Diversifying autism neuroimaging research: An arterial spin labeling review.

LAY ABSTRACT: Brain function and health depend on cerebral blood flow to secure the necessary delivery of oxygen and nutrients to the brain tissue. However, cerebral blood flow appears to be altered in autistic compared to non-autistic individuals, potentially suggesting this difference to be a cause and potential identification point of autism. Recent technological development enables precise and non-invasive measurement of cerebral blood flow via the magnetic resonance imaging method referred to as arterial spin labeling. However, most neuroimaging studies still prefer using the physiologically indirect measure derived from functional magnetic resonance imaging. Therefore, this review examines the use of arterial spin labeling to further investigate the neurobiology of autism. Furthermore, the review includes a comparison of results from molecular imaging and arterial spin labeling followed by a discussion concerning the future direction and potential of arterial spin labeling. We found that arterial spin labeling study results are consistent with those of molecular imaging, especially after considering the effect of age and sex. In addition, arterial spin labeling has numerous application possibilities besides the quantification of cerebral blood flow. Therefore, we encourage researchers to explore and consider the application of arterial spin labeling for future scientific studies in the quest to better understand the neurobiology of autism.

Time perception at different EEG-vigilance levels.

BACKGROUND: Human time perception is influenced by various factors such as attention and drowsiness. Nevertheless, the impact of cerebral vigilance fluctuations on temporal perception has not been sufficiently explored. We assumed that the state of vigilance ascertained by electroencephalography (EEG) during the perception of a given auditory rhythm would influence its reproduction. Thus, we hypothesised that the re-tapping interval length and the accuracy of reproduction performance would vary depending on the state of vigilance determined by EEG. METHODS: 12 female and 9 male subjects ranging from 21 to 38 years (M = 25.52, SD = 3.75) participated in a test paradigm comprising a) a resting EEG for the determination of vigilance while an auditory rhythm was presented, b) a short activity of the proband to be sure of sufficient alertness, and c) a tapping task to reproduce the presented rhythm. Vigilance states of three consecutive 1-sec-EEG-segments of the resting EEG before the reproduction phase were classified using the Vigilance Algorithm Leipzig (VIGALL). RESULTS AND DISCUSSION: Reproduction accuracy was more precise after high EEG-vigilance stages. Thus, the subjects' mean deviation from the given rhythm was lower (t(17) = -2.733, p < 0.05) after high vigilance stage A (MW = 0.046, SD = 0.049) than after low vigilance stage B (MW = 0.065, SD = 0.067). The re-tapping-length was significantly shorter (t(17) = -2.190, p < 0.05) for reproduction phases following high EEG-vigilance stage A compared to the lower EEG-vigilance stage B. CONCLUSION: These findings support the hypothesis of a varying time perception and of speed alterations of the internal clock after different states of EEG-vigilance, which were automatically classified by VIGALL. Thus, alterations of cognitive processing may be assessable by specific EEG-patterns.

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

Prestimulus vigilance predicts response speed in an easy visual discrimination task.

BACKGROUND: Healthy adults show considerable within-subject variation of reaction time (RT) when performing cognitive tests. So far, the neurophysiological correlates of these inconsistencies have not yet been investigated sufficiently. In particular, studies rarely have focused on alterations of prestimulus EEG-vigilance as a factor which possibly influences the outcome of cognitive tests. We hypothesised that a low EEG-vigilance state immediately before a reaction task would entail a longer RT. Shorter RTs were expected for a high EEG-vigilance state. METHODS: 24 female students performed an easy visual discrimination task while an electroencephalogram (EEG) was recorded. The vigilance stages of 1-sec-EEG-segments before stimulus presentation were classified automatically using the computer-based Vigilance Algorithm Leipzig (VIGALL). The mean RTs of each EEG-vigilance stage were calculated for each subject. A paired t-test for the EEG-vigilance main stage analysis (A vs. B) and a variance analysis for repeated measures for the EEG-vigilance sub-stage analysis (A1, A2, A3, B1, B2/3) were calculated. RESULTS: Individual mean RT was significantly shorter for events following the high EEG-vigilance stage A compared to the lower EEG-vigilance stage B. The main effect of the sub-stage analysis was marginal significant. A trend of gradually increasing RT was observable within the EEG-vigilance stage A. CONCLUSION: We conclude that an automatically classified low EEG-vigilance level is associated with an increased RT. Thus, intra-individual variances in cognitive test might be explainable in parts by the individual state of EEG-vigilance. Therefore, the accuracy of neuro-cognitive investigations might be improvable by simultaneously controlling for vigilance shifts using the EEG and VIGALL.

