to survive axonal injury is not known. Here we describe how the expression of the small heat shock protein 27 (HSP27) is correlated with neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. The number of HSP27-immunoreactive neurons in the L4 DRG is low at birth and does not change significantly for 21 d after postnatal day 0 (P0) sciatic nerve axotomy. In contrast, in the adult all axotomized neurons begin to express HSP27. One week after P0 sciatic nerve section the total number of neurons in the L4 DRG is dramatically reduced, but all surviving axotomized neurons, as identified by c-jun immunoreactivity, are immunoreactive for HSP27. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling reveals that very few HSP27-expressing neurons are dying 48 hr after neonatal axotomy. In vitro, a similar correlation exists between HSP27 expression and survival; in P0 DRG cultures, neurons that express HSP27 preferentially survive NGF withdrawal. Finally, overexpression of human HSP27 in neonatal rat sensory and sympathetic neurons significantly increases survival after NGF withdrawal, with nearly twice as many neurons surviving at 48 hr. Together these results suggest that HSP27 in sensory neurons plays a role in promoting survival after axotomy or neurotrophin withdrawal.

Early psychological reactions in parents of children with a life threatening illness within a pediatric hospital setting.

RESEARCH IN CONTEXT: Parents of children with life threatening illness or injuries are at elevated risk of distress reactions, involving symptoms of acute stress disorder, depression and anxiety. Currently, the impact of child illness factors is unclear, and to date research systematically examining the prevalence of these psychological reactions across different illness groups with an acute life threat is sparse. This is important to explore given that studies show that parent functioning impacts on the psychological adjustment and recovery of the ill child. WHAT DOES THIS STUDY ADD?: At four weeks following a child's diagnosis of a serious illness, 49-54% of parents met DSM-IV criteria for acute stress disorder, across a number of illness groups, whereas 15-27% of parents were in the moderate/severe range for depression and anxiety, and 25-31% for stress. Results from this study demonstrate that rates and severity of these psychological reactions in parents of seriously ill children do not vary according to illness type. BACKGROUND: A life threatening childhood illness/injury can lead to significant distress reactions in parents, with independent studies finding such reactions in several different illness groups. To date, there is limited research systematically comparing the prevalence of adverse parental psychological reactions across different childhood illness groups with an acute life threat. This study aimed to investigate the frequency and severity of symptoms of acute traumatic stress, depression, anxiety and general stress in parents, following admission of their child to hospital for a life threatening illness. The study also aimed to explore the relationship between these symptoms, and to determine whether they differ according to illness/injury. METHODS: Cross-sectional data from a prospective, longitudinal study are reported. Participants were 194 parents of 145 children (49 couples), admitted to cardiology (n=53), oncology (n=40) and pediatric intensive care units (n=52), for serious illnesses/injuries. Parents completed self-report questionnaires within four weeks of hospital admission. RESULTS: Rates of acute traumatic stress (P=0.262), depression (P=0.525), anxiety (P=0.453) and general stress symptoms (P=0.720) in parents were comparable across illness type, with 49-54% reaching criteria for acute stress disorder, 15-27% having clinical levels of depression and anxiety, and 25-31% for general stress. Anxiety was most strongly associated with acute traumatic stress (r=0.56), closely followed by stress (r=0.52) and depression (r=0.49), with all correlations highly significant (P<0.001). CONCLUSIONS: These findings provide evidence that the child's medical condition is not associated with parents' experience of clinically significant psychological symptoms, and emphasize the importance for health care providers to be aware of these potential psychological reactions in parents, regardless of the type of illness.

Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2.

Remarkable progress has been made recently in identifying a new gene family related to the capsaicin (vanilloid) receptor, VR1. Using a combination of in silico analysis of expressed sequence tag (EST) databases and conventional molecular cloning, we have isolated a novel vanilloid-like receptor, which we call VRL-2, from human kidney. The translated gene shares 46% and 43% identity with VR1 and VRL-1, respectively, and maps to chromosome 12q23-24.1, a locus associated with bipolar affective disorder. VRL-2 mRNA was most strongly expressed in the trachea, kidney, and salivary gland. An affinity-purified antibody against a peptide incorporating the COOH terminal of the receptor localized VRL-2 immunolabel in the distal tubules of the kidney, the epithelial linings of both trachea and lung airways, serous cells of submucosal glands, and mononuclear cells. Unlike VR1 and VRL-1, VRL-2 was not detected in cell bodies of dorsal root ganglia (DRG) or sensory nerve fibers. However, VRL-2 was found on sympathetic and parasympathetic nerve fibers, such as those innervating the arrector pili smooth muscle in skin, sweat glands, intestine, and blood vessels. At least four vanilloid receptor-like genes exist, the newest member, VRL-2 is found in airway and kidney epithelia and in the autonomic nervous system.

Central terminations of cutaneous mechanoreceptive afferents in the rat lumbar spinal cord.

