Age-related grey matter changes in preterm infants: An MRI study

According to the Reinforcement Sensitivity Theory (RST), Gray’s dimension of impulsivity, reflecting human trait reward sensitivity, determines the extent to which stimuli activate the Behavioural Approach System (BAS). The potential neural underpinnings of the BAS, however, remain poorly understood. In the present study, we examined the association between Gray’s impulsivity as defined by the RST and event-related fMRI BOLD-response to anticipation of reward in twenty healthy human subjects in brain regions previously associated with reward processing. Anticipation of reward during a Monetary Incentive Delay Task elicited activation in key components of the human reward circuitry such as the ventral striatum, the amygdala and the orbitofrontal cortex. Interindividual differences in Gray’s impulsivity accounted for a significant amount of variance of the reward-related BOLD-response in the ventral striatum and the orbitofrontal cortex. Specifically, higher trait reward sensitivity was associated with increased activation in response to cues indicating potential reward. Extending previous evidence, here we show that variance in functional brain activation during anticipation of reward is attributed to interindividual differences regarding Gray’s dimension of impulsivity. Thus, trait reward sensitivity contributes to the modulation of responsiveness in major components of the human reward system which thereby display a core property of the BAS. Generally, fostering our understanding of the neural underpinnings of the association of reward-related interindividual differences in affective traits might aid researchers in quest for custom-tailored treatments of psychiatric disorders, further disentangling the complex relationship between personality traits, emotion, and health.     

Selective impairment of prediction error signaling in human dorsolateral but not ventral striatum in Parkinson's disease patients: evidence from a model-based fMRI study

Animal studies have found that the phasic activity of dopamine neurons during reward-related learning resembles a “prediction error” (PE) signal derived from a class of computational models called reinforcement learning (RL). An apparently similar signal can be measured using fMRI in the human striatum, a primary dopaminergic target. However, the fMRI signal does not measure dopamine per se, and therefore further evidence is needed to determine if these signals are related to each other. Parkinson's disease (PD) involves the neurodegeneration of the dopamine system and is accompanied by deficits in reward-related decision-making tasks. In the current study we used a computational RL model to assess striatal error signals in PD patients performing an RL task during fMRI scanning. Results show that error signals were preserved in ventral striatum of PD patients, but impaired in dorsolateral striatum, relative to healthy controls, a pattern reflecting the known selective anatomical degeneration of dopamine nuclei in PD. These findings support the notion that PE signals measured in the human striatum by the BOLD signal may reflect phasic DA activity. These results also provide evidence for a deficiency in PE signaling in the dorsolateral striatum of PD patients that may offer an explanation for their deficits observed in other reward learning tasks.     

The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics

PurposeEmerging work indicates divergence in the neurobiologies of binge-eating disorder (BED) and obesity despite their frequent co-occurrence. This review highlights specific distinguishing aspects of BED, including elevated impulsivity and compulsivity possibly involving the mesocorticolimbic dopamine system, and discusses implications for differential therapeutics for BED.MethodsThis narrative review describes epidemiologic, clinical, genetic, and preclinical differences between BED and obesity. Subsequently, this review discusses human neuroimaging work reporting differences in executive functioning, reward processing, and emotion reactivity in BED compared with obesity. Finally, on the basis of the neurobiology of BED, this review identifies existing and new therapeutic agents that may be most promising given their specific targets based on putative mechanisms of action relevant specifically to BED.FindingsBED is characterized by elevated impulsivity and compulsivity compared with obesity, which is reflected in divergent neurobiological characteristics and effective pharmacotherapies. Therapeutic agents that influence both reward and executive function systems may be especially effective for BED.ImplicationsGreater attention to impulsivity/compulsivity-related, reward-related, and emotion reactivity–related processes may enhance conceptualization and treatment approaches for patients with BED. Consideration of these distinguishing characteristics and processes could have implications for more targeted pharmacologic treatment research and interventions.     

Managing the patient with newly diagnosed Parkinson disease

The treatment of early Parkinson disease (PD) is generally symptomatic, although therapy that also offers neuroprotection in early-stage PD would be welcomed. Levodopa remains the most effective agent for relief of PD symptoms, but chronic levodopa therapy is associated with motor fluctuations and dyskinesias, and clinicians may therefore opt to postpone its use. Alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists. MAO-B inhibitors have only mild symptomatic effects. Amantadine is associated with improvement in functional disability and, in a subset of PD patients, a robust symptomatic improvement. Dopamine agonists improve symptoms and may have a neuroprotective effect. Partial dopamine agonists, adenosine A(2A)-receptor antagonists, and safinamide are symptomatic therapies that are under investigation. Neuro protective strategies under study include enhancement of mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation. Deep brain stimulation may slow cognitive and motor decline when used in early PD. Stem cell therapy and gene therapy are still under investigation.     