COMT genotype and its role on hippocampal-prefrontal regions in declarative memory.

INTRODUCTION: Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal-prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val(158)met status on the neural correlates of declarative memory was investigated in healthy subjects. METHODS: From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val(158)met status was determined for the whole sample and correlated with cortical activation within the group of n=84 individuals. RESULTS: There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval. DISCUSSION: Although declarative memory performance was unaffected, the neural correlates within hippocampal-prefrontal regions demonstrate a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia.

Muscarinic antagonist effects on executive control of attention.

Acetylcholine plays a major role in mediating attention processes. We investigated the muscarinic antagonist effect of scopolamine on functional neuro-anatomy of attention and cognition. We assessed 12 healthy volunteers while performing the Attention Network Task on 0.4 mg scopolamine and placebo in a single-blind randomized trial in a 1.5 T magnetic resonance scanner. Neurocognitive measures included verbal learning, verbal memory, verbal fluency, trail making, digit span, a continuous performance task and a planning task (Tower of London). When compared to placebo, scopolamine increased reaction times for conflicting stimulus processing, together with decreasing brain activation in the anterior cingulate cortex (a brain region involved in conflict processing) suggestive of a muscarinic antagonist effect on executive control of attention. Contrary to the notion of a predominantly right-hemispheric lateralization of cognitive processes associated with orienting attention, scopolamine reduced brain activity in left superior and left middle frontal brain areas. Our neuropsychological test data revealed a selective effect of scopolamine on verbal learning and memory while other cognitive domains, such as planning and working memory, were unaffected. These findings are consistent with muscarinic modulation of dopaminergic neurotransmission in frontal attention networks when processing conflicting information.

Nicotinic antagonist effects on functional attention networks.

Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.

Neurobiology of depression and novel antidepressant drug targets.

Depression is one of the most common psychiatric conditions affecting numerous individuals in the world. However, the currently available antidepressant medication shows low response and remission rates. Thus, new antidepressants need to be discovered or developed. Aiming to describe the current neurobiological hypotheses regarding the pathophysiology of depression and in order to give an overview of novel possible antidepressant drug targets, we reviewed publications and studies referring to the neurobiology of depression. This review included genetics, epigenetics and gene expression, neuroanatomy and structural anatomy, neurochemistry, neuroendocrinology, neuroimmunology and novel drug targets using a MEDLINE/Pubmed search. The search was augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings. On the one hand, the literature reveals in part contradictory information, but on the other hand, it shows convergent information regarding the relevance of research targets apart from the monoamine deficiency hypothesis of depression such as epigenetic phenomena and changes in neuronal and glial function and structure. Recent neurobiological findings in these areas of research provide multidimensional perspectives for the progress in the psychopharmacological treatment of depression.

Lack of data on depression-like states and antidepressant pharmacotherapy in patients with epilepsy: randomised controlled trials are badly needed.

The prevalence of depression in patients with epilepsy (PWE) is high. To elucidate the nature of depression in PWE, a comparison was made between PWE and patients with idiopathic depression (PWID), applying 3 test batteries: Beck Depression Inventory II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D) and Buss-Perry Aggression Questionnaire (BAQ). The former 2 rating scales were developed to measure depressive symptoms, while the latter was designed to detect anger and aggressive states. As a result, the group of patients with PWE showed significantly higher BAQ scores in comparison to those with PWID. Further, the BAQ and BDI scores were closely related within a group of PWE, while BAQ and BDI scores were not correlated with each other within a group of PWID. With regard to pharmaceutical therapy, the safety of antidepressants, especially SSRIs, is well established. However, there has been only one randomized controlled trial (RCT) thus far, which failed to show a significant difference in efficacy between placebo and various antidepressants. In contrast, there are two RCTs regarding the efficacy of LTG. The clinical profile of the depressiolytic effects of LTG in PWE may be different from that of antidepressants in patients with idiopathic depression, in that BAQ is more sensitive measure than BDI or CES-D. It is now widely recognized that the failure to treat depression in PWE can result in serious consequences. However, even a fundamental question, such as whether antidepressants are as effective in this population as in PWID, remains to be answered.

