Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent.
Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells.
Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells.
These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
statins; taxanes; gastric cancer
Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice.
HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry.
L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis.
Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years.
Statins, Gastric cancer; Nude mice; Apoptosis, Angiogenesis
Cystic fibrosis is a prominent genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among the many disease-causing alterations are pre-mRNA splicing defects that can hamper mandatory exon inclusion. CFTR exon 9 splicing depends in part on a polymorphic UG(m)U(n) sequence at the end of intron 8, which can be bound by TDP-43, leading to partial exon 9 skipping. CELF proteins, like CUG-BP1 and ETR-3, can also bind UG repeats and regulate splicing. We show here that ETR-3, but not CUG-BP1, strongly stimulates exon 9 skipping, although both proteins bind efficiently to the same RNA motif as TDP-43 and with higher affinity. We further show that the skipping of this exon may be due to the functional antagonism between U2AF65 and ETR-3 binding onto the polymorphic U or UG stretch, respectively. Importantly, we demonstrate that the divergent domain of ETR-3 is critical for CFTR exon 9 skipping, as shown by deletion and domain-swapping experiments. We propose a model whereby several RNA-binding events account for the complex regulation of CFTR exon 9 inclusion, with strikingly distinct activities of ETR-3 and CUG-BP1, related to the structure of their divergent domain.
Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is often used in clinical routine for diagnosis, staging and response to therapy assessment or prediction. The Standardized Uptake Value (SUV) in the primary or regional area is the most common quantitative measurement derived from PET images used for those purposes. The aim of this study was to propose and evaluate new parameters obtained by textural analysis of baseline PET scans for the prediction of therapy response in esophageal cancer. Methods: 41 patients with a newly diagnosed esophageal cancer treated with combined radio-chemotherapy were included in this study. All patients underwent a pretreatment whole-body 18F-FDG PET scan. Patients were treated with radiotherapy and alkylatin-like agents (5FU-cisplatin or 5FU-carboplatin). Patients were classified as non-responders (NR: progressive or stable disease), partial-responders (PR) or complete-responders (CR) according to RECIST criteria. Different image derived indices obtained from the pretreatment PET tumor images were considered. These included usual indices such as SUVmax, SUVpeak, SUVmean, and a total of 38 features (such as for example entropy, size and magnitude of local and global heterogeneous and homogeneous tumor regions) extracted from the five different textures considered. The capacity of each parameter to classify patients with respect to response to therapy was assessed using the Kruskal-Wallis test (p-value < 0.05). Specificity and sensitivity (including 95% confidence intervals) for each of the studied parameters were derived using Receiver Operating Characteristic (ROC) curves. Results: Relationships between pairs of voxels, characterizing local tumor metabolic non-uniformities, were able to significantly differentiate all three patient groups (p<0.0006). Regional measures of tumor characteristics, such as size of non-uniform metabolic regions and corresponding intensity non-uniformities within these regions, were also significant factors for prediction to therapy (p=0.0002). ROC curve analysis showed that tumor textural analysis can provide NR, PR and CR patient identification with higher sensitivity (76%–92%) than any SUV measurement.
Textural features of tumor metabolic distribution extracted from baseline 18F-FDG PET images allow for the best stratification of esophageal carcinoma patient in the context of therapy response prediction.
Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; therapeutic use; Carboplatin; administration & dosage; Cisplatin; administration & dosage; Combined Modality Therapy; Esophageal Neoplasms; radionuclide imaging; therapy; Female; Fluorodeoxyglucose F18; diagnostic use; Fluorouracil; administration & dosage; Humans; Image Enhancement; methods; Image Interpretation, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; diagnostic use; Radiotherapy, Conformal; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; 18F-FDG PET; esophageal cancer; texture analysis; predictive value; response to therapy
18F-FDG PET measurement of standardized uptake values (SUV) is increasingly used for monitoring therapy response or predicting outcome. Alternative parameters computed through textural analysis were recently proposed to quantify the tumor tracer uptake heterogeneity as significant predictors of response. The primary objective of this study was the evaluation of the reproducibility of these heterogeneity measurements.
