Showing papers in "Journal of Neural Transmission in 2016"

Reward functions of the basal ganglia

Abstract: Besides their fundamental movement function evidenced by Parkinsonian deficits, the basal ganglia are involved in processing closely linked non-motor, cognitive and reward information. This review describes the reward functions of three brain structures that are major components of the basal ganglia or are closely associated with the basal ganglia, namely midbrain dopamine neurons, pedunculopontine nucleus, and striatum (caudate nucleus, putamen, nucleus accumbens). Rewards are involved in learning (positive reinforcement), approach behavior, economic choices and positive emotions. The response of dopamine neurons to rewards consists of an early detection component and a subsequent reward component that reflects a prediction error in economic utility, but is unrelated to movement. Dopamine activations to non-rewarded or aversive stimuli reflect physical impact, but not punishment. Neurons in pedunculopontine nucleus project their axons to dopamine neurons and process sensory stimuli, movements and rewards and reward-predicting stimuli without coding outright reward prediction errors. Neurons in striatum, besides their pronounced movement relationships, process rewards irrespective of sensory and motor aspects, integrate reward information into movement activity, code the reward value of individual actions, change their reward-related activity during learning, and code own reward in social situations depending on whose action produces the reward. These data demonstrate a variety of well-characterized reward processes in specific basal ganglia nuclei consistent with an important function in non-motor aspects of motivated behavior.

Brainstem control of locomotion and muscle tone with special reference to the role of the mesopontine tegmentum and medullary reticulospinal systems

Abstract: The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.

Brain morphological changes in adolescent and adult patients with anorexia nervosa.

Abstract: Gray matter (GM) and white matter (WM) volume loss occur in the brains of patients with acute anorexia nervosa (AN) and improve again upon weight restoration. Adolescence is an important time period for AN to begin. However, little is known about the differences between brain changes in adolescents vs adults. We used a meta-analysis and a qualitative review of all MRI studies regarding acute structural brain volume changes and their recovery in adolescents and adults with AN. 29 studies with 473 acute, 121 short-term weight-recovered and 255 long-term recovered patients with AN were included in the meta-analysis. In acute AN, GM and WM were reduced compared to healthy controls. Acute adolescent patients showed a significantly greater GM reduction than adults (−8.4 vs −3.1 %), the difference in WM (−4.0 vs −2.1 %) did not reach significance. Short-term weight-recovered patients showed a remaining GM deficit of 3.6 % and a non-significant WM reduction of 0.9 % with no age differences. Following 1.5–8 years of remission, GM and WM were no longer significantly reduced in adults (GM −0.4 %, WM −0.7 %); long-term studies for adolescents were scarce. The qualitative review showed that GM volume loss was correlated with cognitive deficits and three studies found GM regions, cerebellar deficits and WM to be predictive of outcome. GM and WM are strongly reduced in acute AN and even more pronounced in adolescence. Long-term recovery appears to be complete for adults while no conclusions can be drawn for adolescents, thus caution remains.

Wearable sensor-based objective assessment of motor symptoms in Parkinson’s disease

Abstract: Effective management and development of new treatment strategies of motor symptoms in Parkinson's disease (PD) largely depend on clinical rating instruments like the Unified PD rating scale (UPDRS) and the modified abnormal involuntary movement scale (mAIMS). Regarding inter-rater variability and continuous monitoring, clinical rating scales have various limitations. Patient-administered questionnaires such as the PD home diary to assess motor stages and fluctuations in late-stage PD are frequently used in clinical routine and as clinical trial endpoints, but diary/questionnaire are tiring, and recall bias impacts on data quality, particularly in patients with cognitive dysfunction or depression. Consequently, there is a strong need for continuous and objective monitoring of motor symptoms in PD for improving therapeutic regimen and for usage in clinical trials. Recent advances in battery technology, movement sensors such as gyroscopes, accelerometers and information technology boosted the field of objective measurement of movement in everyday life and medicine using wearable sensors allowing continuous (long-term) monitoring. This systematic review summarizes the current wearable sensor-based devices to objectively assess the various motor symptoms of PD.