帕金森病患者血淋巴细胞多巴胺转运蛋白功能与密度的研究

目的：研究帕金森病(PD)患多巴胺转运蛋白(DAT)功能与密度的变化及其在：PD早期诊断中的意义。方法：实验对象分为PD组、正常老年对照组和脑血管病组。用放射性核素方法测定3组患的血淋巴细胞对^3H-多巴胺(DA)和^3H-WIN35428的放射性摄取率。结果：PD组的外周血淋巴细胞对^3H-DA和^3H-WIN35428的放射性摄取率低于脑血管病组和正常老年对照组；左旋多巴治疗的PD患外周血淋巴细胞对^3H-DA的放射性摄取率高于未治疗的PD患．对^3H-WIN35428的放射性摄取率两差异无显性。DA受体激动剂治疗的：PD患外周血淋巴细胞对^3H-DA和^3H-WIN35428的放射性摄取率均无影响。结论：PD患血淋巴细胞DAT的功能与密度明显降低，有可能作为疾病早期诊断的生物学指标。左旋多巴治疗对DAT的功能有促进作用但对其密度无影响；DA受体激动剂对DAT的功能和密度均无影响。     

Gastrocnemius inflexibility on foot progression angle and ankle kinetics during walking

Background

Gastrocnemius inflexibility is a major problem in many orthopedic and neurological patients. Clinically, inflexible gastrocnemius muscles interfere with the performance of functional abilities and associate with many overuse injuries of the lower extremity. The purpose of this study was to investigate the effects of the gastrocnemius inflexibility on the foot progression angle and ankle kinetics during walking.

Methods

There were 50 subjects, 23 patients with the inflexible gastrocnemius and 27 normal subjects, included in this investigation. Participants were asked to walk at two preset cadences of 100 steps/min and 140 steps/min. Data were collected from a motion analysis system and force plates. Kinematic and kinetic variables of gait were computed and analyzed.

Findings

Compared with the control group, greater toe-out foot progression angle (P = 0.001, effect size = 0.314) and knee external rotation (P = 0.008, effect size = 0.136) were found in the inflexible group during stance phase. Furthermore, significant greater plantarflexion moment (P = 0.032, effect size = 0.093) and medial ground reaction force (P = 0.009, effect size = 0.135) during midstance were discovered in the inflexible group.

Interpretation

The present results indicate that gastrocnemius inflexibility might bring about the changes in the joint angles, ankle moments and ground reaction forces. The abnormal joint alignment in the lower extremities and greater force upon joint tissue might be significant for the clinical considerations on soft tissue injuries for the patients with inflexible gastrocnemius muscles.     

New Pharmacological Options for Treating Advanced Parkinson’s Disease

Background

Parkinson’s disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today’s randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD.

Objective

To systematically review a number of putative pharmacological options for treating the main impairments in late-stage PD (ie gait disorders, cognitive disorders and behavioural disorders such as apathy).

Methods

We searched the PubMed database up until July 2013 with logical combinations of the following search terms: “Parkinson’s disease”, “gait”, “cognition”, “apathy”, “advanced stage”, “modulation”, “noradrenergic”, “cholinergic”, “glutamatergic” and “neurotransmission”.

Results

In patients undergoing subthalamic nucleus stimulation, the potentiation of noradrenergic and dopaminergic transmission by methylphenidate improves gait and FoG and may relieve apathy. However, the drug failed to improve cognition in this population. Potentiation of the cholinergic system by acetylcholinesterase inhibitors (which are licensed for use in dementia) may reduce pre-dementia apathy and falls. Modulation of the glutamatergic system by an N-methyl-D-aspartate receptor antagonist did not improve gait and dementia but may have reduced axial rigidity. A number of putative DMTs have been reported.

Discussion

Novel therapeutic strategies should seek to reduce the appearance of the very disabling disorders observed in late-stage PD. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, Peroxisome-proliferator-activated-receptor-agonists and iron chelators should at least be investigated as putative DMTs by applying a delayed-start clinical trial paradigm to a large population

Conclusions

There is a need for more randomized clinical trials of treatments for late-stage PD.     

