Targeting phosphocreatine metabolism in relapsing-remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing.

BACKGROUND/OBJECTIVES: Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS. METHODS: We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6. RESULTS: No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores. CONCLUSION: Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism.

Altered default-mode network activation in mild cognitive impairment compared with healthy aging.

INTRODUCTION: Rapidly increasing aging of the world's population is causing a heightened prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). The global burden, caused by this, is tremendous. In order to slow down the progression of the disease and preserve quality of life as much as possible, early identification of subjects at risk is indispensable within this framework. METHODS: In the present study, we combined independent component analysis and statistical parametric analysis to identify and compare the default-mode network (DMN) in healthy elderly and patients with MCI, with a special interest for hippocampal and lateral temporal involvement. RESULTS: Functional results indicated reduced cortical activation in the DMN for MCI patients, compared with age- and education-matched healthy elderly controls, mainly in the retrosplenial region/posterior cingulate cortex, left hippocampus, and bilateral inferior and middle frontal areas. Increased activation for patients was observed in the medial prefrontal and bilateral middle temporal/angular cortex. Lateral temporal involvement in the DMN was in both the elderly control samples, and the patient group detected and suggested a slightly increased activation, more right than left, in middle temporal areas in the MCI patients, compared with healthy elderly. CONCLUSION: Results are discussed with reference to the existing literature on early pathological changes in MCI and AD and subsequent compensation mechanisms in resting state and memory circuits.

The influence of sex, age and heritability on human skeletal muscle carnosine content.

The dipeptide carnosine is found in high concentrations in human skeletal muscle and shows large inter-individual differences. Sex and age are determining factors, however, systematic studies investigating the sex effects on muscle carnosine content throughout the human lifespan are lacking. Despite the large inter-individual variation, the intra-individual variation is limited. The question may be asked whether the carnosine content is a muscle characteristic which may be largely genetically determined. A total of 263 healthy male and female subjects of 9-83 years were divided into five different age groups: prepubertal children (PC), adolescents (A), young adults (YA), middle adults (MA) and elderly (E). We included 25 monozygotic and 22 dizygotic twin pairs among the entire study population to study the heritability. The carnosine content was measured non-invasively in the gastrocnemius medialis and soleus by proton magnetic resonance spectroscopy (1H-MRS). In boys, carnosine content was significantly higher (gastrocnemius 22.9%; soleus 44.6%) in A compared to PC, while it did not differ in girls. A decrease (~16%) was observed both in males and females from YA to MA. However, elderly did not have lower carnosine levels in comparison with MA. Higher correlations were found in monozygotic (r=0.86) compared to dizygotic (r=0.51) twins, in soleus muscle, but not in gastrocnemius. In conclusion, this study found an effect of puberty on muscle carnosine content in males, but not in females. Muscle carnosine decreased mainly during early adulthood and hardly from adulthood to elderly. High intra-twin correlations were observed, but muscle-dependent differences preclude clear conclusions toward heritability.

Mental rotation meets the motion aftereffect: the role of hV5/MT+ in visual mental imagery.

A growing number of studies show that visual mental imagery recruits the same brain areas as visual perception. Although the necessity of hV5/MT+ for motion perception has been revealed by means of TMS, its relevance for motion imagery remains unclear. We induced a direction-selective adaptation in hV5/MT+ by means of an MAE while subjects performed a mental rotation task that elicits imagined motion. We concurrently measured behavioral performance and neural activity with fMRI, enabling us to directly assess the effect of a perturbation of hV5/MT+ on other cortical areas involved in the mental rotation task. The activity in hV5/MT+ increased as more mental rotation was required, and the perturbation of hV5/MT+ affected behavioral performance as well as the neural activity in this area. Moreover, several regions in the posterior parietal cortex were also affected by this perturbation. Our results show that hV5/MT+ is required for imagined visual motion and engages in an interaction with parietal cortex during this cognitive process.

Differentiation between deep and superficial fibers of the lumbar multifidus by magnetic resonance imaging.