Double-baseline 18F-FDG PET scans of 16 patients acquired within a period of 4 days prior to any treatment were considered. A Bland-Altman analysis was carried out on six parameters based on histogram measurements and 17 heterogeneity parameters based on textural features obtained after discretization with values between 8 and 128.
SUVmax and SUVmean reproducibility were similar to previously reported studies with a mean percentage difference of 4.7±19.5% and 5.5±21.2% respectively. By comparison better reproducibility was measured for some of the textural features describing tumor tracer local heterogeneity, such as entropy and homogeneity with a mean percentage difference of −2±5.4% and 1.8±11.5% respectively. Several of the tumor regional heterogeneity parameters such as the variability in the intensity and size of homogeneous tumor activity distribution regions had similar reproducibility to the SUV measurements with 95% confidence intervals of −22.5% to 3.1% and −1.1% to 23.5% respectively. These parameters were largely insensitive to the discretization range values.
Several of the parameters derived from textural analysis describing tumor tracer heterogeneity at local and regional scales had similar or better reproducibility as simple SUV measurements. These reproducibility results suggest that these FDG PET image derived parameters which have already been shown to have a predictive and prognostic value in certain cancer models, may be used within the context of therapy response monitoring or predicting patient outcome.
Biological Transport; Esophageal Neoplasms; metabolism; radionuclide imaging; therapy; Fluorodeoxyglucose F18; diagnostic use; metabolism; Image Processing, Computer-Assisted; methods; Positron-Emission Tomography; methods; Reproducibility of Results; Retrospective Studies; Treatment Outcome
Background and Purpose
Post-mortem studies of advanced Parkinson’s disease (PD) have revealed disease-related pathology in the thalamus with an apparent predilection for specific thalamic nuclei. In the present study, we used diffusion tensor imaging (DTI) to investigate in vivo the microstructural integrity of six thalamic regions in de novo PD patients relative to healthy controls.
Materials and Methods
Forty subjects (20 with early-stage, untreated PD and 20 age- and sex-matched controls) were studied with a high-resolution DTI protocol at 3 Tesla to investigate the integrity of thalamic nuclei projection fibers. Two blinded, independent raters drew regions of interest (ROIs) in the following six thalamic regions: anterior nucleus (AN), ventral anterior nucleus (VA), ventral lateral nucleus (VL), dorsomedial nucleus (DM), ventral posterior lateral nucleus (VPL)/ventral posterior medial nucleus (VPM), and pulvinar (PU). Fractional anisotropy (FA) values were then calculated from the projection fibers in each region.
FA values were reduced significantly in the fibers projecting from the AN, VA, and DM, but not the VPL/VPM and PU, in the PD group compared to the control group. In addition, there was a reduction in FA values that approached significance in the VL of PD patients. These findings were consistent across both raters.
The present study provides preliminary in vivo evidence of thalamic projection fiber degeneration in de novo PD and sheds light on the extent of disrupted thalamic circuitry as a result of the disease itself.
Parkinson’s disease; thalamus; diffusion tensor imaging; tractography; fractional anisotropy; magnetic resonance imaging
The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.
This study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp.
We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests.
PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity.
Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.
Our objective was to understand the functional link between the composition of faecal microbiota and the clinical characteristics of adults with short bowel syndrome (SBS).
Sixteen patients suffering from type II SBS were included in the study. They displayed a total oral intake of 2661±1005 Kcal/day with superior sugar absorption (83±12%) than protein (42±13%) or fat (39±26%). These patients displayed a marked dysbiosis in faecal microbiota, with a predominance of Lactobacillus/Leuconostoc group, while Clostridium and Bacteroides were under-represented. Each patient exhibited a diverse lactic acid bacteria composition (L. delbrueckii subsp. bulgaricus, L. crispatus, L. gasseri, L. johnsonii, L. reuteri, L. mucosae), displaying specific D and L-lactate production profiles in vitro. Of 16 patients, 9/16 (56%) accumulated lactates in their faecal samples, from 2 to 110 mM of D-lactate and from 2 to 80 mM of L-lactate. The presence of lactates in faeces (56% patients) was used to define the Lactate-accumulator group (LA), while absence of faecal lactates (44% patients) defines the Non lactate-accumulator group (NLA). The LA group had a lower plasma HCO3− concentration (17.1±2.8 mM) than the NLA group (22.8±4.6 mM), indicating that LA and NLA groups are clinically relevant sub–types. Two patients, belonging to the LA group and who particularly accumulated faecal D-lactate, were at risk of D-encephalopathic reactions. Furthermore, all patients of the NLA group and those accumulating preferentially L isoform in the LA group had never developed D-acidosis. The D/L faecal lactate ratio seems to be the most relevant index for a higher D- encephalopathy risk, rather than D- and L-lactate faecal concentrations per se. Testing criteria that take into account HCO3− value, total faecal lactate and the faecal D/L lactate ratio may become useful tools for identifying SBS patients at risk for D-encephalopathy.
