Things you wanted to know (but might have been afraid to ask) about how and why to explore and modulate brain plasticity with non-invasive neurostimulation technologies.

Brain plasticity can be defined as the ability of local and extended neural systems to organize either the structure and/or the function of their connectivity patterns to better adapt to changes of our inner/outer environment and optimally respond to new challenging behavioral demands. Plasticity has been traditionally conceived as a spontaneous phenomenon naturally occurring during pre and postnatal development, tied to learning and memory processes, or enabled following neural damage and their rehabilitation. Such effects can be easily observed and measured but remain hard to harness or to tame 'at will'. Non-invasive brain stimulation (NIBS) technologies offer the possibility to engage plastic phenomena, and use this ability to characterize the relationship between brain regions, networks and their functional connectivity patterns with cognitive process or disease symptoms, to estimate cortical malleability, and ultimately contribute to neuropsychiatric therapy and rehabilitation. NIBS technologies are unique tools in the field of fundamental and clinical research in humans. Nonetheless, their abilities (and also limitations) remain rather unknown and in the hands of a small community of experts, compared to widely established methods such as functional neuroimaging (fMRI) or electrophysiology (EEG, MEG). In the current review, we first introduce the features, mechanisms of action and operational principles of the two most widely used NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Current Stimulation (tCS), for exploratory or therapeutic purposes, emphasizing their bearings on neural plasticity mechanisms. In a second step, we walk the reader through two examples of recent domains explored by our team to further emphasize the potential and limitations of NIBS to either explore or improve brain function in healthy individuals and neuropsychiatric populations. A final outlook will identify a series of future topics of interest that can foster progress in the field and achieve more effective manipulation of brain plasticity and interventions to explore and improve cognition and treat the symptoms of neuropsychiatric diseases.

Non-invasive and invasive brain stimulation in alcohol use disorders: A critical review of selected human evidence and methodological considerations to guide future research.

INTRODUCTION: Alcohol use disorder (AUD) ranks among the leading causes of decrements in disability-adjusted life-years. Long-term exposure to alcohol leads to an imbalance of activity between frontal cortical systems and the striatum, thereby enhancing impulsive behaviours and weakening inhibitory control. Alternative therapeutic approaches such as non-invasive and invasive brain stimulation have gained some momentum in the field of addictology by capitalizing on their ability to target specific anatomical structures and correct abnormalities in dysfunctional brain circuits. MATERIALS AND METHODS: The current review, covers original peer-reviewed published research on the use of brain stimulation methods for the rehabilitation of AUD. A broad and systematic search was carried out on four electronic databases: NCBI PubMed, Web of Science, Handbooks and the Cochrane Library. Any original article in English or French language, without restrictions of patient age or gender, article type and publication outlet, were included in the final pool of selected studies. RESULTS: The outcomes of this systematic review suggest that the dorsolateral prefrontral cortex (DLPFC) is a promising target for treating AUD with high frequency repetitive transcranial magnetic stimulation. Such effect would reduce feelings of craving by enhancing cognitive control and modulating striatal function. Existing literature also supports the notion that changes of DLPFC activity driven by transcranial direct current stimulation, could decrease alcohol craving and consumption. However, to date, no major differences have been found between the efficacy of these two non-invasive brain-stimulation approaches, which require further confirmation. In contrast, beneficial stronger evidence supports an impact of deep brain stimulation reducing craving and improving quality of life in AUD, effects that would be mediated by an impact on the nucleus accumbens, a central structure of the brain's reward circuitry. Overall, neurostimulation shows promise contributing to the treatment of AUD. Nonetheless, progress has been limited by a number of factors such as the low number of controlled randomized trials, small sample sizes, variety of stimulation parameters precluding comparability and incomplete or questionable sham-conditions. Additionally, a lack of data concerning clinical impact on the severity of AUD or craving and the short follow up periods precluding and accurate estimation of effect duration after discontinuing the treatment, has also limited the clinical relevance of final outcomes. CONCLUSION: Brain stimulation remains a promising approach to contribute to AUD therapy, co-adjuvant of more conventional procedures. However, a stronger therapeutic rational based on solid physio-pathological evidence and accurate estimates of efficacy, are still required to achieve further therapeutic success and expand clinical use.

