Neuroimaging in Functional Movement Disorders.

PURPOSE OF REVIEW: Functional movement disorders are common and disabling causes of abnormal movement control. Here, we review the current state of the evidence on the use of neuroimaging in Functional movement disorders, particularly its role in helping to unravel the pathophysiology of this enigmatic condition. RECENT FINDINGS: In recent years, there has been a shift in thinking about functional movement disorder, away from a focus on high-level psychological precipitants as in Freudian conversion theories, or even an implicit belief they are 'put-on' for secondary gain. New research has emphasised novel neurobiological models incorporating emotional processing, self-representation and agency. Neuroimaging has provided new insights into functional movement disorders, supporting emerging neurobiological theories implicating dysfunctional emotional processing, self-image and sense of agency. Recent studies have also found subtle structural brain changes in patients with functional disorders, arguing against a strict functional/structural dichotomy

Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells.

Neurons and endocrine cells have two types of secretory vesicle that undergo regulated exocytosis. Large dense core vesicles (LDCVs) store neural peptides whereas small clear synaptic vesicles store classical neurotransmitters such as acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate. However, monoamines differ from other classical transmitters and have been reported to appear in both LDCVs and smaller vesicles. To localize the transporter that packages monoamines into secretory vesicles, we have raised antibodies to a COOH-terminal sequence from the vesicular amine transporter expressed in the adrenal gland (VMAT1). Like synaptic vesicle proteins, the transporter occurs in endosomes of transfected CHO cells, accounting for the observed vesicular transport activity. In rat pheochromocytoma PC12 cells, the transporter occurs principally in LDCVs by both immunofluorescence and density gradient centrifugation. Synaptic-like microvesicles in PC12 cells contain relatively little VMAT1. The results appear to account for the storage of monoamines by LDCVs in the adrenal medulla and indicate that VMAT1 provides a novel membrane protein marker unique to LDCVs

Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection

We describe a method for the determination of the two major urinary metabolites of vitamin K as the methyl esters of their agyclone structures, 2-methyl-3-(3-3-carboxymethylpropyl)-1,4-naphthoquinone (5C-side-chain metabolite) and 2-methyl-3-(5-carboxy-3-methyl-2-pentenyl)-1,4-naphthoquinone (7C-side-chain metabolite), by HPLC with electrochemical detection (ECD) in the redox mode. Urinary salts were removed by reversed-phase (C18) solid phase extraction (SPE) and the predominately conjugated vitamin K metabolites hydrolysed with methanolic HCl. The resultant carboxylic acid aglycones were quantitatively methylated with diazomethane and fractionated by normal-phase (silica) SPE. Final analysis was by reversed-phase (C18) HPLC with a methanol-aqueous mobile phase. Metabolites were detected by amperometric, oxidative ECD of their quinol forms, which were generated by post-column coulometric reduction at an upstream electrode. The assay gave excellent linearity (r2 typically = 0.999) and high sensitivity with an on-column detection limit of <3.5 fmol (<1pg). The inter-assay precision was typically 10%. Metabolite recovery was compared to that of an internal standard (2-methyl-3-(7'-carboxy-heptyl)-1,4-naphthoquinone), added to urine samples just before analysis. Using this methodology we confirmed that the 5C- and 7C-metabolite were major catabolites of both phylloquinone (vitamin K1) and menaquinones (vitamin K2) in humans. We propose that the measurement of urinary vitamin K metabolite excretion is a candidate non-invasive marker of total vitamin K status

Limb amputations in fixed dystonia: a form of body integrity identity disorder?

Fixed dystonia is a disabling disorder mainly affecting young women who develop fixed abnormal limb postures and pain after apparently minor peripheral injury. There is continued debate regarding its pathophysiology and management. We report 5 cases of fixed dystonia in patients who sought amputation of the affected limb. We place these cases in the context of previous reports of patients with healthy limbs and patients with chronic regional pain syndrome who have sought amputation. Our cases, combined with recent data regarding disorders of mental rotation in patients with fixed dystonia, as well as previous data regarding body integrity identity disorder and amputations sought by patients with chronic regional pain syndrome, raise the possibility that patients with fixed dystonia might have a deficit in body schema that predisposes them to developing fixed dystonia and drives some to seek amputation. The outcome of amputation in fixed dystonia is invariably unfavorable

Redox linked flavin sites in extracellular decaheme proteins involved in microbe-mineral electron transfer

Extracellular microbe-mineral electron transfer is a major driving force for the oxidation of organic carbon in many subsurface environments. Extracellular multi-heme cytochromes of the Shewenella genus play a major role in this process but the mechanism of electron exchange at the interface between cytochrome and acceptor is widely debated. The 1.8 Å x-ray crystal structure of the decaheme MtrC revealed a highly conserved CX8C disulfide that, when substituted for AX8A, severely compromised the ability of S. oneidensis to grow under aerobic conditions. Reductive cleavage of the disulfide in the presence of flavin mononucleotide (FMN) resulted in the reversible formation of a stable flavocytochrome. Similar results were also observed with other decaheme cytochromes, OmcA, MtrF and UndA. The data suggest that these decaheme cytochromes can transition between highly reactive flavocytochromes or less reactive cytochromes, and that this transition is controlled by a redox active disulfide that responds to the presence of oxygen

A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review.

