Cognitive-behavioural theories of helplessness/hopelessness: Valid models of depression?

Helplessness and hopelessness are central aspects of cognitive-behavioural explanations for the development and persistence of depression. In this article a general overview concerning the evolution of those approaches to depression is provided. Included is a critical examination of the theories. The review of the literature suggests that those cognitive models describing helplessness/hopelessness as trait factors mediating depression do not really have a strong empirical base. The majority of those studies had been conducted in healthy or only mildly depressed subjects. Thus, there seems to be little justification for broad generalisations beyond the populations studied. It seems that some of the reported studies have not tested the underlying theories adequately (e. g. correlation had sometimes been interpreted as causation; adequate prospective longitudinal study designs had seldom been applied). Moreover, the theoretical models are not generally prepared to explain all depressive features (e. g. the possibility of a spontaneous shift in a manic episode). Despite those limitations, there is a relevant impact of the learned helplessness paradigm on preclinical research in neurobiological correlates of depressive states. Last but not least, the models are of high interest with respect to the theoretical background of important modules of cognitive-behavioural therapy and its acute and prophylactic effects. Received: 1 October 2002 / Accepted: 2 October 2002 Correspondence to Verena Henkel; MD     

The many substrates of presenilin/γ-secretase

The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins.     

Are purines mediators of the anticonvulsant/neuroprotective effects of ketogenic diets?

Abnormal neuronal signaling caused by metabolic changes characterizes several neurological disorders, and in some instances metabolic interventions provide therapeutic benefits. Indeed, altering metabolism either by fasting or by maintaining a low-carbohydrate (ketogenic) diet might reduce epileptic seizures and offer neuroprotection in part because the diet increases mitochondrial biogenesis and brain energy levels. Here we focus on a novel hypothesis that a ketogenic diet-induced change in energy metabolism increases levels of ATP and adenosine, purines that are critically involved in neuron-glia interactions, neuromodulation and synaptic plasticity. Enhancing brain bioenergetics (ATP) and increasing levels of adenosine, an endogenous anticonvulsant and neuroprotective molecule, might help with understanding and treating a variety of neurological disorders.     

Phagocytosis of β/A4 amyloid fibrils of the neuritic neocortical plaques

Summary Immunocytochemistry using monoclonal antibodies to /A₄ protein was applied to study the macrophages involved in the removal of amyloid deposits. The material examined included necrotic brain tissue areas with abundant amyloid deposits collected from 32 autopsy cases. The /A₄-immunoreactive products were found in numerous macrophages, appearing as early as 24 h after the onset of stroke. Immunogold electron microscope studies allowed us to localize the reaction product to the secondary lysosomes. Our study clearly demonstrates the differences between macrophages engaged in amyloid removal and microglial cells associated with amyloid deposits, which according to previous observations contain /A₄ material within endoplasmic reticular channels.M. Barcikowska and E. Kida are visiting scientists from the Polish Academy of Sciences, Medical Research Centre, Warsaw, Poland     

Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood?

Serotonin [5-hydroxytryptamine (5-HT)] and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT_2A receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT_2A receptors (and possibly also 5-HT_2C receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT_2A/2C receptor-mediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions.     

Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.     

Do children with ADHD and/or PDD-NOS differ in reactivity of alpha/theta ERD/ERS to manipulations of cognitive load and stimulus relevance?