The human cerebellum has been implicated in the control of a wide variety of motor control parameters, such as force amplitude, movement extent, and movement velocity. These parameters often covary in both movement and isometric force production tasks, so it is difficult to resolve whether specific regions of the cerebellum relate to specific parameters. In order to address this issue, the current study used two experiments and SUIT normalization to determine whether BOLD activation in the cerebellum scales with the amplitude or rate of change of isometric force production or both. In the first experiment, subjects produced isometric pinch-grip force over a range of force amplitudes without any constraints on the rate of force development. In the second experiment, subjects varied the rate of force production, but the target force amplitude remained constant. The data demonstrate that BOLD activation in separate sub-areas of cerebellar regions lobule VI and Crus I/II scale with both force amplitude and force rate. In addition, BOLD activation in cerebellar lobule V and vermis VI was specific to force amplitude, whereas BOLD activation in lobule VIIb was specific to force rate. Overall, cerebellar activity related to force amplitude was located superior and medial, whereas activity related to force rate was inferior and lateral. These findings suggest that specific circuitry in the cerebellum may be dedicated to specific motor control parameters such as force amplitude and force rate.
BOLD; Cerebellum; fMRI; Isometric
To examine whether behavioral and electrophysiological measures of motor performance accurately differentiate Parkinson’s disease (PD) and essential tremor (ET).
Twenty-four patients (12 PD; 12 ET) performed isometric force, ballistic movements, and tremor tasks. Receiver operating characteristic (ROC) analyses were conducted on all dependent measures that were significantly different between the two patient groups.
Patients with PD were more impaired on measures of movement deceleration than ET. Patients with ET were more impaired on measures of force variability than PD. ROC analyses revealed that sensitivity and specificity were excellent when combining measures during the isometric force task (torque rise time and force variability; 92% sensitivity and 92% specificity; AUC = 0.97). When combining measures across the force and movement tasks, the ROC analysis revealed improved sensitivity and specificity (force variability and peak deceleration; 92% sensitivity and 100% specificity; AUC = 0.99).
Combining measures of force variability and movement deceleration accurately differentiate patients with PD from those with ET with high sensitivity and specificity.
If validated in a larger sample, these measures can serve as markers to confirm the diagnosis of PD or ET and thus, enhance decision making for appropriate treatments for patients with these respective diseases.
Parkinson’s disease; Essential tremor; Variability; Bradykinesia; Biomarker
The origin of genetic instability in tumors is a matter of debate: while the prevailing model postulates a mutator phenotype resulting from an alteration in a caretaker gene as a prerequisite for genetic alterations leading to tumor formation, there is evidence against this model in the majority of cancers. A model for chromosomal instability should take into account the role of oncogenes in directly stimulating DNA and cellular component replication, creating aberrant structures when overexpressed. I will distinguish here two distinct mechanisms for the genetic instability of tumors: primary and secondary. Primary genetic instability is dependent on the inactivation of genes involved in maintaining genetic stability (caretaker genes), whereas secondary genetic instability is dependent on genes involved in tumor progression, i.e. oncogenes and tumor suppressor genes of the gatekeeper type. Secondary genetic instability, the most frequent condition, can be explained by the fact that some of the genes involved in tumor progression control replication of cell structures from within, leading to replication unbalance.