Dopamine agonists

Dopamine agonists have been used in the treatment of Parkinson's disease (PD) since the mid 1970s. With the approval of two new agents in 1997, the number available in the United States is up to four; bromocriptine, pergolide, pramipexole, ropinirole. These agents differ in dopamine receptor affinities and chemical structure, which, in turn, may possibly result in differences in efficacy tolerability and safety. Dopamine have historically been used in combination with levodopa in patients with advanced PD, but indicators are now expanding. With is expansion comes increasing controversy. This article reviews dopamine receptor pharmacology and the results of the clinical trials that have used for agonists available in the United States as well as a discussion of three minor agonists.     

Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.     

White matter hyperintensities do not impact cognitive function in patients with newly diagnosed Parkinson's disease

The objective of this study was to investigate total volume and spatial distribution of white matter hyperintensities (WMH) in a large sample of newly diagnosed Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to normal controls (NC). Furthermore, we aimed to examine the impact of the WMH on attention–executive performance in PD. MCI is regarded as a pre-dementia stage. Studies on MCI have found WMH associated with reduced cognitive function, especially in the attention and executive domains. The present study included 163 incident, drug-naïve PD patients (66.2 ± 9.1 years and disease duration 27.1 ± 19.8 months) and 102 age-matched NC (65.7 ± 9.4 years). Thirty (30) subjects in the PD sample presented MCI, whereas 133 did not. MCI was classified based on tests for memory, attention–executive and visuospatial function compared to the NC group, taking age, sex and education into consideration. WMH were outlined on FLAIR scans using a semi-automated technique. Total WMH volumes were compared between the 3 study groups, and spatial distribution of normalized WMH masks in each group were compared using voxel-wise probability maps. Regression analysis examined the possible impact of WMH on attention–executive scores in the PD group. Analysis showed that there were no significant differences between the 3 groups in total volume or spatial distribution of WMH. In addition there was no significant relationship between total volume or spatial distribution of WMH and attention–executive functions in PD. We conclude that in this PD cohort, cognitive impairment seems to be independent of WMH damage.     

Epigenetic targeting of histone deacetylase: Therapeutic potential in Parkinson's disease?

Parkinson's disease (PD) is the most common movement disorder affecting more than 4 million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD?     

(How) do we learn from errors? A prospective study of the link between the ward's learning practices and medication administration errors

Background

Attention in the ward should shift from preventing medication administration errors to managing them. Nevertheless, little is known in regard with the practices nursing wards apply to learn from medication administration errors as a means of limiting them.

Aims

To test the effectiveness of four types of learning practices, namely, non-integrated, integrated, supervisory and patchy learning practices in limiting medication administration errors.

Methods

Data were collected from a convenient sample of 4 hospitals in Israel by multiple methods (observations and self-report questionnaires) at two time points. The sample included 76 wards (360 nurses). Medication administration error was defined as any deviation from prescribed medication processes and measured by a validated structured observation sheet. Wards’ use of medication administration technologies, location of the medication station, and workload were observed; learning practices and demographics were measured by validated questionnaires.

Findings

Results of the mixed linear model analysis indicated that the use of technology and quiet location of the medication cabinet were significantly associated with reduced medication administration errors (estimate = .03, p < .05 and estimate = −.17, p < .01 correspondently), while workload was significantly linked to inflated medication administration errors (estimate = .04, p < .05). Of the learning practices, supervisory learning was the only practice significantly linked to reduced medication administration errors (estimate = −.04, p < .05). Integrated and patchy learning were significantly linked to higher levels of medication administration errors (estimate = −.03, p < .05 and estimate = −.04, p < .01 correspondently). Non-integrated learning was not associated with it (p > .05).

Conclusions

How wards manage errors might have implications for medication administration errors beyond the effects of typical individual, organizational and technology risk factors. Head nurse can facilitate learning from errors by “management by walking around” and monitoring nurses’ medication administration behaviors.     

心理干预辅助药物治疗帕金森病抑郁与认知障碍

目的:探讨心理干预对帕金森病(PD)抑郁及认知功能障碍的影响.方法:PD患者70例按入院顺序(单双号)分为心理干预组(在常规药物治疗基础上给予心理干预)和常规治疗组(仅给予常规药物治疗),各35例,于入组、治疗1周及2个月时,采用汉密尔顿抑郁量表(HAMD)、抑郁自评量表(SDS)、简易智能精神状态检查量表(MMSE)...     