MMSE and MoCA in Parkinson's disease and dementia with Lewy bodies: a multicenter 1-year follow-up study.

Abstract: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients [Parkinson's disease (PD) without dementia (PDnD, N = 197), PD with dementia (PDD, N = 40), and dementia with Lewy bodies (DLB, N = 28)] from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (N = 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen's d) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (p = 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %, p < 0.01), but not in PDD (30 vs. 19 %, p = 0.37) or DLB (15 vs. 14 %, p = 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen's effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects.

Role of iron in neurodegenerative diseases.

Abstract: Currently, we still lack effective measures to modify disease progression in neurodegenerative diseases. Iron-containing proteins play an essential role in many fundamental biological processes in the central nervous system. In addition, iron is a redox-active ion and can induce oxidative stress in the cell. Although the causes and pathology hallmarks of different neurodegenerative diseases vary, iron dyshomeostasis, oxidative stress and mitochondrial injury constitute a common pathway to cell death in several neurodegenerative diseases. MRI is capable of depicting iron content in the brain, and serves as a potential biomarker for early and differential diagnosis, tracking disease progression and evaluating the effectiveness of neuroprotective therapy. Iron chelators have shown their efficacy against neurodegeneration in a series of animal models, and been applied in several clinical trials. In this review, we summarize recent developments on iron dyshomeostasis in Parkinson's disease, Alzheimer's disease, Friedreich ataxia, and Huntington's disease.

Transcranial direct current stimulation in children and adolescents: a comprehensive review.

Abstract: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that has shown promising results in various neuropsychiatric disorders in adults. This review addresses the therapeutic use of tDCS in children and adolescents including safety, ethical, and legal considerations. There are several studies addressing the dosage of tDCS in children and adolescents by computational modeling of electric fields in the pediatric brain. Results suggest halving the amperage used in adults to obtain the same peak electric fields, however, there are some studies reporting on the safe application of tDCS with standard adult parameters in children (2 mA; 20–30 min). There are several randomized placebo controlled trials suggesting beneficial effects of tDCS for the treatment of cerebral palsy. For dystonia there are mixed data. Some studies suggest efficacy of tDCS for the treatment of refractory epilepsy, and for the improvement of attention deficit/hyperactivity disorder and autism. Interestingly, there is a lack of data for the treatment of childhood and adolescent psychiatric disorders, i.e., childhood onset schizophrenia and affective disorders. Overall, tDCS seems to be safe in pediatric population. More studies are needed to confirm the preliminary encouraging results; however, ethical deliberation has to be weighed carefully for every single case.

Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

Abstract: Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinson’s and Alzheimer’s diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the “type-specificity” of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death.

Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: clinical experience.

Abstract: Alzheimer’s disease (AD) is the most common type of dementia among the elderly. Common treatments available and non-pharmacological interventions have their limitations, and new therapeutic approaches are critically needed. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current-inducing modulation in cortical excitability. The previous clinical trials showed that combinations of rTMS and cognitive training (rTMS-COG), as provided by the NeuroAD medical device system, offer a novel, safe, and effective method improving mild-to-moderate AD patients. In this article, we present our experience with rTMS-COG treatment, in clinical settings, of 30 mild-to-moderate AD patients that received rTMS-COG commercial treatments in two clinics for 1-h daily sessions, 5 days per week, for 6 weeks (30 sessions). Five patients returned for a second treatment. ADAS-Cog and MMSE scores were measured pre- and post-treatments. The main analyses were conducted on patients who received 1 treatment (n = 30). Data received from the five returning patients were analyzed separately. The effect of rTMS-COG treatment was statistically significant regarding both ADAS-Cog (−2.4 point improvement, PV <0.001) and MMSE (+1.7 points improvement, PV <0.001) scores. About 80 % of patients gained some cognitive improvement following NeuroAD treatment, with more than 60 % improving by more than two points, for a minimum of 9 months. The Neuronix NeuroAD System was shown to be a safe and effective non-invasive modality for cognitive improvement of Alzheimer patients, with measurable outcomes lasting, in some of them, for up to 1 year, following completion of the 6-week daily intervention course (a carryover effect).

Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson's disease (PD): historical overview and future prospects.

Abstract: Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic L-amino acid decarboxylase (AADC); dopamine β-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD. We purified all human CA-synthesizing enzymes, produced their antibodies for immunohistochemistry and immunoassay, and cloned all human genes, especially the human TH gene and the human gene for GCH1, which synthesizes BH4 as a cofactor of TH. This review discusses the historical overview of TH, BH4-, and other CA-related enzymes and their genes in relation to the pathophysiology of PD, the development of drugs, such as L-DOPA, and future prospects for drug and gene therapy for PD, especially the potential of induced pluripotent stem (iPS) cells.

Nrf2: a modulator of Parkinson’s disease?

Abstract: Parkinson's disease (PD) is a complex multifactorial disorder that has been associated with the processes of oxidative stress. In the absence of curative therapies, modification of the neurodegenerative process-including the manipulation of endogenous antioxidant pathways-is the focus of intensive research. Recently, genetic and pharmacological accretion of the transcription factor, and phase II antioxidant 'master regulator' Nrf2, has shown to demonstrably mitigate the toxic neuronal effects of parkinsonian agents such as MPP(+), rotenone, and hydrogen peroxide in vitro and in vivo. Furthermore, baseline genetic variability in Nrf2-dependant pathways may promote neuronal susceptibility to exogenous agents and correlate with PD onset within certain populations. While contemporary evidence directly implicating Nrf2 in the pathogenesis of PD is not conclusive and likely contingent upon the evaluation of complex interacting factors-including genetic variation and a history of environmental exposures-it remains a promising target for therapeutic benefit in the modulation of oxidative stress.

Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease

Abstract: Evidence suggests that aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3) gene, protein expression and activity are substantially decreased in the substantia nigra of patients with Parkinson’s disease (PD). This holds especially true for cytosolic ALDH1A1, while mitochondrial ALDH2 is increased in the putamen of PD. Similarly, in Alzheimer’s disease (AD) several studies in genetic, transcriptomic, protein and animal models suggest ALDH involvement in the neurodegeneration processes. Such data are in line with findings of increased toxic aldehydes, like for example malondialdehyde, nonenal, 3,4-dihydroxyphenylacetaldehyde and others. Genetic, transcriptomic and protein alterations may contribute to such data. Also in vitro and in vivo experimental work points to an important role of ALDH in the pathology of neurodegenerative disorders. Aims at investigating dysfunctions of aldehyde detoxification are suitable to define genetic/molecular targets for new therapeutic strategies balancing amine metabolism in devastating disorders like PD and probably also AD.

Multiple system atrophy: pathogenic mechanisms and biomarkers

Abstract: Multiple system atrophy (MSA) is a unique proteinopathy that differs from other α-synucleinopathies since the pathological process resulting from accumulation of aberrant α-synuclein (αSyn) involves the oligodendroglia rather than neurons, although both pathologies affect multiple parts of the brain, spinal cord, autonomic and peripheral nervous system. Both the etiology and pathogenesis of MSA are unknown, although animal models have provided insight into the basic molecular changes of this disorder. Accumulation of aberrant αSyn in oligodendroglial cells and preceded by relocation of p25α protein from myelin to oligodendroglia results in the formation of insoluble glial cytoplasmic inclusions that cause cell dysfunction and demise. These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their complex interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by “prion-like” transfer and its spreading associated with neuronal pathways result in a multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed.

Ventral medial prefrontal cortex (vmPFC) as a target of the dorsolateral prefrontal modulation by transcranial direct current stimulation (tDCS) in drug addiction