The purpose of this study was to investigate the differentiation in muscle tissue characteristics and recruitment between the deep and superficial multifidus muscle by magnetic resonance imaging. The multifidus is a very complex muscle in which a superficial and deep component can be differentiated from an anatomical, biomechanical, histological and neuromotorial point of view. To date, the histological evidence is limited to low back pain patients undergoing surgery and cadavers. The multifidus muscles of 15 healthy subjects were investigated with muscle functional MRI. Images were taken under three different conditions: (1) rest, (2) activity without pain and (3) activity after experimentally induced low back muscle pain. The T2 relaxation time in rest and the shift in T2 relaxation time after activity were compared for the deep and superficial samples of the multifidus. At rest, the T2 relaxation time of the deep portion was significantly higher compared to the superficial portion. Following exercise, there was no significant difference in shift in T2 relaxation time between the deep and superficial portions, and in the pain or in the non-pain condition. In conclusion, this study demonstrates a higher T2 relaxation time in the deep portion, which supports the current assumption that the deep multifidus has a higher percentage of slow twitch fibers compared to the superficial multifidus. No differential recruitment has been found following trunk extension with and without pain induction. For further research, it would be interesting to investigate a clinical LBP population, using this non-invasive muscle functional MRI approach.

Hippocampal activation during face-name associative memory encoding: blocked versus permuted design.

INTRODUCTION: The contribution of the hippocampal subregions to episodic memory through the formation of new associations between previously unrelated items such as faces and names is established but remains under discussion. Block design studies in this area of research generally tend to show posterior hippocampal activation during encoding of novel associational material while event-related studies emphasize anterior hippocampal involvement. We used functional magnetic resonance imaging to assess the involvement of anterior and posterior hippocampus in the encoding of novel associational material compared to the viewing of previously seen associational material. METHODS: We used two different experimental designs, a block design and a permuted block design, and applied it to the same associative memory task to perform valid statistical comparisons. RESULTS: Our results indicate that the permuted design was able to capture more anterior hippocampal activation compared to the block design, which emphasized more posterior hippocampal involvement. These differences were further investigated and attributed to a combination of the polymodal stimuli we used and the experimental design. CONCLUSIONS: Activation patterns during encoding in both designs occurred along the entire longitudinal axis of the hippocampus, but with different centers of gravity. The maximal activated voxel in the block design was situated in the posterior half of the hippocampus while in the permuted design this was located in the anterior half.

Changes in lumbar muscle activity because of induced muscle pain evaluated by muscle functional magnetic resonance imaging.

STUDY DESIGN: Experimental study of changes in muscle recruitment during trunk extension exercise at 40% of the repetition maximum, because of induced muscle pain. OBJECTIVE: To investigate the effect of lumbar muscle pain on muscle activity of the trunk muscles using muscle functional magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: Changed muscle recruitment in patients has an important impact on the etiology and recurrence of low back pain. The mechanisms of these changes in muscle activity are still poorly understood. An experimental study investigating the cause-effect relationship of muscle pain on muscle recruitment patterns can help to clarify these mechanisms. METHODS: In 15 healthy subjects, the muscle activity of the lumbar multifidus, lumbar erector spinae, and psoas muscles was investigated with muscle functional magnetic resonance imaging. Measurements at rest and after trunk extension exercise at 40% of repetition maximum were performed without and with induced pain. RESULTS: The lumbar multifidus and lumbar erector spinae were significantly active during the trunk extension exercise, whereas the psoas showed no significant activity. The activity of the lumbar multifidus, lumbar erector spinae, and psoas muscles, was reduced bilaterally and multilevel during the exercise with unilateral low back muscle pain. CONCLUSION: These data demonstrate that unilateral muscle pain can cause hypoactivity of muscles during trunk extension at 40% of the repetition maximum. The changes were not limited to the side and level of pain. Moreover, the inhibition was not limited to the multifidus muscle; also the lumbar erector spinae and psoas muscles showed decreased activity during the pain condition. Further research has to assess possible compensation mechanisms for this reduced activity in other muscles.

Trial pacing in mental rotation tasks.