ObjectiveWe examined whether the method of event-related (de-)synchronization (ERD/ERS) revealed differential effects of selective attention and working memory load in children (8–11 years) with pervasive developmental disorder – not otherwise specified (PDD-NOS) or attention-deficit/hyperactivity disorder (ADHD).MethodsFifteen healthy controls and three equally large groups of children with symptoms of PDD-NOS, ADHD or both (PDD/HD) performed a visual selective memory search task. The EEG was recorded from which occipital alpha and frontal theta were derived.ResultsThe effects of the overall task manipulations of task load, relevance and target/nontarget were clearly present in the overall analyses of alpha and theta ERD/ERS. However, no significant differences with respect to these manipulations existed between any of the subject groups.ConclusionsThe results supply no evidence for a distinction in information processing abilities of selective attention and working memory as reflected by alpha and theta ERD/ERS between children diagnosed with either ADHD, PDD-NOS or healthy controls.SignificanceAlpha and theta ERD/ERS are sensitive to manipulations of task load, relevance and target/nontarget, but supply no additional information on possible group differences in comparison to the more frequently used method of event-related potentials.     

Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas��possible role of Cannabis inhalation

Introduction  

Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression.     

Investigating the role of Ca2+/calmodulin-dependent protein kinaseⅡin the survival of retinal ganglion cells

Retinal ganglion cells(RGCs)are the sole output neurons of the retina that project long axons and transmit visual information to the brain.The degeneration of RGCs leads to irreversible vision loss in a variety of pathological states,including excitotoxicity,traum atic nerve injury,and glaucoma.     

1000/Symptomatic and pathogenetic treatment of diabetic neuropathy. The role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy worldwide, presents in different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, i.e. oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns the therapy of neuropathic pain with antidepressants (tricyclics and serotonin-norepinephrine inhibitors), anticonvulsants (in particular, alpha2delta calcium channel modulator), opioids (oxycodone CR and tramadol), and local treatment and physical therapy. Symptomatic treatment of autonomic neuropathy includes different interventions targeted at the organ systems involved. The management of diabetic foot is directed at the various combined factors resulting in foot ulceration, such as infection, peripheral ischemia, and pressure relief. Various therapeutic approaches pathogenetically oriented have been proposed and investigated in experimental and clinical studies, targeted to the different components involved in the causation of nerve damage. In particular, oxidative stress has been demonstrated to play a central role in the cascade of events triggered by hyperglycemia, thus it appears as an ideal target for a pathogenetic therapeutic approach. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in a series of controlled randomized clinical trials in patients with diabetic neuropathy, with either oral administration or intravenous infusion. Most of the trials demonstrated the efficacy of alpha-lipoic acid on the chief symptoms of diabetic neuropathy, and in particular on neuropathic pain, also indicating that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for modifying the natural history of diabetic neuropathy. The potential role of alpha-lipoic acid in contrasting the progression of diabetic neuropathy is being explored in the NATHAN 1 study, using an oral dose of 600 mg once daily over 4 years in diabetic patients with mild to moderate distal symmetric polyneuropathy, and evaluating the long-term effects with a composite score that combines clinical and neurophysiological assessment.     

Effects of nerve growth factor on the expression of caspase-12 of nerve cells in cerebral ischemia/reperfusion area

INTRODUCTIONApoptosis plays a key role in cerebral ischemia/reperfusion injury [1-5].Recently, researches suggest that stress of endoplasmic reticulumcan mediate apoptosis [6-12]; especially, stress apoptosis of endoplas-mic reticulum mediated by caspase-…     

Meta-analysis of APOE ε2/ε3/ε4 polymorphism and cerebral infarction

The risk of cerebral infarction (CI) is contributed to the combination of environmental influences and genetic factors. The Apolipoprotein E (APOE) gene polymorphism as a risk factor in CI has been suggested, but direct evidence from genetic association studies remains inconclusive even in Chinese population. The purpose of this study was to identify association between the APOE ε2/ε3/ε4 polymorphism and the development of CI. Published relevant case–control studies were collected from electronic databases. Data were combined using odds ratio (OR) with 95 % confidence interval (CI). Totally, 29 studies published from 1997 to 2012, involving 2,737 CI cases and 2,689 controls in Chinese population were subjected to final analysis. The pooled results suggested that CI subjects carrying ε4 allele had an increased risk for CI (ε4 vs. ε3: OR = 2.50, 95 % CI 1.98–3.16, P < 0.001, ε4 carriers vs. E3E3 genotype: OR = 2.82, 95 % CI 2.16–3.67, P < 0.001), compared with those carrying ε3 allele. However, carriers of APOE ε2 allele had no significant increased risk for CI, compared with those carrying ε3 allele. Potential publication bias was observed in the genetic model of ε4 versus ε3, but the results might not be affected deeply by the publication bias. Using the trim and fill method, the adjusted risk estimate for ε4 allele versus ε3 allele was attenuated but remained significant (OR = 2.00, 95 % CI 1.59–2.53, P < 0.001), suggesting the stability of our results. Taken together, our study suggests that APOE ε4 allele is associated with an increased risk of developing CI in Chinese population.     