Abstract: Here, we report some electrophysiologic and imaging effects of the transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) in drug addiction, notably in alcohol and crack-cocaine dependence. The low resolution electromagnetic tomography (LORETA) analysis obtained through event-related potentials (ERPs) under drug-related cues, more specifically in its P3 segment (300-500 ms) in both, alcoholics and crack-cocaine users, showed that the ventral medial prefrontal cortex (vmPFC) was the brain area with the largest change towards increasing activation under drug-related cues in those subjects that kept abstinence during and after the treatment with bilateral tDCS (2 mA, 35 cm(2), cathodal left and anodal right) over dlPFC, applied repetitively (five daily sessions). In an additional study in crack-cocaine, which showed craving decreases after repetitive bilateral tDCS, we examined data originating from diffusion tensor imaging (DTI), and we found increased DTI parameters in the left connection between vmPFC and nucleus accumbens (NAcc), such as the number of voxels, fractional anisotropy (FA) and apparent diffusion coefficient (ADC), in tDCS-treated crack-cocaine users when compared to the sham-tDCS group. This increasing of DTI parameters was significantly correlated with craving decreasing after the repetitive tDCS. The vmPFC relates to the control of drug seeking, possibly by extinguishing this behavior. In our studies, the bilateral dlPFC tDCS reduced relapses and craving to the drug use, and increased the vmPFC activation under drug cues, which may be of a great importance in the control of drug use in drug addiction.

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond

Abstract: Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.

Hydrogen polysulfide (H2S n ) signaling along with hydrogen sulfide (H2S) and nitric oxide (NO).

Abstract: Hydrogen sulfide (H2S) is a physiological mediator with various roles, including neuro-modulation, vascular tone regulation, and cytoprotection against ischemia-reperfusion injury, angiogenesis, and oxygen sensing. Hydrogen polysulfide (H2S n ), which possesses a higher number of sulfur atoms than H2S, recently emerged as a potential signaling molecule that regulates the activity of ion channels, a tumor suppressor, transcription factors, and protein kinases. Some of the previously reported effects of H2S are now attributed to the more potent H2S n . H2S n is produced by 3-mercaptopyruvate sulfurtransferase (3MST) from 3-mercaptopyruvate (3MP) and is generated by the chemical interaction of H2S with nitric oxide (NO). H2S n sulfhydrates (sulfurates) cysteine residues of target proteins and modifies their activity, whereas H2S sulfurates oxidized cysteine residues as well as reduces cysteine disulfide bonds. This review focuses on the recent progress made in studies concerning the production and physiological roles of H2S n and H2S.

Effects of dopaminergic replacement therapy on motor speech disorders in Parkinson's disease: longitudinal follow-up study on previously untreated patients.

Abstract: Although speech disorders represent an early and common manifestation of Parkinson's disease (PD), little is known about their progression and relationship to dopaminergic replacement therapy. The aim of the current study was to examine longitudinal motor speech changes after the initiation of pharmacotherapy in PD. Fifteen newly-diagnosed, untreated PD patients and ten healthy controls of comparable age were investigated. PD patients were tested before the introduction of antiparkinsonian therapy and then twice within the following 6 years. Quantitative acoustic analyses of seven key speech dimensions of hypokinetic dysarthria were performed. At baseline, PD patients showed significantly altered speech including imprecise consonants, monopitch, inappropriate silences, decreased quality of voice, slow alternating motion rates, imprecise vowels and monoloudness. At follow-up assessment, preservation or slight improvement of speech performance was objectively observed in two-thirds of PD patients within the first 3-6 years of dopaminergic treatment, primarily associated with the improvement of stop consonant articulation. The extent of speech improvement correlated with L-dopa equivalent dose (r = 0.66, p = 0.008) as well as with reduction in principal motor manifestations based on the Unified Parkinson's Disease Rating Scale (r = -0.61, p = 0.02), particularly reflecting treatment-related changes in bradykinesia but not in rigidity, tremor, or axial motor manifestations. While speech disorders are frequently present in drug-naive PD patients, they tend to improve or remain relatively stable after the initiation of dopaminergic treatment and appear to be related to the dopaminergic responsiveness of bradykinesia.

Prevalence of small intestinal bacterial overgrowth in Chinese patients with Parkinson's disease.