Functional imaging of mental rotation has revealed a wide variety of cortical activation patterns besides the consensus on parietal involvement. Some insight has been gained on the role of motor cortex, but the differential activation of other brain regions has received little attention. A previous fMRI study using a blocked substraction design [D'Esposito et al., NeuroImage 6 (1997) 113-121] has shown an effect of trial pacing on the observed activation pattern of a simple visuospatial task requiring mental rotation. In this study, we want to assess if trial pacing can help clarify some of the diversity in the observed cortical activation patterns associated with fMRI blocked designs of mental rotation so far, especially when comparing mental rotation of different stimuli. We used two different stimuli, i.e. hands and tools, that have been used in previous mental rotation studies. Our results revealed a bilateral involvement of lateral premotor and parietal cortex irrespective of trial pacing, but there was a marked influence of trial pacing on the observed activation of occipital and other frontal regions. Stimulus type specific activation patterns were entirely limited to the fixed-paced design. We conclude that trial pacing is a vital aspect when developing and interpreting the related imaging results of a blocked subtraction design. Fixed-paced designs may be more sensitive for duration effects. A self-paced trial schedule may be more appropriate to isolate the neural substrate of the cognitive component of interest or to exclude response time differences as a confounding factor.

In vivo characterization of 123/125I-2-iodo-L-phenylalanine in an R1M rhabdomyosarcoma athymic mouse model as a potential tumor tracer for SPECT.

UNLABELLED: The application of 123I-3-iodo-alpha-methyltyrosine is limited to diagnosis of brain tumors due to its marked long-term uptake in kidneys. In vitro evaluation of 125I-2-iodo-L-phenylalanine showed high uptake in R1M cells by L-type amino acid transport system 1 (LAT1). This study evaluates 123I-2-iodo-L-phenylalanine as a new specific tumor tracer for SPECT. METHODS: 123/125I-2-Iodo-L-phenylalanine is prepared as a one-pot kit using the Cu1+-assisted isotopic exchange method. The characteristics of 125I-2-iodo-L-phenylalanine were examined in vivo in R1M tumor-bearing athymic mice and in acute inflammation-bearing NMRI mice. The uptake of 123/125I-2-iodo-L-phenylalanine in tumor and other organs of interest was measured by dynamic planar imaging (DPI) and gamma-counting after dissection. Displacement of 123I-2-iodo-L-phenylalanine radioactivity by L-phenylalanine, L-methionine, and L-cysteine was measured. 123I-Iodo-human serum albumin planar imaging was performed to correct for blood-pool activity and MRI was performed to delineate the tumor in DPI. 18F-FDG uptake was measured with an animal PET scanner. 125I-2-Iodo-L-phenylalanine and 18F-FDG uptake in inflamed muscle were compared. RESULTS: 123/125I-2-Iodo-L-phenylalanine showed a high and fast tumor uptake and followed a reversible first-order pattern allowing calculation of the half-life and the time to reach equilibrium (t(R)). Net tumor-to-background ratios up to 6.7 at 60 min were obtained. This radioactivity was significantly displaced by L-phenylalanine, L-methionine, and L-cysteine, pointing to reversible LAT transport. When plotting t(R) of the tumor uptake as a function of tumor volume, a rectangular hyperbolic curve was obtained. The almost constant t(R) values at higher tumor volumes (>4 mL) could be linked to increased necrotic tissue. Fast blood clearance of the tracer through the kidneys to the bladder and low tracer activity in the abdomen and brain were observed. The inflamed muscle showed only a slight increase of 125I-2-iodo-L-phenylalanine uptake (inflammation-to-background ratio, RIB = 1.30 +/- 0.02), in contrast to the high 18F-FDG uptake (RIB = 11.1 +/- 1.7). The in vivo stability of 123/125I-2-iodo-L-phenylalanine was good: Only 7% of free radioiodide and no other labeled metabolites were observed after 90 min. CONCLUSION: 123/125I-2-Iodo-L-phenylalanine is quickly taken up by the overexpressed LAT1 system in R1M tumors with high tumor specificity. The availability of a kit and the specificity of the tracer make 123I-2-iodo-L-phenylalanine a promising tool for oncologic SPECT.

Vagus nerve stimulation for refractory epilepsy: a transatlantic experience.