The morphology in the dorsal horn of the lumbar spinal cord of the collateral branches and terminal arborizations of three different types of low-threshold mechanoreceptor innervating the skin of the rat hindlimb has been studied by the intracellular injection of horseradish peroxidase into physiologically characterized afferent fibres. The central terminals of five rapidly adapting glabrous skin mechanoreceptors (RA), six hair follicle afferents (HFA), and four slowly adapting type I afferent fibres (SA I; two from glabrous and two from hairy skin) were recovered for detailed analysis. The number of collaterals per axon varied from eight to 12, and the length of axon stained from 3.5 to 4.7 mm. In each afferent, while the majority (52-67%) of the terminal arborizations displayed extensive branching with large numbers of en passant and terminal synaptic boutons, the arborizations at the caudal and rostral extremes of the terminal field tended to be much simpler and less profuse, with few and in some cases no boutons. This did not appear to be the consequence of inadequate filling. The general pattern of the terminal arborizations was one of mediolaterally compressed, rostrocaudally oriented sheets. In the case of the RA afferents there was no overlap between the adjacent terminal arborizations; a few of the arborizations of the SA I afferents overlapped; most, but not all, of the HFA terminal arborizations overlapped. The terminal arborizations of the HFAs had a distinctive morphology identical to the flame-shaped arbors described in earlier Golgi studies and included synaptic boutons extending from inner lamina II to lamina IV. The morphologies of the RA and SA terminal arborizations were similar to each other, but the former tended to be concentrated in lamina IV with branches in III and V, whereas the latter tended to V with few branches more superficial than lamina IV. There were also differences in the intercollateral spacing between these two types of afferent fibre. While there are similarities between the morphology of the central terminals of cutaneous low-threshold mechanoreceptors in the rat and those previously described in the cat (for example, the longitudinally continuous arrangement of the mediolaterally restricted flame-shaped HFA arborizations and the discontinuous RA arborizations arising from a dorsally located axon), there are also some major differences: the large number of HFA arbors extending to lamina IIi and to lamina IV rather than being restricted to lamina III, the deeper location of the RA arbors (in laminae IV and V rather than lamina III),(ABSTRACT TRUNCATED AT 400 WORDS)

Growth-associated protein 43 immunoreactivity in the superficial dorsal horn of the rat spinal cord is localized in atrophic C-fiber, and not in sprouted A-fiber, central terminals after peripheral nerve injury.

Peripheral nerve injury induces the up-regulation in dorsal root ganglion cells of growth-associated protein 43 (GAP-43) and its transport to the superficial laminae of the dorsal horn of the spinal cord, where it is located primarily in unmyelinated axons and growth-cone like structures. Peripheral nerve injury also induces the central terminals of axotomized myelinated axons to sprout and form novel synaptic contacts in lamina II of the dorsal horn. To investigate whether the sprouting of A-fiber central terminals into lamina II is the consequence of GAP-43 incorporation into their terminal membranes, we have used an ultrastructural analysis with double labelling to identify the localization of GAP-43 immunoreactivity. Transganglionic transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was used to identify C-fiber terminals. Transganglionic transport of the B fragment of cholera toxin conjugated to horseradish peroxidase (B-HRP) was used to label A-fiber sciatic nerve central terminals in combination with GAP-43 immunocytochemistry. GAP-43 was found to colocalize only with WGA-HRP- and not with B-HRP-labelled synapses or axons. In addition, many single-labelled GAP-43 synapses were observed. Many of the WGA-HRP-labelled terminals that were characterized by degenerative changes were GAP-43 immunoreactive. Our results indicate that peripheral nerve injury induces novel synapse formation of A fibers in lamina II but that up-regulated levels of GAP-43 are present mainly in other axon projections to the superficial dorsal horn.

Morphology and somatotopy of the central arborizations of rapidly adapting glabrous skin afferents in the rat lumbar spinal cord.

The central arborizations in the dorsal horn of the spinal cord of 23 rapidly adapting (RA) A-beta primary afferent neurons innervating different regions of the glabrous skin of the hindpaw were studied by the intra-axonal injection of horseradish peroxidase in adult rats. A total of 284 arbors of the complex, simple, and blind-ending variety were recovered. The arbors of RA afferents innervating the toes, paw pads, and non-pad hindpaw differed from each other in branch pattern and dimensions. The simple and complex arbors, which are both bouton-containing, were distributed mainly in laminae III-V, although some complex arbors projected dorsally into lamina IIi. The hindpaw glabrous skin afferent terminals were located in the lumbar enlargement from caudal L3 to rostral L6. A crude somatotopic organization was observed such that toes 1-5 were represented successively in more caudal positions from mid-L4 to caudal L5. The paw pads were organized in a rostrocaudal sequence moving from the paw pads proximal to toe 1 across the foot to the paw pads proximal to toe 5, from caudal L3 to mid-L5. Non-pad hindpaw afferents were located in caudal L5. Overlap between toe, paw pad and non-pad afferent central fields was present, however, and the central terminals of afferents with non-adjacent peripheral receptive fields were shown to occupy the same region of the dorsal horn.

Chronic peripheral nerve section results in a rearrangement of the central axonal arborizations of axotomized A beta primary afferent neurons in the rat spinal cord.

In order to investigate the reorganization of the neuropil of the dorsal horn following peripheral nerve injury, the central terminal arborizations of 35 A beta primary afferent neurons, chronically injured by a cut and ligation of the sural nerve 6-12 weeks previously, were studied by the intra-axonal injection of horseradish peroxidase. Their morphology was compared to 13 intact sural nerve hair follicle afferents. Following axotomy, three kinds of morphological abnormalities were observed in the collateral arbors of the 26 afferents that were hair follicle-like. Atrophy with thin stem axons and reduced terminal branch patterns with few boutons was seen in 5 afferents. Sprouting of bouton-containing terminals into lamina I and IIo was found in 8 afferents. Finally, abnormal arborization patterns in the deeper laminae were observed in 29% of the collateral arbors. Changes included the loss in some arbors of a flame-shaped appearance, which is characteristic of hair follicle afferents, atypical branching patterns and ventrally directed axons producing wider and deeper arbors, compared to normal. Axotomy also caused a disruption of the normal somatotopic organization of sural nerve A beta afferents. This disruption manifested as a variability in the normally mediolaterally restricted terminal sheet, with a consequent loss of the strict somatotopic register in the rostrocaudal direction. Damage to the peripheral axon of A beta primary afferents induces a structural reorganization of their central terminals in the dorsal horn of the spinal cord, which may modify sensory input to the central nervous system.