Abstract: Parkinson's disease (PD) is associated with gastrointestinal motility abnormalities that could favor the occurrence of small intestinal bacterial overgrowth (SIBO). The aim of the study was to assess the prevalence of SIBO in Chinese patients with PD and the potential impact of SIBO on gastrointestinal symptoms and motor function. 182 consecutive Chinese patients with PD patients and 200 sex, age, and BMI-matched subjects without PD were included. All participants underwent the glucose breath test to assess SIBO. We examined the associations between factors and SIBO with logistic regression using SPSS. Fifty-five of the 182 PD patients were SIBO positive (30.2 %; 95 % CI 23.5-36.9 %) compared with 19 of 200 in the control group (9.5 %; 95 % CI 5.4-13.6 %); the difference was statistically significant (P < 0.0001; OR 4.13; 95 % CI 2.34-7.29). Motor fluctuations present was higher in the PD patients with SIBO than in the patients without SIBO (70.9 vs. 45.7 %; P = 0.002). Multivariate analysis showed that disease duration, Hoehn and Yahr stage, Unified PD Rating-III score, Unified PD Rating-IV score, and Non-Motor Symptoms Scale score were the factors associated with the SIBO-positive status in PD patients. SIBO was highly prevalent in PD, and nearly one-third was detected. SIBO was associated with worse gastrointestinal symptoms and worse motor function. Further studies are needed to specify the reasons underlying SIBO and worse motor function in PD.

The effect of the interval-between-sessions on prefrontal transcranial direct current stimulation (tDCS) on cognitive outcomes: a systematic review and meta-analysis

Abstract: Recently, there has been wide interest in the effects of transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) on cognitive functioning. However, many methodological questions remain unanswered. One of them is whether the time interval between active and sham-controlled stimulation sessions, i.e. the interval between sessions (IBS), influences DLPFC tDCS effects on cognitive functioning. Therefore, a systematic review and meta-analysis was performed of experimental studies published in PubMed, Science Direct, and other databases from the first data available to February 2016. Single session sham-controlled within-subject studies reporting the effects of tDCS of the DLPFC on cognitive functioning in healthy controls and neuropsychiatric patients were included. Cognitive tasks were categorized in tasks assessing memory, attention, and executive functioning. Evaluation of 188 trials showed that anodal vs. sham tDCS significantly decreased response times and increased accuracy, and specifically for the executive functioning tasks, in a sample of healthy participants and neuropsychiatric patients (although a slightly different pattern of improvement was found in analyses for both samples separately). The effects of cathodal vs. sham tDCS (45 trials), on the other hand, were not significant. IBS ranged from less than 1 h to up to 1 week (i.e. cathodal tDCS) or 2 weeks (i.e. anodal tDCS). This IBS length had no influence on the estimated effect size when performing a meta-regression of IBS on reaction time and accuracy outcomes in all three cognitive categories, both for anodal and cathodal stimulation. Practical recommendations and limitations of the study are further discussed.

A systematic review of the effects of low-frequency repetitive transcranial magnetic stimulation on cognition.

Abstract: rTMS is increasingly used for a variety of neuropsychiatric conditions. There are data to support ‘fast’ rTMS (≥10 Hz) having some positive effects on cognitive functioning, but a dearth of research looking at any such effects of ‘slow’ rTMS. This question is important as cognitive dysfunction accompanies many neuropsychiatric conditions and neuromodulation that potentially enhances or hinders such functioning has important clinical consequences. To determine cognitive effects of slow (≤1 Hz) rTMS, a systematic review of randomized control trials assayed cognition in neurological, psychiatric, and healthy volunteer ≤1 Hz rTMS paradigms. Both active (fast rTMS) and placebo comparators were included. 497 Records were initially obtained; 20 met inclusion criteria for evaluation. Four major categories emerged: mood disorders; psychotic disorders; cerebrovascular accidents; and ‘other’ (PTSD, OCD, epilepsy, anxiety, and tinnitus). Cognitive effects were measured across several domains: attention, executive functioning, learning, and psychomotor speed. Variability of study paradigms and reporting precluded meta-analytical analysis. No statistically significant improvement or deterioration was consistently found in any cognitive domain or illness category. These data support the overall safety of rTMS in not adversely affecting cognitive functioning. There are some data indicating that rTMS might have cognitive enhancing potential, but these are too limited at this time to make any firm conclusions, and the literature is marked by considerable heterogeneity in study parameters that hinder interpretation. Greater consensus is required in future studies in cognitive markers, and particularly in reporting of protocols. Future work should evaluate the effects of rTMS on cognitive training.