Alcohol consumption, genetic variants in alcohol deydrogenases, and risk of cardiovascular diseases: a prospective study and meta-analysis.

OBJECTIVE: First, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk. METHODS: We conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011. RESULTS: Compared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10-0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33-0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12-0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98-1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90-1.27; p for heterogeneity: 0.098)]. CONCLUSION: The well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation.

Impact of clozapine, N-desmethylclozapine and chlorpromazine on thromboxane production in vitro.

Thromboxane A2 (TxA2) and the activation of its receptor have been shown to modulate vasoconstriction and platelet aggregation as well as dopaminergic and serotonergic signalling. Dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and these systems are the main targets of antipsychotics (APs). As the first antipsychotic (AP) chlorpromazine (CPZ) has already been shown to reduce TxA2, we hypothesized that the AP clozapine and its metabolite N-desmethylclozapine (NDMC) might also influence TxA2 production. We measured levels of thromboxane B2 (TxB2), the metabolite of the very unstable molecule TxA2, in unstimulated and stimulated blood samples of 10 healthy female subjects in a whole blood assay using toxic shock syndrome toxin-1 (TSST-1) and monoclonal antibody against surface antigen CD3 combined with protein CD40 (OKT3/CD40) as stimulants. Blood was supplemented with the APs CPZ, clozapine or NDMC in one of four different concentrations. Additionally, thromboxane levels were measured in blood without the addition of APs under different stimulation conditions. Under TSST-1 as well as OKT3/CD40 stimulation, mean TxB2 concentrations were significantly (p < 0.05) decreased by clozapine over all applied concentrations. NDMC led to a decrease in TxB2 levels under unstimulated conditions as well as under TSST-1 stimulation. CPZ reduced TxB2 production at low concentrations under unstimulated and TSST-1- stimulated conditions. Clozapine, NDMC and CPZ possibly act on neurotransmitter systems via modulation of TxA2 or TxB2 production. Additionally, known side effects of APs such as orthostatic hypotension may be a result of changes in the concentrations of TxA2 or TxB2.

Impact of antipsychotics on cytokine production in-vitro.

OBJECTIVE: A growing body of data from genetic, immunological and clinical studies indicates an involvement of the immune system in the pathophysiology of schizophrenia and suggests that the modulation of the cytokine system by antipsychotics may be one cause for the improvement of psychotic symptoms. However, the influence of the typical antipsychotics chlorpromazine and haloperidol, and the effect of typical and atypical antipsychotics on the TSST-1-stimulated blood cell secretion of cytokines, and specifically the interleukin (IL)-17 production have not been studied so far, although IL-17 is a leading pro-inflammatory cytokine. METHOD: We measured levels of IL-1ß, IL-2, IL-4, IL-6, IL-17 and tumor necrosis factor-α (TNF-α) in stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antipsychotics (chlorpromazine, haloperidol, clozapine, N-desmethylclozapine and quetiapine with four different concentrations each) or not. RESULTS: Under TSST-1 stimulation, antipsychotics as a group had no influence on IL-1ß or IL-6 concentrations but increased IL-4 levels. The most consistent findings were seen regarding IL-17. Mean IL-17 concentrations differed significantly between blood with and without antipsychotic supplements and were increased over all antipsychotics and almost all of the applied antipsychotic concentrations. TNF-α levels were increased by chlorpromazine; N-desmethylclozapine and quetiapine reduced IL-2 production. CONCLUSIONS: Antipsychotics might, among other mechanisms, act as such by increasing the production of IL-17.

TNF-alpha and ghrelin: opposite effects on immune system, metabolism and mental health.

