Healthy Controls In Response Research Articles

Can explicit suggestions about the harmfulness of EMF exposure exacerbate a nocebo response in healthy controls?

While there has been consistent evidence that symptoms reported by individuals who suffer from Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) are not caused by EMF and are more closely associated with a nocebo effect, whether this response is specific to IEI-EMF sufferers and what triggers it, remains unclear. The present experiment tested whether perceived EMF exposure could elicit symptoms in healthy participants, and whether viewing an ‘alarmist’ video could exacerbate a nocebo response. Participants were randomly assigned to watch either an alarmist (N = 22) or control video (N = 22) before completing a series of sham and active radiofrequency (RF) EMF exposure provocation trials (2 open-label, followed by 12 randomized, double-blind, counterbalanced trials). Pre- and post-video state anxiety and risk perception, as well as belief of exposure and symptom ratings during the open-label and double-blind provocation trials, were assessed. Symptoms were higher in the open-label RF-ON than RF-OFF trial (p < .001). No difference in either symptoms (p = .183) or belief of exposure (p = .144) was observed in the double-blind trials. Participants who viewed the alarmist video had a significant increase in symptoms (p = .041), state anxiety (p < .01) and risk perception (p < .001) relative to the control group. These results reveal the crucial role of awareness and belief in the presentation of symptoms during perceived exposure to EMF, showing that healthy participants exhibit a nocebo response, and that alarmist media reports emphasizing adverse effects of EMF also contribute to a nocebo response.

Hippocampal activations in mesial temporal lobe epilepsy due to hippocampal sclerosis- an observational study on intramural encoding-delayed recall paradigms using task-based memory fMRI

ObjectivesTo validate concurrent utility of within-scanner encoding and delayed recognition-memory paradigms to ascertain hippocampal activations during task-based memory fMRI. MethodsMemory paradigms were designed for faces, word-pairs and abstract designs. A deep-encoding task was designed comprising of a total of 9 cycles run within a 1.5T MRI scanner. A recall session was performed after 1 h within the scanner using an event-related design. Group analysis was done with ‘correct-incorrect' responses applied as parametric modulators in Statistical Parametric Mapping version 8 using boot-strap method to enable estimation of laterality indices (LI) using custom anatomical masks involving the medio-basal temporal structures. ResultsTwenty seven subjects with drug-resistant mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE-HS) [17 patients of left-MTLE and 10 patients of right-MTLE] and 21 right handed age-matched healthy controls (HC) were recruited. For the encoding paradigm blood oxygen level dependent (BOLD) responses in HC demonstrated right laterality for faces, left laterality for word pairs, and bilaterality for design encoding over the regions of interest. Both right and left MTLE-HS groups revealed left lateralisation for word-pair encoding, bilateral activation for face encoding, with design encoding in right MTLE-HS demonstrating a left shift. As opposed to lateralization shown in controls, group analysis of cued-recall BOLD signals acquired within scanner in left MTLE-HS demonstrated right lateralization for word-pairs with bilaterality for faces and designs. The right MTLE-HS group demonstrated bilateral activations for faces, word-pairs and designs. ConclusionRecall-based fMRI paradigms indicate hippocampal plasticity in MTLE-HS, maximal for word-pair associate recall tasks.

STAT3-Mediated Transcriptional Regulation of Osteopontin in STAT3 Loss-of-Function Related Hyper IgE Syndrome.