Long-term treatment of chronic migraine with OnabotulinumtoxinA: efficacy, quality of life and tolerability in a real-life setting

Abstract: Botulinum toxin was shown to be effective in treatment of chronic migraine. We wanted to explore its efficacy and tolerability in chronic application under real-life conditions. For this, 27 consecutive patients (age 45.6 ± 10.8 years, 25 females, 2 males) received altogether 176 injection series (IS) with 189.7 ± 45.8MU onabotulinumtoxinA (Botox(®)) according to the PREEMPT scheme. During the study period altogether 6.5 ± 2.9 (min 4, max 13) IS were applied per patient (total treatment time of 73.1 ± 36.9 weeks). 96 % of the patients reported benefit. Monthly headache days were reduced from 18.9 ± 3.9 to 8.7 ± 4.5 (p < 0.001, -53.7 %), migraine days from 16.8 ± 4.9 to 7.4 ± 4.6 (p < 0.001, -55.1 %), autonomic days from 8.6 ± 7.5 to 2.7 ± 4.2 (p < 0.001, -71.9 %) and medication days from 14.2 ± 4.6 to 8.3 ± 4.2 (p < 0.001, -71.1 %). Health-related quality of life improved by 0.6-1.5 standard deviations (SD) (Short Form Health Survey), migraine-related quality of life by 1.4-2.0 SD (Migraine-Specific Quality of Life Questionnaire) and by 1.9 SD (Headache Impact Test), depression by 1.1 SD (Beck Depression Inventory). Subjective global clinical improvement was 2.6 ± 0.6 (Global Clinical Improvement Scale). All improvements were stable throughout the entire study period. Adverse effects were infrequent, mild and transient. Botulinum toxin provides highly effective and safe long-term treatment of chronic migraine.

Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) performance in progressive supranuclear palsy and multiple system atrophy

Abstract: To determine if Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting cognitive abnormalities in patients with probable progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) compared with Parkinson's disease (PD). In this multicenter observational study, MMSE and MoCA were administered in a random order to 130 patients: 35 MSA, 30 PSP and 65 age, and education and gender matched-PD. We assessed between-group differences for MMSE, MoCA, and their subitems. Receiver-operating characteristic (ROC) curves were calculated. The mean MMSE was higher than the mean MoCA score in each MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p < 0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p < 0.0001), and PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p < 0.0001). MoCA total score as well as its letter fluency subitem differentiated PSP from MSA and PD with high specificity and moderate sensitivity. More specifically, a cut-off score of 7 F-words or less per minute would support a diagnosis of PSP (PSP vs. PD: 86 % specificity, 70 % sensitivity; PSP vs. MSA: 71 % specificity, 70 % sensitivity). By contrast, MMSE presented an overall ceiling effect for most subitems, except for the pentagon scores, where PSP did less well than MSA or PD patients. These preliminary results suggest that PSP and MSA, similar to PD patients, may present normal MMSE and reduced MoCA performance. Overall, MoCA is more sensitive than MMSE in detecting cognitive impairment in atypical parkinsonism and together with verbal fluency would be a useful test to support PSP diagnosis.

Heart rate variability in patients with post-traumatic stress disorder or borderline personality disorder: relationship to early life maltreatment