Stimulation therapeutic approaches to better understand Obsessive Compulsive Disorder: The issue of 'where' to treat.

The use of invasive and non-invasive brain stimulation and neuromodulation technologies combined with neuroimaging approaches can help refine with causal evidence our physiopathological understanding of the Obsessive-Compulsive Disorder (OCD). Two key structures, the Orbitofrontal Cortex (OFC) and the Anterior Cingulate Cortex (ACC) have been found dysfunctional in OCD compared to healthy volunteers and on such basis have been tested as therapeutic targets for invasive and non-invasive neuromodulation therapy. Hereinafter, evidence addressing the cognitive processes subtended by to those two brain regions and their role in wider associated cortico-subcortical networks is reviewed. Very specifically, their relevance for OCD clinical features is discussed in extenso and its modulation with invasive and non-invasive focal brain stimulation such as deep brain stimulation (DBS) or transcranial magnetic Stimulation (TMS). Most importantly, this article brings new insights bridging causal evidence on the structural and functional neuroanatomy subtending OCD and novel therapeutic perspectives based on focal brain stimulation.

Brain connectivity and auditory hallucinations: In search of novel noninvasive brain stimulation therapeutic approaches for schizophrenia.

Auditory verbal hallucinations (AVH) are among the most characteristic symptoms of schizophrenia and have been linked to likely disturbances of structural and functional connectivity within frontal, temporal, parietal and subcortical networks involved in language and auditory functions. Resting-state functional magnetic resonance imaging (fMRI) has shown that alterations in the functional connectivity activity of the default-mode network (DMN) may also subtend hallucinations. Noninvasive neurostimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) have the ability to modulate activity of targeted cortical sites and their associated networks, showing a high potential for modulating altered connectivity subtending schizophrenia. Notwithstanding, the clinical benefit of these approaches remains weak and variable. Further studies in the field should foster a better understanding concerning the status of networks subtending AVH and the neural impact of rTMS in relation with symptom improvement. Additionally, the identification and characterization of clinical biomarkers able to predict response to treatment would be a critical asset allowing better care for patients with schizophrenia.

FABP4 plasma concentrations are determined by acquired metabolic derangements rather than genetic determinants.

BACKGROUND AND AIMS: Circulating FABP4 is strongly associated with metabolic and cardiovascular risk (CVR) and has been proposed as a new risk biomarker. Several FABP4 gene polymorphisms have been associated with protein expression in vitro and metabolic and vascular alterations in vivo. The aim of this study is to evaluate the impact of FABP4 polymorphisms on FABP4 plasma levels and subclinical arteriosclerosis in patients with obesity, metabolic syndrome (MS) or type 2 diabetes (T2DM). METHODS AND RESULTS: We studied 440 individuals with obesity, MS, T2DM or other cardiovascular risk conditions who attended the vascular medicine and metabolism unit of our hospital. Anamnesis, physical examination and anthropometry data were recorded. Standard biochemical parameters were determined. Plasma FABP4 concentrations were measured. Carotid intima-media thickness (cIMT) was assessed using ultrasonography. The following FABP4 gene single-nucleotide polymorphisms (SNPs) were analyzed: rs3834363, rs16909233, rs1054135, rs77878271, rs10808846 and rs8192688. None of the studied gene allele variants were hyper-represented in patients grouped according the presence of metabolic alterations nor were they associated with the FABP4 concentration. The FABP4 gene variants did not determine cIMT differences between the groups. In a multivariate analysis, gender and BMI, but not gene variants, significantly determined plasma FABP4 concentrations. CONCLUSIONS: In clinical settings, the circulating FABP4 levels are determined by the acquired metabolic derangements and not genetic variation.