Vagus nerve stimulation (VNS) is an alternative treatment for medically or surgically refractory epilepsy. The long-term efficacy and safety of VNS were evaluated in a large patient series at Ghent University Hospital and Dartmouth-Hitchcock Medical Center. Between March 1995 and February 2003, seizure frequency and type as well as prescribed antiepileptic drugs and side effects were prospectively assessed in 131 patients treated with VNS in either center. Patients with a minimum follow-up duration of 6 months were included in the efficacy and safety analysis. A total of 118 of 131 implanted patients had a minimum postimplantation follow-up period of 6 months (mean, 33 months). The mean age of these patients was 32 years and the mean duration of refractory epilepsy was 22 years. The mean reduction in monthly seizure frequency in all patients was 55% (range, 0-100; SD = 31.6). Seven percent of patients were free of seizures with impaired consciousness, 50% of patients had a seizure frequency reduction of more than 50%, and 21% of patients were nonresponders. Fifteen patients reported stimulation-related side effects such as hoarseness or gagging. In a large patient series from two geographically distinct epilepsy centers located in two different continents, VNS proved to be efficacious and safe during long-term follow-up.

Neurostimulation for refractory epilepsy.

Neurostimulation is an emerging treatment for refractory epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond to such a treatment and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing vagus nerve stimulation (VNS). Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Deep brain stimulation (DBS) for epilepsy has regained interest. Central nervous system structures known to play a key role in the epileptogenic network such as the thalamus and subthalamic nucleus have been targeted. Another approach is to target the ictal onset zone such as the medial temporal lobe. At Ghent University Hospital 10 patients have been treated with long-term amygdalohippocampal DBS. Several hypotheses have been raised for the mechanism of action of DBS for refractory seizures. Seizure reduction may be due to a microlesion caused by electrode insertion or by provoking a reversible functional lesion due to the effect of electrical current on hyperexcitable tissue. Neurophysiological techniques such as evoked potentials monitoring and intraoperative single unit potential recordings may guide correct electrode placement, individual DBS titration and elucidation of the mechanims of action of DBS for epilepsy.

Motor imagery in mental rotation: an fMRI study.

Twelve right-handed men performed two mental rotation tasks and two control tasks while whole-head functional magnetic resonance imaging was applied. Mental rotation tasks implied the comparison of different sorts of stimulus pairs, viz. pictures of hands and pictures of tools, which were either identical or mirror images and which were rotated in the plane of the picture. Control tasks were equal except that stimuli pairs were not rotated. Reaction time profiles were consistent with those found in previous research. Imaging data replicate classic areas of activation in mental rotation for hands and tools (bilateral superior parietal lobule and visual extrastriate cortex) but show an important difference in premotor area activation: pairs of hands engender bilateral premotor activation while pairs of tools elicit only left premotor brain activation. The results suggest that participants imagined moving both their hands in the hand condition, while imagining manipulating objects with their hand of preference (right hand) in the tool condition. The covert actions of motor imagery appear to mimic the "natural way" in which a person would manipulate the object in reality, and the activation of cortical regions during mental rotation seems at least in part determined by an intrinsic process that depends on the afforded actions elicited by the kind of stimuli presented.

Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy.

Short-term deep brain stimulation (DBS) recently has been shown to be efficacious in refractory temporal lobe epilepsy. We (1) evaluated long-term DBS in medial temporal lobe structures in patients with normal magnetic resonance imaging (MRI) findings and (2) investigated the use of chronic DBS electrodes for the localization of the ictal onset zone before DBS. In three patients with complex partial seizures (CPSs), DBS electrodes were implanted in the amygdalohippocampal region to identify and subsequently stimulate the ictal onset zone. CPSs were compared before and after chronic DBS. Side effects were carefully monitored. DBS electrodes yielded high-quality electroencephalogram recordings showing unilateral seizure onset in medial temporal lobe structures. For all patients, unilateral amygdalohippocampal stimulation was performed. After a mean follow-up of 5 months (range, 3-6 months), all patients had a greater than 50% reduction in seizure frequency. In two patients, antiepileptic drugs could be tapered. None of the patients reported side effects. This open study demonstrates the feasibility of consecutive electroencephalographic recordings and DBS in medial temporal lobe structures using DBS electrodes. These results prompt further studies in a larger patient population to establish the efficacy and safety of chronic DBS as an alternative treatment for refractory temporal lobe epilepsy.