Hyper-IgE syndrome (HIES) caused by loss-of-function (LOF) mutations in STAT3 gene (STAT3 LOF HIES) is associated with dental and facial abnormalities in addition to immunological defects. The role of STAT3 in the pathogenesis of the dental/facial features is, however, poorly elucidated. Since mechanism of cellular resorption of mineralized tissues such as bone and teeth are similar, we attempted to study the expression of genes involved in bone homeostasis in STAT3 LOF HIES. Peripheral blood mononuclear cells from healthy controls (HCs), STAT3 LOF HIES patients, STAT3-/- PC-3 cells and STAT3+/+ LNCaP cells were stimulated with IL-6 and quantitative PCR array was performed to study the relative mRNA expression of 43 pre-selected genes. PCR array finding were further evaluated after stattic induced STAT3 inhibition. Osteopontin (OPN) gene was seen to be significantly upregulated after IL-6 stimulation in HC (mean fold change 18.6, p = 0.01) compared with HIES subjects. Inhibition of STAT3 signaling by stattic followed by IL-6 stimulation abrogated the OPN response in HCs suggesting that IL-6-induced STAT3 signaling regulates OPN expression. Bioinformatics analysis predicted the presence of STAT3 response element TTCCAAGAA at position -2005 of the OPN gene. Regulation of OPN gene through IL-6-mediated STAT3 activation and its significant dysregulation in STAT3 LOF HIES subjects could make OPN a plausible candidate involved in the pathogenesis of dental/facial manifestations in HIES.

Platform Session – NIBS: Spatiotemporal dynamics of single and paired pulse TMS-EEG responses in healthy subjects

Introduction Transcranial magnetic stimulation (TMS) is used for assessing cortical excitability in a variety of neurological disorders. Additional information from inhibitory and excitatory networks can be obtained with paired pulse stimulation. Combining TMS with electroencephalography (EEG) allows assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spread and distribution of single and paired pulse TMS-EEG responses in healthy controls. As cortical excitability is modified in various central nervous system disorders and for central acting drugs, these patterns can serve as a reference for future neurological and pharmacological studies. Methods Thirty healthy subjects (10 males, mean age 28.4 ± 8.2 years) underwent a single and paired pulse TMS-EEG session. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 50, 100, 150, 200, 250 and 300 ms. The cluster based permutation test (FieldTrip; http://www.fieldtriptoolbox.org ) was used to analyze the spatiotemporal dynamics of the TMS-EEG response. Significant clusters were formed based on adjacent time bins and neighboring electrodes using 64-channel EEG data. Results Single pulse TMS-EEG responses showed the characteristic P30, N45, P55, N100 and P180 components at channel Cz. The P30 cluster was located centro-parietal in the ipsilateral hemisphere, the N45 centro-frontal contralateral, the P55 parieto-temporal ipsilateral, the N100 central contralateral and the P180 central contralateral and parieto-temporal ipsilateral. Both hemispheres showed a mirrored single pulse TMS-EEG response. For ISI 250 ms, the paired pulse TMS-EEG response also showed the characteristic components at Cz. However, the amplitudes were much smaller compared to single pulse stimulation. Furthermore, fewer, smaller and shorter-lasting significant clusters were found. For ISI 100 ms, no TMS-EEG components were visible at Cz and the response amplitude was much smaller compared to the single pulse response. Next, we will also compare single and paired pulse responses for the other ISIs (50, 150, 200 and 300 ms). Conclusion Stimulation of both hemispheres showed a mirrored single pulse TMS-EEG response. Paired pulse stimulation resulted in fewer, smaller and shorter-lasting clusters compared to single pulse TMS. In combination with a smaller response amplitude, this indicates inhibition of cortical excitability after a conditioning first stimulus. These spatiotemporal dynamics of the single and paired pulse TMS-EEG responses in healthy controls can serve as reference values for future TMS-EEG studies.

Acute Effects of Transcranial Direct Current Stimulation on the Gamma Auditory Steady-State Response in Healthy Controls

Acute Effects of Transcranial Direct Current Stimulation on the Gamma Auditory Steady-State Response in Healthy Controls

Cerebrovascular reactivity in acute hyperoxia in patients with acute ischaemic stroke