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function

Background: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. Objective: We aimed to study the impact of a lower level of PA on cardiovascular health. Design: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. Results: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P < 0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r = 0.341, P = 0.022), GPx (r = 0.303, P = 0.047) and decreases in RHR (r=−0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21–4.01), decrease in RHR (1.91, 95%CI: 1.01–4.98), and an increase in GPx (2.61, 95%CI: 1.16–5.01). Conclusion: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity

Introducción: Los niveles moderados de actividad física (AF), 30 min al día de caminar, reducen el riesgo cardiovascular. No existe evidencia si los niveles bajos de actividad física, por debajo de las recomendaciones internacionales, afectan la salud cardiovascular. Objetivo: Estudiar el efecto de los niveles bajos de actividad física sobre la salud cardiovascular Diseño: Se seleccionaron 64 hombres y mujeres con sobrepeso u obesidad para completar un programa comunitario de actividad física consistente en 1h, 2 días a la semana, durante 4 meses, de AF de intensidad baja. Antes y después del programa se evaluó la AF (MET/h/semana), el estado antioxidante endógeno (SOD y GPX concentración y actividad), las concentraciones de ADMA, la función endotelial de pequeña arteria mediante el índice de hiperemia reactiva (saRHI) y la frecuencia cardíaca (FC) en reposo. Resultados: Después de la intervención se observó un aumento significativo en el saRHI (p=0,031), en la actividad de la SOD y la GPX, y una disminución de las concentraciones plasmáticas de ADMA y de la FC (p<0,001 para todos). El aumento en la AF se asoció directamente con el aumento del saRHI (r = 0,341, p = 0,022), GPx (r = 0,303, p = 0,047) y disminución en FC (r = -0.297, p = 0,047). Los predictores independientes de la mejora del saRHI fueron un aumento en la AF (2,65; IC95%: 1,21-4,01), la disminución de la FC (1,91; IC95%:1,01-4,98) y el aumento de la GPx (2,61; IC95%:1,16-5,01). Conclusiones: Un aumento de la AF, incluso por debajo de las recomendaciones internacionales de AF, mejoró la capacidad antioxidante, la FC y la función endotelial de las pequeñas arterias en hombres y mujeres con sobrepeso u obesidad

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function.

BACKGROUND: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. OBJECTIVE: We aimed to study the impact of a lower level of PA on cardiovascular health. DESIGN: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P<0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r=0.341, P=0.022), GPx (r=0.303, P=0.047) and decreases in RHR (r=-0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21-4.01), decrease in RHR (1.91, 95%CI: 1.01-4.98), and an increase in GPx (2.61, 95%CI: 1.16-5.01). CONCLUSION: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity.

Subclinical atherosclerosis determinants in morbid obesity.

BACKGROUND AND AIMS: Obesity is associated with increased cardiovascular risk. However, the impact of morbid obesity on vascular structure and function is not well understood. This study was designed to appraise subclinical atherosclerosis markers, including carotid intima media thickness (cIMT), endothelial function, and arterial wall stiffness, and their determinants, in morbidly obese patients. METHODS AND RESULTS: In this cross-sectional study 194 overweight and obese patients were distributed in morbid-obese patients (MOP, n = 110), obese (OP, n = 84) and overweight patients (OwP, n = 33) groups. Demography, anthropometry, clinical and standard biochemical data were recorded. cIMT, endothelial function, defined as the small artery reactivity index (saRHI), and artery wall rigidity, studied by the augmentation index, were determined. More than 50% of the MOP, OP and OwP had a cIMT above the 75th percentile per age and gender. No differences in cIMT or saRHI were observed, although overweight and obese patients (OOP) had higher arterial rigidity compared with the morbid-obese patients. In a multivariate regression test, while cholesterol was the main determinant of cIMT in overweight and obese patients, glucose metabolism was the determinant in MOP. CONCLUSION: More than half of the population have a cIMT above general population ranges. OwP, OP and MOP have similar cIMT and saRHI. However, OOP have greater arterial wall rigidity. Dysglycemia is the main factor associated with subclinical atherosclerosis in MOP.

Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients.

The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

Multiple sessions of transcranial direct current stimulation to the intact hemisphere improves visual function after unilateral ablation of visual cortex.

Damage to cerebral systems is frequently followed by the emergence of compensatory mechanisms, which serve to reduce the effects of brain damage and allow recovery of function. Intrinsic recovery, however, is rarely complete. Non-invasive brain stimulation technologies have the potential to actively shape neural circuits and enhance recovery from brain damage. In this study, a stable deficit for detecting and orienting to visual stimuli presented in the contralesional visual hemifield was generated by producing unilateral brain damage of the right posterior parietal and contiguous visual cortical areas. A long regimen of inhibitory non-invasive transcranial direct-current stimulation (cathodal tDCS, 2 mA, 20 min) was applied to the contralateral (intact) posterior parietal cortex over 14 weeks (total of 70 sessions, one per day, 5 days per week) and behavioral outcomes were periodically assessed. In three out of four stimulated cats, lasting recovery of visuospatial function was observed. Recovery started after 2-3 weeks of stimulation, and recovered targets were located first in the periphery, and moved to more central visual field locations with the accrual of stimulation sessions. Recovery for moving tasks followed a biphasic pattern before reaching plateau levels. Recovery did not occur for more difficult visual tasks. These findings highlight the ability of multiple sessions of transcranial direct-current stimulation to produce recovery of visuospatial function after unilateral brain damage.

Body weight loss by very-low-calorie diet program improves small artery reactive hyperemia in severely obese patients.

BACKGROUND: Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). METHODS: Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. RESULTS: SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 ± 0.236 vs. 1.737 ± 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (ß -0.049, IC 95 % -0.091-0.008, p = 0.021). CONCLUSIONS: Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP.

[Transcranial magnetic stimulation (TMS) in basic and clinical neuroscience research]. / La stimulation magnétique transcrânienne (SMT) dans la recherche fondamentale et clinique en neuroscience.

INTRODUCTION: Non-invasive brain stimulation methods such as transcranial magnetic stimulation (TMS) are starting to be widely used to make causality-based inferences about brain-behavior interactions. Moreover, TMS-based clinical applications are under development to treat specific neurological or psychiatric conditions, such as depression, dystonia, pain, tinnitus and the sequels of stroke, among others. BACKGROUND: TMS works by inducing non-invasively electric currents in localized cortical regions thus modulating their activity levels according to settings, such as frequency, number of pulses, train and regime duration and intertrain intervals. For instance, it is known for the motor cortex that low frequency or continuous patterns of TMS pulses tend to depress local activity whereas high frequency and discontinuous TMS patterns tend to enhance it. Additionally, local cortical effects of TMS can result in dramatic patterns in distant brain regions. These distant effects are mediated via anatomical connectivity in a magnitude that depends on the efficiency and sign of such connections. PERSPECTIVES: An efficient use of TMS in both fields requires however, a deep understanding of its operational principles, its risks, its potential and limitations. In this article, we will briefly present the principles through which non-invasive brain stimulation methods, and in particular TMS, operate. CONCLUSION: Readers will be provided with fundamental information needed to critically discuss TMS studies and design hypothesis-driven TMS applications for cognitive and clinical neuroscience research.

The APOA5-1131 T>C variant enhances the association between RBP4 and hypertriglyceridemia in diabetes.