α/β oscillations indicate inhibition of interfering visual memories

Selective retrieval of a specific target memory often leads to the forgetting of related but irrelevant memories. Current cognitive theory states that such retrieval-induced forgetting arises due to inhibition of competing memory traces. To date, however, direct neural evidence for this claim has not been forthcoming. Studies on selective attention suggest that cortical inhibition is mediated by increased brain oscillatory activity in the alpha/beta frequency band. The present study, testing 18 human subjects, investigated whether these mechanisms can be generalized to selective memory retrieval in which competing memories interfere with the retrieval of a target memory. Our experiment was designed so that each cue used to search memory was associated with a target memory and a competitor memory stored in separate brain hemispheres. Retrieval-induced forgetting was observed in a condition in which the competitor memory interfered with target retrieval. Increased oscillatory alpha/beta power was observed over the hemisphere housing the sensory representation of the competitor memory trace and predicted the amount of retrieval-induced forgetting in the subsequent memory test. These results provide the first direct evidence for inhibition of competing memories during episodic memory retrieval and suggest that competitive retrieval is governed by inhibitory mechanisms similar to those employed in selective attention.     

Phosphorylation of the Third Intracellular Loop of the Mouse α1b-Adrenergic Receptor by cAMP-dependent Protein Kinase

The third intracellular loop of adrenergic receptors has been implicated in their interaction with guanine nucleotide-binding proteins (G proteins). One of the mechanisms involved in the modulation of receptor function is the phosphorylation of specific residues by intracellular kinases.

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-Adrenergic receptor is phosphorylated in vitro by cAMP-dependent protein kinase (PKA), although its physiological effect remains to be determined. We have produced fusion proteins formed by glutathione S-transferase and sequences of the third intracellular loop of mouse

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-,

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-, and

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-adrenergic receptor subtypes, and used them as substrates for PKA. Only the fusion protein containing the

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sequence was phosphorylated in vitro by this kinase. Site-directed mutagenesis of a serine (homologue to serine 278 of the rat sequence, RSS) to an alanine residue precluded phosphorylation by PKA.     

Exploration of dimensions of psychopathology in neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-na?ve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-na?ve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-na?ve schizophrenic patients.     

What is a clinically important level of improvement in symptoms of attention-deficit/hyperactivity disorder?

OBJECTIVE: To compare the desired and actual reduction in scores on a parent reported behaviour rating scale in a naturalistic sample of children and adolescents who had been treated with psychostimulant medication, referenced to global ratings of treatment benefit. METHOD: Forty-five parents reporting poor global response to psychostimulant treatment, 44 reporting moderate response, and 49 reporting a high response retrospectively completed Conners rating scales describing their child prior to treatment, the child currently, and how the parent hoped the child would be following treatment. RESULTS: Percentage actual improvement in behaviour rating scales from baseline ranged from around 25% for the poor responders to above 50% for the high responders. Desired improvement was above 50%, with no significant difference between the groups on level of expectation. CONCLUSIONS: Percentage cut points used to indicate clinical improvement reported in previous controlled trials of psychostimulant medication are probably too low, and could lead to an overestimate of treatment effect. Expectation of treatment benefit is unlikely to contribute to variation in treatment response.     