ABSTRACTAim: This study aimed to assess the effect of acute hyperoxia on cerebral and systemic heamodynamics and the plasma concentration of prostacyclin and thromboxane in patients with stroke.Methods: Mean blood flow velocity (MBFV), pulsatility and resistance indices of the middle cerebral artery using transcranial Doppler ultrasound before and during acute hyperoxia (4 L of 100%O2/15’ over facial mask) in 92 participants – 25 patients with acute ischaemic stroke (AIS) that occurred within 72 hours and diabetes mellitus (SPDM), 26 AIS patients without DM (SP) and in 41 healthy controls (HS), were measured. Partial pressure of O2 (pO2), blood pressure and heart rate were measured using pulse oxymeter and pressure gauge, respectively. All the above measurements, as well as cerebral vasoreactivity assessments were performed, before, at the end of the 15 minute period of hyperoxia, and 15 minutes after hyperoxia. The plasma concentration of thromboxane and prostacyclin were determined by ELISA assays.Results: MBFV increased in both SP and SPDM, while MBFV decreased in HS in response to hyperoxia. Thromboxane correlated negatively and prostacyclin positively with MBVF in the SPDM, although their concentrations did not differ significantly after hyperoxia among groups.Conclusion: Results suggest impaired vascular reactivity to acute hyperoxia in patients with stroke and the possible role of thromboxane A2/prostacycline in mediating cerebrovascular reactivity in SPDM.Abbreviations: ANG, II angiotensin II; ASA, acetylsalicylic acid; ATP, Adenosine triphosphate; BP, blood pressure; CBF, cerebral blood flow; CDI, colour Doppler imaging; COX, cyclooxigenase; COVR, cerebrovascular oxygen vasoreactivity; CVR, cerebrovascular reactivity; HR, heart rate; HS, healthy subjects; MBFV, mean blood flow velocity; MCA, middle cerebral artery; PG, 6-keto-PGF1alfa; PGI2, prostacycline; PI, pulsatility index; pO2 partial pressure of O2; RI, resistance index; ROS, reactive oxygen species; SP, stroke patients; TCD, transcranial doppler; TXA2, thromboxane A2; TXB, thromboxane B2; VSMC, vascular smooth muscle cell; 20-HETE, 20-hydroxieicosatetraenoic acid

Emotion avoidance and fear bradycardia in patients with borderline personality disorder and healthy controls

Background and objectivesExaggerated emotional reactivity is supposed to be essential in the etiology of borderline personality disorder (BPD). More specifically, models of defensive behavior would predict reduced freezing behavior –indicated by fear bradycardia-in response to threat. This study examined automatic fear bradycardia responses in BPD versus healthy controls and the role of emotion dysregulation, more specifically tendencies to avoid emotions. MethodsPatients with BPD (n = 23) and healthy controls (n = 18) completed questionnaires and then watched neutral, pleasant and unpleasant pictures while heart rate was assessed. ResultsEmotion avoidance interacted with group: it was associated with distinct autonomic responses in healthy controls but not in BPD patients. Controls with lower emotion avoidance tendencies showed bradycardia in response to unpleasant pictures, while controls with higher emotion avoidance tendencies did not. BPD patients showed no bradycardia, irrespective of their emotion avoidance tendencies. LimitationsThis study is limited by a small sample size. Comorbidity or medication intake were not controlled for. ConclusionsThe results may suggest impaired automatic defense responses in BPD. Further understanding of the regulation of distress and defense responses might improve BPD treatment.

Brain activation to task-irrelevant disorder-related threat in social anxiety disorder: The impact of symptom severity.

Unintentional and uncontrollable processing of threat has been suggested to contribute to the pathology of social anxiety disorder (SAD). The present study investigated the neural correlates of processing task-irrelevant, highly ecologically valid, disorder-related stimuli as a function of symptom severity in SAD. Twenty-four SAD patients and 24 healthy controls (HC) performed a feature-based comparison task during functional magnetic resonance imaging, while task-irrelevant, disorder-related or neutral scenes were presented simultaneously at a different spatial position. SAD patients showed greater activity than HC in response to disorder-related versus neutral scenes in brain regions associated with self-referential processing (e.g. insula, precuneus, dorsomedial prefrontal cortex) and emotion regulation (e.g. dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus). Symptom severity was positively associated with amygdala activity, and negatively with activation in dorsal anterior cingulate cortex and dlPFC in SAD patients. Additional correlation analysis revealed that amygdala-prefrontal coupling was positively associated with symptom severity. A network of brain regions is thus involved in SAD patients' processing of task-irrelevant, complex, ecologically valid, disorder-related scenes. Furthermore, increasing symptom severity in SAD patients seems to reflect a growing imbalance between neural mechanisms related to stimulus-driven bottom-up and regulatory top-down processes resulting in dysfunctional regulation strategies.