Genetic instability; tumorigenesis; oncogenes; tumor suppressor genes; DNA replication; cell replication; replication unbalance; chromosomal instability
At the conclusion of the sessions on stress urinary incontinence (SUI) in women, participants at the 2012 Canadian Urology Forum (academic and clinical urologists from across Canada) engaged in a discussion of optimal SUI evaluation and management. The discussion was led by Dr. Lesley Carr and co-facilitated by the other members of the Forum’s steering committee and was based on a patient case. This review provides a summary of the case and the discussion it generated.
Gastric cancer is one of the most common cancers in the world. The “economically developed countries” life style, including diet, constitutes a risk factor favoring this cancer. Diet modulation may lower digestive cancer incidence. Among promising food components, dairy propionibacteria were shown to trigger apoptosis of human colon cancer cells, via the release of short-chain fatty acids acetate and propionate.
A fermented milk, exclusively fermented by P. freudenreichii, was recently designed. In this work, the pro-apoptotic potential of this new fermented milk was demonstrated on HGT-1 human gastric cancer cells. Fermented milk supernatant induced typical features of apoptosis including chromatin condensation, formation of apoptotic bodies, DNA laddering, cell cycle arrest and emergence of a subG1 population, phosphatidylserine exposure at the plasma membrane outer leaflet, reactive oxygen species accumulation, mitochondrial transmembrane potential disruption, caspase activation and cytochrome c release. Remarkably, this new fermented milk containing P. freudenreichii enhanced the cytotoxicity of camptothecin, a drug used in gastric cancer chemotherapy.
Such new probiotic fermented milk may thus be useful as part of a preventive diet designed to prevent gastric cancer and/or as a food supplement to potentiate cancer therapeutic treatments.
The spatial and temporal features of visual stimuli are either processed independently or are conflated in specific cells of visual cortex. Although spatial and temporal features of visual stimuli influence motor performance, it remains unclear how spatiotemporal information is processed beyond visual cortex in brain regions that control movement. We used functional magnetic resonance imaging to examine how brain activity and force control are influenced by visual gain at a high visual feedback frequency of 6.4 Hz and a low visual feedback frequency of 0.4 Hz. At 6.4 Hz, increasing visual gain led to improved force performance and increased activity in classic areas of the visuomotor system – V5, IPL, SPL, PMv, SMA-proper, and M1. At 0.4 Hz, increasing gain also lead to improved force performance. In addition to activation in M1/PMd and IPL in the visuomotor system, increasing visual gain at 0.4 Hz also corresponded with activity in the striatal-frontal circuit including DLPFC, ACC, and widespread activity in putamen, caudate, and SMA-proper. This study demonstrates that the frequency of visual feedback drives where in the brain visual gain mediated reductions in force error are regulated.
basal ganglia; memory; prediction; visuomotor; fMRI
Research on treatments in anorexia nervosa (AN) is scarce. Although most of the therapeutic programs used in ‘real world practice’ in AN treatment resort to multidisciplinary approaches, they have rarely been evaluated.
To compare two multidimensional post-hospitalization outpatients treatment programs for adolescents with severe AN: Treatment as Usual (TAU) versus this treatment plus family therapy (TAU+FT).
Sixty female AN adolescents, aged 13 to 19 years, were included in a randomized parallel controlled trial conducted from 1999 to 2002 for the recruitment, and until 2004 for the 18 months follow-up. Allocation to one of the two treatment groups (30 in each arm) was randomised. The TAU program included sessions for the patient alone as well as sessions with a psychiatrist for the patient and her parents. The TAU+FT program was identical to the usual one but also included family therapy sessions targeting intra-familial dynamics, but not eating disorder symptoms. The main Outcome Measure was the Morgan and Russell outcome category (Good or Intermediate versus Poor outcome). Secondary outcome indicators included AN symptoms or their consequences (eating symptoms, body mass index, amenorrhea, number of hospitalizations in the course of follow-up, social adjustment). The evaluators, but not participants, were blind to randomization.
At 18 months follow-up, we found a significant group effect for the Morgan and Russell outcome category in favor of the program with family therapy (Intention-to-treat: TAU+FT :12/30 (40%); TAU : 5/29 (17.2%) p = 0.05; Per Protocol analysis: respectively 12/26 (46.2%); 4/27 (14.8%), p = 0.01). Similar group effects were observed in terms of achievement of a healthy weight (i.e., BMI≥10th percentile) and menstrual status.