Tumor necrosis factor-alpha (TNF-alpha) is a glycoprotein hormone with important functions in inflammation and apoptosis. It plays a significant role as a pro-inflammatory cytokine in the defense against viral, bacterial and parasitic infections and autoimmune disorders. Furthermore, it influences energy homeostasis and has an anorexigenic effect on the hypothalamus. TNF-alpha has also been shown to be involved in the pathogenesis of psychiatric disorders such as depression or narcolepsy. Ghrelin is a peptide hormone which primarily regulates eating behavior through modulation of expression of orexigenic peptides in the hypothalamus. Ghrelin administration increases food intake and body weight, while weight loss in turn increases ghrelin levels. Secondly, it posesses anti-inflammatory properties. It also seems to have an impact on mental health as it is has been suggested to have antidepressant and anxiolytic properties. Therefore, TNF-alpha and ghrelin seem to have opposite effects regarding the hypothalamic regulation of eating behavior, modulation of the immune response and the state of mental health.

Laboratory parameters and appetite regulators in patients with anorexia nervosa.

Anorexia nervosa (AN) has serious negative effects on multiple organs and systems of the human body. As patients often do not make their eating disorder the subject of discussion, the physician is forced to rely on the physical examination and laboratory parameters as diagnostic hints. Obvious signs of AN are a body mass index (BMI) below 17.5 kg/m, dry and scaly skin, lanugo, edema, acrocyanosis, petechias, dental problems, and low blood pressure. However, because the often complex laboratory alterations can be difficult for the general psychiatrist to interpret, this article presents some useful guidelines. The plasma of patients with AN often shows alterations in laboratory parameters and appetite regulators, including electrolytes, liver enzymes, leukocyte count, hemoglobin (Hb), leptin, neuropeptide Y (NPY), triiodothyronine (T3), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, ghrelin, pancreatic polypeptide (PP), tumor necrosis factor-alpha (TNF-alpha), and cortisol. Medical problems secondary to AN or due to the treatment itself may lead to further laboratory abnormalities. To date, despite these associated laboratory alterations, the diagnosis of anorexia is a clinical one, based on weight and specific psychopathology.

IFN-gamma reduction by tricyclic antidepressants.

OBJECTIVE: A growing body of data indicates that an activation of proinflammatory cytokines such as interferon-gamma (IFN-gamma) is involved in the pathophysiology of depression and that the suppression of pro-inflammatory cytokine production by antidepressants may lead to an improvement of depressive symptoms. However, the influence of the serotonin and noradrenalin reuptake inhibitor (SNRI) venlafaxine and its metabolite O-desmethylvenlafaxine on the stimulated blood cell secretion of IFN-gamma has not been studied so far. METHOD: We measured IFN-gamma levels in the stimulated blood of healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antidepressants or not. RESULTS: Mean IFN-gamma concentrations differed between blood with and without antidepressant supplements (p = 0.026). Planned contrasts revealed that compared to non-supplemented blood, four of the blood samples supplemented with the tricyclic antidepressants (TCAs) reduced IFN-gamma levels: amitriptyline (adjusted p-value (p = 0.004), nortriptyline (p = 0.037), imipramine (p = 0.021), and desipramine (p = 0.048). There was no significant difference between the control condition and the venlafaxine or O-desmethylvenlafaxine condition. CONCLUSIONS: TCAs might, among other mechanisms, act as antidepressants by suppressing the production of pro-inflammatory cytokines, whereas no significant effect of venlafaxine and O-desmethylvenlafaxine on IFN-gamma secretion could be demonstrated.

Regulatory T cells increased while IL-1ß decreased during antidepressant therapy.

BACKGROUND: Regulatory T cells (Tregs, CD4(+)CD25(hi)) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1ß, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4(+)CD25(hi) Tregs in these immunological processes during antidepressant therapy. METHODS: 16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctor's choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1ß, and measured IL-1ß, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4(+)CD25(hi) Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21). RESULTS: HAMD-21 score, IL-1ß serum levels as well as LPS-stimulated IL-1ß and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4(+)CD25(hi) cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed. CONCLUSIONS: The increase in CD4(+)CD25(hi) Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.

From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.