Abstract: Traumatic experiences have severe impact on the autonomous nervous system. Heart rate variability (HRV) is a reliable psychophysiological marker for the autonomous nervous system functioning. Reduced vagally mediated HRV has been found in patients with post-traumatic stress disorder (PTSD) and, in some studies, in patients with borderline personality disorder (BPD). In this study, we compared HRV parameters of patients with PTSD, current BPD, and BPD in remission with healthy volunteers in a 5 min resting-state electrocardiogram recording. 91 unmedicated female participants took part in the study (18 with PTSD, 27 with the current BPD, 23 with BPD in remission, and 23 healthy volunteers). We found significant group differences in both time-domain and frequency-domain (total power, low-frequency and high-frequency power) HRV parameters. Root mean square of the successive differences (RMSSD) was lowest in patients with PTSD (M = 48.6 ms, SD = 23.5 ms) followed by patients with BPD in remission (M = 57.7 ms, SD = 31.5 ms) and patients with the current BPD (M = 71.1 ms, SD = 44.5 ms), while the highest RMSSD was found in healthy volunteers (M = 84.1 ms, SD = 41.7 ms). Variance of HRV was higher in patients with BPD than in patients with PTSD. In addition, RMSSD was significantly negatively correlated with self-reported early life maltreatment assessed with the Childhood Trauma Questionnaire. Our findings point out a complex interaction between traumatic experiences, the functioning of the autonomic nervous system, and psychopathology. Alterations in HRV might be related to early life maltreatment or associated psychological factors rather than diagnostic entities.

Influence of 5-HTT variation, childhood trauma and self-efficacy on anxiety traits: a gene-environment-coping interaction study.

Abstract: Environmental vulnerability factors such as adverse childhood experiences in interaction with genetic risk variants, e.g., the serotonin transporter gene linked polymorphic region (5-HTTLPR), are assumed to play a role in the development of anxiety and affective disorders. However, positive influences such as general self-efficacy (GSE) may exert a compensatory effect on genetic disposition, environmental adversity, and anxiety traits. We, thus, assessed childhood trauma (Childhood Trauma Questionnaire, CTQ) and GSE in 678 adults genotyped for 5-HTTLPR/rs25531 and their interaction on agoraphobic cognitions (Agoraphobic Cognitions Questionnaire, ACQ), social anxiety (Liebowitz Social Anxiety Scale, LSAS), and trait anxiety (State-Trait Anxiety Inventory, STAI-T). The relationship between anxiety traits and childhood trauma was moderated by self-efficacy in 5-HTTLPR/rs25531 LALA genotype carriers: LALA probands maltreated as children showed high anxiety scores when self-efficacy was low, but low anxiety scores in the presence of high self-efficacy despite childhood maltreatment. Our results extend previous findings regarding anxiety-related traits showing an interactive relationship between 5-HTT genotype and adverse childhood experiences by suggesting coping-related measures to function as an additional dimension buffering the effects of a gene-environment risk constellation. Given that anxiety disorders manifest already early in childhood, this insight could contribute to the improvement of psychotherapeutic interventions by including measures strengthening self-efficacy and inform early targeted preventive interventions in at-risk populations, particularly within the crucial time window of childhood and adolescence.

The transgenerational transmission of childhood adversity: behavioral, cellular, and epigenetic correlates.

Abstract: The view that the functional maturation of the brain is the result of an environmentally driven adaptation of genetically preprogrammed neuronal networks is an important current concept in developmental neuroscience and psychology. This hypothesis proposes that early traumatic experiences or early life stress (ELS) as a negative environmental experience provide a major risk factor for the development of dysfunctional brain circuits and as a consequence for the emergence of behavioral dysfunctions and mental disorders in later life periods. This view is supported by an increasing number of clinical as well as experimental animal studies revealing that early life traumas can induce functional ‘scars’ in the brain, especially in brain circuits, which are essential for emotional control, learning, and memory functions. Such gene × environment interactions are modulated by specific epigenetic mechanisms, which are suggested to be the key factors of transgenerational epigenetic inheritance. Indeed, there is increasing evidence for inter- and transgenerational cycles of environmentally driven neuronal and behavioral adaptations mediated by epigenetic mechanisms. Finally, recent concepts postulate that, dependent on type, time point, and duration of ELS exposure, also positive functional adaptations may occur in the relevant brain pathways, leading to better stress coping and resilience against adversities later in life.

The contribution of white matter lesions to Parkinson's disease motor and gait symptoms: a critical review of the literature.