Adding family therapy sessions, focusing on intra-familial dynamics rather than eating symptomatology, to a multidimensional program improves treatment effectiveness in girls with severe AN.
This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.
To aid the development of symptomatic and disease modifying therapies in Parkinson's disease (PD), there is a strong need to identify non-invasive measures of basal ganglia function that are sensitive to disease severity. This study examines the relation between blood oxygenation level dependent (BOLD) activation in every nucleus of the basal ganglia and symptom-specific disease severity in early stage, de novo PD. BOLD activation measured at 3 Tesla was compared between 20 early stage de novo PD patients and 20 controls during an established precision grip force task. In addition to the basal ganglia nuclei, activation in specific thalamic and cortical regions was examined. There were three novel findings. First, there were significant negative correlations between total motor Unified Parkinson's Disease Rating Scale (UPDRS) and BOLD activation in bilateral caudate, bilateral putamen, contralateral external segment of the globus pallidus, bilateral subthalamic nucleus, contralateral substantia nigra, and thalamus. Second, bradykinesia was the symptom that most consistently predicted BOLD activation in the basal ganglia and thalamus. Also, BOLD activation in the contralateral internal globus pallidus was related to tremor. Third, the reduced cortical activity in primary motor cortex and supplementary motor area in de novo PD did not relate to motor symptoms. These findings demonstrate that BOLD activity in nuclei of the basal ganglia relates most consistently to bradykinesia. The findings demonstrate that functional magnetic resonance imaging has strong potential to serve as a non-invasive marker for the state of basal ganglia function in de novo PD.
fMRI; Parkinson's disease; Basal Ganglia; BOLD; disease severity
The aims of this study were to assess the prevalence of a comorbid Attention Deficit Hyperactivity Disorder (ADHD) diagnosis in Borderline Personality Disorder (BPD), and its impact on the clinical presentation of BPD in adolescents, and to determine which type of impulsivity specifically characterizes adolescents with BPD-ADHD.
ADHD diagnoses were sought in a sample of 85 DSM-IV BPD adolescents drawn from the EURNET BPD. Axis-I and -II disorders were determined with the K-SADS-PL and the SIDP-IV, respectively. Impulsivity was assessed with the BIS-11.
11% (N = 9) of BPD participants had a current ADHD diagnosis. BPD-ADHD adolescents showed higher prevalence of Disruptive disorders (Chi2 = 9.09, p = 0.01) and a non-significant trend for a higher prevalence of other cluster B personality disorders (Chi2 = 2.70, p = 0.08). Regression analyses revealed a significant association between Attentional/Cognitive impulsivity scores and ADHD (Wald Z = 6.69; p = 0.01; Exp(B) = 2.02, CI 95% 1.19-3.45).
Comorbid ADHD influences the clinical presentation of adolescents with BPD and is associated with higher rates of disruptive disorders, with a trend towards a greater likelihood of cluster B personality disorders and with higher levels of impulsivity, especially of the attentional/cognitive type. A subgroup of BPD patients may exhibit developmentally driven impairments of the inhibitory system persisting since childhood. Specific interventions should be recommended for this subsample of BPD adolescents.
Viewing emotional as compared with neutral images results in an increase in force production. An emotion-driven increase in force production has been associated with increased brain activity in ventrolateral prefrontal cortex and primary motor cortex (M1). In many instances, however, force production must be held constant despite changes in emotional state and the neural circuits underlying this form of control are not well understood. To address this issue, we designed a task in which subjects viewed pleasant, unpleasant, and neutral images during a force production task. We measured brain activity using functional magnetic resonance imaging and examined functional connectivity between emotion and motor circuits. Despite similar force performance across conditions, increased brain activity was evidenced in dorsomedial prefrontal cortex (dmPFC) and left ventral premotor cortex (PMv) when force was produced during emotional as compared with neutral conditions. Connectivity analyses extended these findings by demonstrating a task-dependent functional circuit between dmPFC and ventral and dorsal portions of premotor cortex. Our findings show that when force production has to be consistent despite changes in emotional context, a functional circuit between dmPFC and PMv and dorsal premotor cortex is engaged.