Empathy and aversion: the neural signature of mentalizing in Tourette syndrome.

Previous studies suggest that adults with Tourette syndrome (TS) can respond unconventionally on tasks involving social cognition. We therefore hypothesized that these patients would exhibit different neural responses to healthy controls in response to emotionally salient expressions of human eyes. Twenty-five adults with TS and 25 matched healthy controls were scanned using fMRI during the standard version of the Reading the Mind in the Eyes Task which requires mental state judgements, and a novel comparison version requiring judgements about age. During prompted mental state recognition, greater activity was apparent in TS within left orbitofrontal cortex, posterior cingulate, right amygdala and right temporo-parietal junction (TPJ), while reduced activity was apparent in regions including left inferior parietal cortex. Age judgement elicited greater activity in TS within precuneus, medial prefrontal and temporal regions involved in mentalizing. The interaction between group and task revealed differential activity in areas including right inferior frontal gyrus. Task-related activity in the TPJ covaried with global ratings of the urge to tic. While recognizing mental states, adults with TS exhibit greater activity than controls in brain areas involved in the processing of negative emotion, in addition to reduced activity in regions associated with the attribution of agency. In addition, increased recruitment of areas involved in mental state reasoning is apparent in these patients when mentalizing is not a task requirement. Our findings highlight differential neural reactivity in response to emotive social cues in TS, which may interact with tic expression.

Eosinophil Peroxidase Catalyzed Protein Carbamylation Participates in Asthma

The biochemical mechanisms through which eosinophils contribute to asthma pathogenesis are unclear. Here we show eosinophil peroxidase (EPO), an abundant granule protein released by activated eosinophils, contributes to characteristic asthma-related phenotypes through oxidative posttranslational modification (PTM) of proteins in asthmatic airways through a process called carbamylation. Using a combination of studies we now show EPO uses plasma levels of the pseudohalide thiocyanate (SCN-) as substrate to catalyze protein carbamylation, as monitored by PTM of protein lysine residues into Nϵ-carbamyllysine (homocitrulline), and contributes to the pathophysiological sequelae of eosinophil activation. Studies using EPO-deficient mice confirm EPO serves as a major enzymatic source for protein carbamylation during eosinophilic inflammatory models, including aeroallergen challenge. Clinical studies similarly revealed significant enrichment in carbamylation of airway proteins recovered from atopic asthmatics versus healthy controls in response to segmental allergen challenge. Protein-bound homocitrulline is shown to be co-localized with EPO within human asthmatic airways. Moreover, pathophysiologically relevant levels of carbamylated protein either incubated with cultured human airway epithelial cells in vitro, or provided as an aerosolized exposure in non-sensitized mice, induced multiple asthma-associated phenotypes including induction of mucin, Th2 cytokines, IFNγ, TGFβ, and epithelial cell apoptosis. Studies with scavenger receptor-A1 null mice reveal reduced IL-13 generation following exposure to aerosolized carbamylated protein, but no changes in other asthma-related phenotypes. In summary, EPO-mediated protein carbamylation is promoted during allergen-induced asthma exacerbation, and can both modulate immune responses and trigger a cascade of many of the inflammatory signals present in asthma.

Association of DNA methylation marks in the stress response regulating gene KITLG to schizophrenia and bipolar disorder