Abstract: White matter lesions (WML) associated with cerebrovascular disease (CVD) may be observed on magnetic resonance imaging in Parkinson's disease (PD) patients. WML are an important factor contributing to postural, gait, and cognitive impairment in the elderly without PD and worsening the course of Alzheimer's disease (AD). Numerous articles are available on this topic. Whether WML modify and negatively influence the clinical symptoms, and course of PD is a subject of debate. The aim of this review is to examine the available literature on the contribution of WML to PD motor symptoms in relation to clinical characteristics and methods of assessing WML on MRI. After reviewing the database, we identified 19 studies reporting the relationship between WML and PD; ten studies focusing on the impact of WML on the cognitive status in PD were excluded. We analysed altogether nine studies reporting the relationship between WML and motor signs of PD. The review found association between WML severity and freezing of gait, less significant to responsiveness to dopaminergic treatment and postural instability; no negative impact on tremor and falls was observed. The impact of WML on bradykinesia and rigidity was inconsistent. Comorbid WML is associated with worsening axial motor performance, probably independently from the degree of nigrostriatal dopaminergic denervation in PD. Reducing the vascular risk factors that cause WML may be helpful in preventing the development of axial symptoms and ultimately in improving the quality of life of patients with PD. Given the lack of systematic studies, additional research in this field is needed.

Increased neurogranin concentrations in cerebrospinal fluid of Alzheimer’s disease and in mild cognitive impairment due to AD

Abstract: Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer’s disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an “AD-like” CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies.

Structural and functional considerations of the cholinergic brainstem

Abstract: Cholinergic neurons of the brainstem have traditionally been associated with a role in wakefulness as part of the reticular activating system, but their function cannot be explained solely on the basis of their modulation of the brain state. Recent findings about their connectivity and functional heterogeneity suggest a wider role in behavior, where basal ganglia is at the center of their influence. This review focuses on recent findings that suggest an intrinsic functional organization of the cholinergic brainstem that is closely correlated with its connectivity with midbrain and forebrain circuits. Furthermore, recent evidence on the temporal structure of the activation of brainstem cholinergic neurons reveals fundamental aspects about the nature of cholinergic signaling. Consideration of the cholinergic brainstem complex in the context of wider brain circuits is critical to understand its contribution to normal behavior.

Transcranial direct current stimulation of the prefrontal cortex reduces cue-reactivity in alcohol-dependent patients.

Abstract: Alcohol craving has been shown to be an important factor for relapses in alcohol-dependent patients. Furthermore, brain activity in reward-related areas in response to alcohol-related cues is positively related to the amount of post-relapse alcohol consumption. On the other hand, it has been shown that cue-exposure based extinction training (CET) leads to larger decrease of striatal and left dorsolateral prefrontal cortex (dLPFC) cue-induced activation compared to standard clinical day-care treatment, but the effect sizes are relatively small. The question of this study was, whether it is possible to change cue-reactivity and subjective craving by applying bilateral prefrontal transcranial direct current stimulation (tDCS). We stimulated 30 detoxified alcohol-dependent patients (50 % with a sham and 50 % with left cathodal/right anodal stimulation) and presented emotional as well as alcohol-related pictures. We measured the emotional startle modulation and found significantly increased startle amplitudes in the verum stimulation condition for alcohol-related cues, indicating a more negative processing of this cues in alcohol-dependent patients after verum tDCS stimulation. Additionally we found tendencies for stronger reduction in subjective craving in verum-stimulated patients. Therefore our study underscores the positive value of DCS in reducing craving and might help to improve the understanding and therapy of alcohol dependence.

Botulinum toxin drugs: brief history and outlook.

Abstract: The global botulinum toxin (BT) market is currently undergoing rapid changes: this may be the time to review the history and the future of BT drug development. Since the early 1990s Botox(®) and Dysport(®) dominated the international BT market. Later, Myobloc(®)/NeuroBloc(®), a liquid BT type B drug, came out, but failed. Xeomin(®) is the latest major BT drug. It features removal of complexing proteins and improved neurotoxin purity. Several new BT drugs are coming out of Korea, China and Russia. Scientific challenges for BT drug development include modification of BT's duration of action, its transdermal transport and the design of BT hybrid drugs for specific target tissues. The increased competition will change the global BT market fundamentally and a re-organisation according to large indication groups, such as therapeutic and cosmetic applications, might occur.