BACKGROUND AND AIM: Type 2 diabetic patients have an increased prevalence of hypertriglyceridemia. RBP4 has been associated with insulin resistance and hypertriglyceridemia in obesity, the metabolic syndrome and type 2 diabetes. APOA5 is proposed to be a genetic modulator of triglycerides. The aim of this study was to evaluate the relationship between RBP4 plasma levels and lipid disturbances and to determine the impact of the APOA5-1131 T>C variant on this relationship in type 2 diabetic patients. METHODS AND RESULTS: A total of 165 type 2 diabetic patients were included in the study. RBP4 plasma levels and the APOA5-1131 T>C variant were determined and the complete lipid profile was assessed by sequential ultracentrifugation. RBP4 was positively correlated with triglyceride levels in plasma and with all the components of triglyceride-rich lipoproteins. Despite the fact that a statistically significant relationship between the APOA5 genetic variant and RBP4 plasma levels was not found, the hypertriglyceridemic effect of high RBP4 levels was enhanced by the presence of the APOA5-1131 T>C genetic variant. Correlation coefficients were 2-fold higher for TC carriers compared to TT carriers with regard to RBP4 plasma levels and all the components of triglyceride-rich lipoproteins. Those type 2 diabetic patients with high RBP4 plasma concentrations and who were TC carriers showed an increased incidence of hypertriglyceridemia (OR=7.46, P=0.010). CONCLUSION: RBP4 is associated with hypertriglyceridemia in type 2 diabetic patients. The RBP4 effect is conditioned by the presence of the APOA5-1131 T>C genetic variant.

Cathodal transcranial direct current stimulation on posterior parietal cortex disrupts visuo-spatial processing in the contralateral visual field.

Transcranial direct current stimulation (tDCS) has recently undergone a resurgence in popularity as a powerful tool to non-invasively manipulate brain activity. While tDCS has been used to alter functions tied to primary motor and visual cortices, its impact on extrastriate visual areas involved in visuo-spatial processing has not yet been examined. In the current study, we applied tDCS to the cat visuoparietal (VP) cortex and assayed performance in a paradigm designed to assess the capacity to detect, localize and orient to static targets appearing at different spatial eccentricities within the visual field. Real or sham cathodal tDCS was unilaterally applied to the VP cortex, and orienting performance was assessed during (online), immediately after (offline; Experiments 1 and 2), and 1 or 24 h after the end of the tDCS stimulation (Experiment 2). Performance was compared to baseline data collected immediately prior to stimulation. Real, but not sham, tDCS induced significant decreases in performance for static visual targets presented in the contrastimulated visual hemifield. The behavioral impact of tDCS was most apparent during the online and immediate offline periods. The tDCS effect decayed progressively over time and performance returned to baseline levels approximately 60 min after stimulation. These results are consistent with the effects of both invasive and non-invasive deactivation methods applied to the same brain region, and indicate that tDCS has the potential to modify neuronal activity in extrastriate visual regions and to sculpt brain activity and behavior in normal and neurologically impaired subjects.

Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes.

OBJECTIVE: The retinol-binding protein 4 (RBP4) has been linked to the insulin resistance state in obesity and type 2 diabetes in animal studies. Data in humans are controversial and their relationship with organ damage in diabetic patients is lacking. We studied the association of plasma RBP4 with organ complications in type 2 diabetic patients. SETTING: Sant Joan University Hospital, Reus, Spain. SUBJECTS: 165 nonsmoker type 2 diabetic subjects according to American Diabetes Association criteria, aged 36-79 years, without proteinuria or severely decreased glomerular filtration rates (MDRD-GFR <30 mL min(-1) 1.73 m(-2)), were included in the study. MAIN OUTCOME MEASURE: Plasma RBP4 concentrations were the primary outcome variable. Statistics were performed in relation to clinical and subclinical arteriosclerosis, renal function parameters and biochemical data. RESULTS: Plasma RBP4 concentrations were positively correlated with serum creatinine levels (r = 0.322, P < 0.001) and inversely correlated with MDRD-GFR (r = -0.468, P = 0.009). Patients with moderately renal dysfunction (MDRD-GFR <60 mL min(-1) 1.73 m(-2)) had higher plasma RBP4 concentrations than those with normal to mildly decreased GFR (55.3 +/- 24.6 vs. 40.8 +/- 15.4, P <0.001). Patients in the top quartile of RBP4 concentrations had an increased adjusted odds ratio for moderately renal dysfunction compared with lower quartiles (4.68; 95% CI: 1.52-14.36, P = 0.007). The presence of microalbuminuria was not associated with RBP4. Plasma RBP4 concentrations were higher in those subjects with previous clinical arteriosclerosis than in event-free subjects (48.8 +/- 24.2 vs. 40.6 +/- 13.9, P = 0.045). The presence of retinopathy or polyneuropathy did not differ across RBP4 quartiles. CONCLUSIONS: Plasma RBP4 concentration might be a biomarker of nephropathy and cardiovascular disease in type 2 diabetic subjects.

Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients.

OBJECTIVE: To study the role of FABP4 in the plasma of type 2 diabetic (T2D) subjects with and without metabolic syndrome (MS) and the impact of thiazolidinedione (TZD) treatment. METHODS AND RESULTS: FABP4 was analyzed in 274 individuals (169 T2D subjects and 105 controls). MS-T2D subjects had higher FABP4 levels than non-MS-T2D subjects and controls (53% and 76% increase, respectively, p<0.005). FABP4 levels in T2D subjects were positively correlated to the number of MS elements, obesity degree, adiponectin, triglycerides, lipoperoxides, C-reactive protein, age, systolic blood pressure and diabetes duration (p<0.05). Neither clinical or subclinical atherosclerosis, nor plasma levels of insulin, glucose or RBP4 were associated to FABP4. TZD-treated T2D subjects showed >30% higher FABP4 levels (p<0.05) than non-TZD-treated T2D. A subgroup study confirmed that TZD treatment prospectively increased FABP4 levels (p<0.05) along with an increase of peripheral blood mononuclear cell PPARgamma activity (p<0.05). Furthermore, in vitro studies showed that TZD treatment increased FABP4 mRNA, intracellular protein levels and extracellular secretion from human adipocytes. CONCLUSIONS/INTERPRETATION: FABP4 plasma concentrations are increased with the early presence of MS components, as well as inflammation and oxidation markers in T2D subjects. TZD increases FABP4 plasma concentrations, reflecting PPARgamma activation. FABP4 plasma measurements could be useful in the management of T2D subjects.

Low frequency transcranial magnetic stimulation on the posterior parietal cortex induces visuotopically specific neglect-like syndrome.

The visuo-parietal (VP) region of the cerebral cortex is critically involved in the generation of orienting responses towards visual stimuli. In this study we use repetitive transcranial magnetic stimulation (rTMS) to unilaterally and non-invasively deactivate the VP cortex during a simple spatial visual detection task tested in real space. Adult cats were intensively trained over 4 months on a task requiring them to detect and orient to a peripheral punctuate static LED presented at a peripheral location between 0 degrees and 90 degrees , to the right or left of a 0 degrees fixation target. In 16 different interleaved sessions, real or sham low frequency (1 Hz) rTMS was unilaterally applied during 20 min (1,200 pulses) to the VP cortex. The percentage of mistakes detecting and orienting to contralateral visual targets increased significantly during the 15-20 min immediately following real but not sham rTMS. Behavioral deficits were most marked in peripheral eccentricities, whereas more central locations were largely unaffected. Performance returned to baseline (pre-TMS) levels when animals were tested 45 min later and remained in pre-TMS levels 24 h after the end of the stimulation. Our results confirm that the VP cortex of the cat is critical for successful detection and orienting to visual stimuli presented in the corresponding contralateral visual field. In addition, we show that rTMS disrupts a robust behavioral task known to depend on VP cortex and does so for the far periphery of the visual field, but not for more central targets.