A test of the role of two prefrontal/ subcortical networks in the ��sequencing�� of non-motor, visuo-spatial information

There are a number of prefrontal/sub-cortical networks in the brain (e.g., cerebellar-thalamic-prefrontal or basal ganglia/supplementary motor cortex circuits) that despite having a clear role in motor function have been shown to be involved in non-motor tasks. In this project we test for the involvement of these networks in a dimensional judgment task that utilizes visual perceptual, visual spatial processing and requires the ordering of dimensional (height) information. Unlike previous studies examining non-motor sequencing, we directly compare both non-motor and motor versions of our dimensional judgment task. In addition, we examine activation uniquely associated with correct task responses. The findings provide evidence for the role of cortical not subcortical structures in the sequencing of visuo-spatial material apart from any motor output requirements. Our results suggest that the inferior parietal cortex (BA 7, 40) and medial frontal regions (BA 6, 8, 9 including the SMA) are instrumental to the task. Based on these results, we propose a prefrontal/parietal network plays a role in the implementation of a comparator mechanism that makes accurate comparisons along the dimension of interest, holds the information in working memory, and then (regardless of whether the information is correct or incorrect) generates a tag or abstract code that assigns the information a place in an ordered sequence. Most important, the information involved can be visual/symbolic and non-motor (not just motor) in nature.     

Patients’ Perceptions of Opioid Replacement Therapy: a Comparison of Diamorphine and Methadone/Levomethadone

Diamorphine was first legalized as a novel treatment option for heroin dependence in Germany in 2009. Today, specialized clinics in ten German cities provide diamorphine to heavily addicted patients. As the medical and societal context of diamorphine-assisted therapy is evolving, continued research into patients’ perceptions of opioid replacement therapy remains important. From February 2018 to June 2018, we conducted a survey study of outpatients on maintenance treatment with either diamorphine (n = 85) or methadone/levomethadone (n = 126). Patients were asked to complete a self-report questionnaire querying, besides socio-demographic information, the study participant’s satisfaction with the substitute drug, relapse with illicit drugs, patterns of craving, and alcohol consumption. Duration of opioid dependence did not differ significantly between groups. Patients on diamorphine were approximately 3 years younger than patients on methadone/levomethadone. They also had a higher frequency of daily intake of their substitute drug and had had their dosage adjusted more often during the preceding 6 months. Still, diamorphine patients reported greater satisfaction with their substitute drug in tandem with significant reductions in relapse-related behaviors and cravings. While the most common relapse reported by patients on methadone replacement was heroin relapse (68%), most instances of illicit drug use in the diamorphine group involved cocaine (48%). Although self-reported alcohol consumption did not differ significantly between groups, a higher percentage of diamorphine patients than methadone patients endorsed decreased alcohol consumption since entering therapy. Taken together, these findings point to meaningful differences between diamorphine and methadone/levomethadone in opioid replacement therapy.

     

Increased Levels of mRNA for β- but not α-Subunit of Calmoduline Kinase II Following Kindled Seizures

We studied levels of mRNA for the

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- and

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-subunits of calmodulin (CaM) kinase II using the amygdaloid kindling model of epilepsy. There were significant increases in mRNA for the

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-subunit of CaM kinase II in the hippocampus 4—24 h after stage 5-kindled seizures. Moreover, this mRNA was significantly increased by 20.0–26.5% in the bilateral dentate gyrus 8 to 24 h after kindled seizures. The

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-subunit mRNA was also significantly increased by 13.5–19.0% in the CA3 on the side ipsilateral to the stimulation, 4 to 8 h after kindled seizures. mRNA for the

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-subunit of CaM kinase II was not significantly changed in the regions examined for up to 24 h after the kindled seizures. These results suggest that CaM kinase II mediates the molecular processes that follow kindled seizures. It is possible that increases in CaM kinase II-dependent protein phosphorylation are associated with the plastic changes in kindling.