Background: Transcriptional regulation of the KITLG gene by DNA methylation marks at cg27512205 is associated with cortisol stress response in healthy controls and early exposure to childhood adversities. Compelling evidence shows a higher prevalence of childhood adversities in psychotic disorders, but what the role of this methylation mark is in bipolar disorder and schizophrenia is not clear. Methods: We investigated the association of KITLG methylation to schizophrenia and bipolar disorder and the relationship to childhood adversities in whole blood DNA of a sample of 50 patients with bipolar disorder, 15 with schizophrenia and 91 healthy controls. To further tie KITLG function to stress response regulation we analyses the response of KITLG expression to dexamethasone exposure in vitro using 4 human fibroblasts cultures. Results:KITLG methylation was significantly different between the diagnostics groups (F(187,2) = 22.0, p < 0.001). KITLG methylation was lower in bipolar disorder patients (B = −0.33, p < 0.001) and schizophrenia patients (B = −0.33, p < 0.001) also after adjustment for increased KITLG methylation related to childhood adversities in these patient groups (BP; B = 0.009, p = 0.003, Scz; B = 0.012, p = 0.004). Dexamethasone exposure lead to a 50 percent reduction of KITLG expression (FC = 0.45). Conclusions: The results shed new light on the relationship between epigenetic modifications associated with childhood adversities and increased rates of psychotic disorders. The results are consistent with a model whereby failure to increase KITLG methylation in response to childhood adversities leads to maladaptive epigenetic regulation of the stress response in psychotic disorders Houtepen et al. (2016).

Enhanced Brain Responses to Pain-Related Words in Chronic Back Pain Patients and Their Modulation by Current Pain.

Previous functional magnetic resonance imaging (fMRI) studies in healthy controls (HC) and pain-free migraine patients found activations to pain-related words in brain regions known to be activated while subjects experience pain. The aim of the present study was to identify neural activations induced by pain-related words in a sample of chronic back pain (CBP) patients experiencing current chronic pain compared to HC. In particular, we were interested in how current pain influences brain activations induced by pain-related adjectives. Subjects viewed pain-related, negative, positive, and neutral words; subjects were asked to generate mental images related to these words during fMRI scanning. Brain activation was compared between CBP patients and HC in response to the different word categories and examined in relation to current pain in CBP patients. Pain-related words vs. neutral words activated a network of brain regions including cingulate cortex and insula in subjects and patients. There was stronger activation in medial and dorsolateral prefrontal cortex (DLPFC) and anterior midcingulate cortex in CPB patients than in HC. The magnitude of activation for pain-related vs. negative words showed a negative linear relationship to CBP patients’ current pain. Our findings confirm earlier observations showing that pain-related words activate brain networks similar to noxious stimulation. Importantly, CBP patients show even stronger activation of these structures while merely processing pain-related words. Current pain directly influences on this activation.

Enhanced LPS-induced activation of IL-27 signalling in sarcoidosis

RationaleGranulomas in sarcoidosis have recently been described as containing Interleukin (IL)-27, one of the members of the IL-12 family of cytokines, which also includes IL-35. Levels of these cytokines and the IL-27 receptor subunits were hypothesised to differ between patients with sarcoidosis compared to healthy controls in peripheral blood. MethodsUsing a cross-sectional study design, plasma and peripheral blood mononuclear cells (PBMC) were collected from patients and control subjects. Protein and mRNA (in PBMC) levels for IL-27 and IL-35 (IL27, EBI3, IL12A subunits) as well as IL-27 receptor (IL6ST and IL27RA subunits) were assessed spontaneously and following direct (LPS) and indirect (anti-CD3/28 activation beads) macrophage stimulation using RT- PCR, ELISA and flow cytometry. ResultsFollowing stimulation with LPS, PBMC of patients with sarcoidosis displayed significantly enhanced expression of IL27 and EBI3 mRNA (p = 0.020 and p = 0.037 respectively) compared to PBMCs from healthy controls. There was also significantly enhanced production of IL-27 by PBMC from patients with sarcoidosis compared to healthy controls in response to LPS stimulation (p = 0.027).IL6ST mRNA and IL6ST protein were significantly lower in patients with sarcoidosis (mRNA p = 0.0002; MFI p = 0.0015) whilst IL27RA protein levels were significantly higher in patients with sarcoidosis compared to healthy controls (MFI p < 0.0001).Plasma IL-35 protein levels did not differ between control and sarcoidosis subjects (p = 0.23). ConclusionThese results suggest there may be exaggerated activation of IL-27 signalling in response to LPS in sarcoidosis.

Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes.