Hyperalgesia and functional sensory loss in restless legs syndrome

Pain and other sensory signs in patients with restless legs syndrome (RLS) are still poorly understood, as most investigations focus on motor system dysfunctions. This study aimed to investigate somatosensory changes in patients with primary RLS and the restoration of somatosensory function by guideline-based treatment. Forty previously untreated RLS patients were investigated unilaterally over hand and foot using quantitative sensory testing (QST) and were compared with 40 age- and gender-matched healthy subjects. The predominant finding in RLS patients was 3- to 4-fold increase of sensitivity to pinprick stimuli in both extremities (hand: P < .05; foot: P < .001), a sensory pathway involved in withdrawal reflexes. Pinprick hyperalgesia was not paralleled by dynamic mechanical allodynia. Additional significant sensory changes were tactile hypoesthesia in both extremities (hand: P < .05; foot P < .01) and dysesthesia to non-noxious cold stimuli (paradoxical heat sensation), which was present in the foot in an unusually high proportion (14 of 40 patients; P < .01). In 8 patients, follow-up QST 2 to 20 months after treatment with l-DOPA (L-3,4-dihydroxyphenylalanine) revealed a significant reduction of pinprick hyperalgesia (−60%, P < .001), improved tactile detection (+50%, P < .05), and disappearance of paradoxical heat sensation in half of the patients. QST suggested a type of spinal or supraspinal central sensitization differing from neuropathic pain or human experimental models of central sensitization by the absence of dynamic mechanical allodynia. Reversal of pinprick hyperalgesia by l-DOPA may be explained by impaired descending inhibitory dopaminergic control on spinal nociceptive neurons. Restoration of tactile sensitivity and paradoxical heat sensations suggest that they were functional disturbances resulting from central disinhibition.     

Internet sex addiction treated with naltrexone

Malfunctioning of the brain's reward center is increasingly understood to underlie all addictive behavior. Composed of mesolimbic incentive salience circuitry, the reward center governs all behavior in which motivation has a central role, including acquiring food, nurturing young, and having sex. To the detriment of normal functioning, basic survival activities can pale in importance when challenged by the allure of addictive substances or behaviors. Dopamine is the neurotransmitter driving both normal and addictive behavior. Other neurotransmitters modulate the amount of dopamine released in response to a stimulus, with the salience determined by the intensity of the dopamine pulse. Opiates (either endogenous or exogenous) exemplify such modulators. Prescribed for treating alcoholism, naltrexone blocks opiates' capacity to augment dopamine release. This article reviews naltrexone's mechanism of action in the reward center and describes a novel use for naltrexone in suppressing a euphorically compulsive and interpersonally devastating addiction to Internet pornography.     

Craving love? Enduring grief activates brain's reward center

Complicated Grief (CG) occurs when an individual experiences prolonged, unabated grief. The neural mechanisms distinguishing CG from Noncomplicated Grief (NCG) are unclear, but hypothesized mechanisms include both pain-related activity (related to the social pain of loss) and reward-related activity (related to attachment behavior). Bereaved women (11 CG, 12 NCG) participated in an event-related functional magnetic resonance imaging scan, during grief elicitation with idiographic stimuli. Analyses revealed that whereas both CG and NCG participants showed pain-related neural activity in response to reminders of the deceased, only those with CG showed reward-related activity in the nucleus accumbens (NA). This NA cluster was positively correlated with self-reported yearning, but not with time since death, participant age, or positive/negative affect. This study supports the hypothesis that attachment activates reward pathways. For those with CG, reminders of the deceased still activate neural reward activity, which may interfere with adapting to the loss in the present.     

Neural reward processing is modulated by approach- and avoidance-related personality traits

The neural processing of reward can be differentiated into two sub-components with different functions, “wanting” (i.e., the expectation of a reward which includes appetitive and motivational components) and “liking” (i.e., the hedonic impact experienced during the receipt of a reward), involving distinct neural systems. We hypothesize that variability in neural reward processing previously observed in healthy subjects could reflect inter-individual differences in personality. Therefore, the aim of this study was to investigate how the neural processing during expectation and reception of a reward depends on interpersonal differences in reward sensitivity, more specifically the tendency to approach vs. avoid reward-related situations. We employed event-related functional magnetic resonance imaging during a monetary incentive delay task. Subjects with a high approach motivation showed more activation of the Ventral Striatum (VS) during the receipt of a reward, and more medial orbitofrontal activity during both the receipt and omission of a reward. Subjects with a high behavioral inhibition showed less activation in the VS during the receipt of a reward. These findings indicate that the tendency to approach or avoid reward-related situations exhibits a distinct relation with neural reward processing. Specifically, subjects with high behavioral approach appear to be sensitive mainly to positive outcomes and to a lesser extent to the omissions of rewards, whereas subjects with low behavioral approach as well as those with a high inhibition tendency display a blunted response to rewards.     

Treatment of Parkinson's disease and restless legs syndrome with cabergoline,a long-acting dopamine agonist

Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.