BACKGROUND: Functional cognitive disorder (FCD) describes cognitive dysfunction in the absence of an organic cause. It is increasingly prevalent in healthcare settings yet its key neuropsychological features have not been reported in large patient cohorts. We hypothesised that cognitive profiles in fibromyalgia (FM), chronic fatigue syndrome (CFS) and functional neurological disorders (FNDs) would provide a template for characterising FCD. METHODS: We conducted a systematic review of studies with cognition-related outcomes in FM, CFS and FND. RESULTS: We selected 52 studies on FM, 95 on CFS and 39 on FND. We found a general discordance between high rates of subjective cognitive symptoms, including forgetfulness, distractibility and word-finding difficulties, and inconsistent objective neuropsychological deficits. Objective deficits were reported, including poor selective and divided attention, slow information processing and vulnerability to distraction. In some studies, cognitive performance was inversely correlated with pain, exertion and fatigue. Performance validity testing demonstrated poor effort in only a minority of subjects, and patients with CFS showed a heightened perception of effort. DISCUSSION: The cognitive profiles of FM, CFS and non-cognitive FND are similar to the proposed features of FCD, suggesting common mechanistic underpinnings. Similar findings have been reported in patients with mild traumatic brain injury and whiplash. We hypothesise that pain, fatigue and excessive interoceptive monitoring produce a decrease in externally directed attention. This increases susceptibility to distraction and slows information processing, interfering with cognitive function, in particular multitasking. Routine cognitive processes are experienced as unduly effortful. This may reflect a switch from an automatic to a less efficient controlled or explicit cognitive mode, a mechanism that has also been proposed for impaired motor control in FND. These experiences might then be overinterpreted due to memory perfectionism and heightened self-monitoring of cognitive performance

Management of functional neurological disorder.

Functional neurological disorder (FND) is a common cause of persistent and disabling neurological symptoms. These symptoms are varied and include abnormal control of movement, episodes of altered awareness resembling epileptic seizures and abnormal sensation and are often comorbid with chronic pain, fatigue and cognitive symptoms. There is increasing evidence for the role of neurologists in both the assessment and management of FND. The aim of this review is to discuss strategies for the management of FND by focusing on the diagnostic discussion and general principles, as well as specific treatment strategies for various FND symptoms, highlighting the role of the neurologist and proposing a structure for an interdisciplinary FND service

Acting without being in control: Exploring volition in Parkinson's disease with impulsive compulsive behaviours.

BACKGROUND: Several aspects of volitional control of action may be relevant in the pathophysiology of impulsive-compulsive behaviours (ICB) in Parkinson's disease (PD). We aimed to explore multiple aspects of action control, assessing reward-related behaviour, inhibition (externally and internally triggered) and sense of agency in PD patients, with and without ICB compared to healthy subjects. METHODS: Nineteen PD patients with ICB (PD-ICB), 19 PD without ICB (PD-no-ICB) and 19 healthy controls (HC) underwent a battery of tests including: Intentional Binding task which measures sense of agency; Stop Signal Reaction Time (SSRT) measuring capacity for reactive inhibition; the Marble task, assessing intentional inhibition; Balloon Analog Risk Task for reward sensitivity. RESULTS: One-way ANOVA showed significant main effect of group for action binding (p = 0.004, F = 6.27). Post hoc analysis revealed that PD-ICB had significantly stronger action binding than HC (p = 0.004), and PD-no-ICB (p = 0.04). There was no difference between PD-no-ICB and HC. SSRT did not differ between PD groups, whereas a significant difference between PD-no-ICB and HC was detected (p = 0.01). No other differences were found among groups in the other tasks. CONCLUSIONS: PD patients with ICB have abnormal performance on a psychophysical task assessing sense of agency, which might be related to a deficit in action representation at cognitive/experiential level. Yet, they have no deficit on tasks evaluating externally and internally triggered inhibitory control, or in reward-based decision-making. We conclude that impaired sense of agency may be a factor contributing to ICB in PD patients