Hepatokines have emerged as liver-derived hormone-like factors. Plasma fibroblast growth factor (FGF)-21 and follistatin increase with a high glucagon to insulin ratio and exercise, and resting levels are elevated in patients with type 2 diabetes (T2D). The objective of the study was to investigate the regulatory roles of glucagon to insulin ratio and T2D on exercise-induced FGF21 and follistatin secretion. Design /Interventions: Young healthy males performed a 2-hour bicycle exercise bout followed by 5 hours of rest in supine position with and without a pancreatic clamp blocking the increase in the glucagon to insulin ratio. In addition, we evaluated exercise-induced plasma FGF21 and follistatin in patients with T2D compared with healthy controls in response to 1 hour of bicycle exercise followed by a 3-hour recovery period. In healthy individuals, we observed a 10-fold (P < .002) increase in the glucagon to insulin ratio during exercise, which was abolished by the pancreatic clamp. Exercise with the pancreatic clamp completely blunted the exercise-induced increase in FGF21 (P = .007), whereas the induction of follistatin was approximately 50% reduced (P = .04). Exercise-induced FGF21 secretion was completely absent in patients with T2D, whereas the exercise-induced follistatin increase was impaired. Exercise-induced increases in plasma FGF21 and follistatin are attenuated by the pancreatic clamp, indicating important roles for glucagon and insulin as upstream regulators. For follistatin, an additional regulatory mechanism must exist. Our data further show that exercise-induced FGF21 and follistatin secretion are impaired in patients with T2D. The magnitude of changes in glucagon and insulin or the sensitivity to these hormones seems central in the regulation of FGF21 and follistatin in humans.

Amino acid and chromium enriched table water added to a standardized meal influences the glucose response depending on insulin sensitivity

Aim: To study the influence of an amino acid (AA) and chromium picolinate (CrPic) enriched table water on glucose response in healthy controls and early diabetes patients.

A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder.

Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1.

To reveal the neuronal underpinnings of sensory processing deficits in patients with schizophrenia, previous studies have investigated brain activity in response to sustained sensory stimulation at various frequencies. This paradigm evoked neural activity at the stimulation frequency and harmonics thereof. During visual and auditory stimulation that elicited enhanced or 'resonant' responses in healthy controls, patients with schizophrenia displayed reduced activity. The present study sought to elucidate the cellular basis of disease-related deficits in sensory resonance properties using mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1 (NRG1). We applied repetitive whisker stimulation at 1-15Hz, a range relevant to whisking behavior in mice, and measured cellular activity in the primary somatosensory cortex. At frequencies where control mice displayed enhancements in measures of response magnitude and precision, NRG1 (+/-) mutants showed reductions. Our results demonstrate for the first time a link between a mutation of a schizophrenia risk gene and altered neuronal resonance properties in sensory cortex.

The characterization of a base-width neutral step as the first step for balance recovery in moderate Parkinson's disease

Purpose: The purpose of this study is to characterize the base-width neutral step (BNS) as the first step in a compensatory step response in persons with moderate Parkinson's disease (PD), and its effect on balance recovery. Materials and Methods: Ten PD and 10 healthy controls (HCs) responded to a posterior waist pull. A BNS was defined if the first step was less than 50 mm. The length, height, duration and velocity of the BNS and its effect on balance recovery time and center of mass location at recovery were compared to the first step within other stepping strategies (single step (SS), multiple step (MS)). A linear mixed model was used to compare across strategies. Results: Six of ten persons with PD compared to zero HC used a BNS. The BNS was shorter in length and duration compared to MS responses in HC, and shorter in duration compared to MS responses in PD. The BNS was slower in velocity compared to every other strategy. BNS use resulted in a longer recovery time compared to all strategies in HC and SS responses in PD, and trended toward a longer recovery time compared to MS responses in PD. Conclusions: The BNS as the first step in a MS response may be an unreported strategy for compensatory stepping in PD. This study suggests that the cost of utilizing the BNS may be a longer time for recovery, but further work is necessary to understand the progression of the BNS as PD severity increases.

Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response

The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60% of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure. The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed. IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients. RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients' inflammatory status.

Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n=35) and BD patients either responder (RBD, n=26) or non responder (nRBD, n=11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.