Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.

BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ±â€¯0.09 ng per µg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ±â€¯0.09 ng/µg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ±â€¯84 pg/µg total protein) compared with placebo (817 ±â€¯78 pg/µg). There were two serious adverse events, both considered unrelated to the study drug. INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease. FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren's disease, with an embedded dose response study.

Dupuytren's disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates. The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disease. The first part is a dose-ranging study where nodules of participants already scheduled for surgery will be injected with either placebo (saline) or varying doses of adalimumab. The excised tissue will then be analysed for markers of myofibroblast activity. The second part of the study will recruit participants with early stage disease. They will be randomised 1: 1 to receive either adalimumab or placebo at 3 month intervals over 1 year and will then be followed for a further 6 months. Outcome measures will include nodule hardness, size and disease progression. The trial will also determine the cost-effectiveness of adalimumb treatment for this group of participants.

MEG responses to the perception of global structure within glass patterns.

BACKGROUND: The perception of global form requires integration of local visual cues across space and is the foundation for object recognition. Here we used magnetoencephalography (MEG) to study the location and time course of neuronal activity associated with the perception of global structure from local image features. To minimize neuronal activity to low-level stimulus properties, such as luminance and contrast, the local image features were held constant during all phases of the MEG recording. This allowed us to assess the relative importance of striate (V1) versus extrastriate cortex in global form perception. METHODOLOGY/PRINCIPAL FINDINGS: Stimuli were horizontal, rotational and radial Glass patterns. Glass patterns without coherent structure were viewed during the baseline period to ensure neuronal responses reflected perception of structure and not changes in local image features. The spatial distribution of task-related changes in source power was mapped using Synthetic Aperture Magnetometry (SAM), and the time course of activity within areas of maximal power change was determined by calculating time-frequency plots using a Hilbert transform. For six out of eight observers, passive viewing of global structure was associated with a reduction in 10-20 Hz cortical oscillatory power within extrastriate occipital cortex. The location of greatest power change was the same for each pattern type, being close to or within visual area V3a. No peaks of activity were observed in area V1. Time-frequency analyses indicated that neural activity was least for horizontal patterns. CONCLUSIONS: We conclude: (i) visual area V3a is involved in the analysis of global form; (ii) the neural signature for perception of structure, as assessed using MEG, is a reduction in 10-20 Hz oscillatory power; (iii) different neural processes may underlie the perception of horizontal as opposed to radial or rotational structure; and (iv) area V1 is not strongly activated by global form in Glass patterns.

Visual gamma oscillations and evoked responses: variability, repeatability and structural MRI correlates.

There is increasing interest in the role gamma oscillations ( approximately 40 Hz) play in visual information processing. Despite this interest, and in contrast to the classically studied visual evoked potential, surprisingly little is known about the intra-individual repeatability of induced gamma oscillations. Similarly, little is known about inter-individual variability in terms of gamma oscillation frequency, bandwidth and amplitude with no extant normative data for these parameters. The purpose of the current study was therefore to examine the repeatability of visual gamma oscillations and to provide the first normative data on them. Our results demonstrate that evoked responses were highly repeatable across recording sessions whereas for induced visual gamma oscillations a large amount of inter-individual variability existed in terms of frequency, bandwidth and amplitude. However, these parameters and the general morphology of the gamma band response were stable within the same individuals for at least 4 weeks. The high degree of individual variability in gamma oscillations for gamma amplitude, bandwidth and frequency suggests that between-group studies on gamma oscillations will be difficult, requiring relatively large amounts of data to detect differences. However, the high degree of individual repeatability for gamma oscillation frequency, bandwidth and amplitude suggests that these dependent variables will be well suited for repeated-measure designs such as pharmacological studies. A number of individuals are described which show clear evoked responses yet a near absence of gamma oscillations and vice versa suggesting dissociations between the generative mechanisms of these responses. Our results also demonstrate that gamma frequency tends to decline with age and is positively correlated with the thickness of the pericalcarine cortex.

Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans.

Functional imaging of the human brain is an increasingly important technique for clinical and cognitive neuroscience research, with functional MRI (fMRI) of the blood oxygen level-dependent (BOLD) response and electroencephalography or magnetoencephalography (MEG) recordings of neural oscillations being 2 of the most popular approaches. However, the neural and physiological mechanisms that generate these responses are only partially understood and sources of interparticipant variability in these measures are rarely investigated. Here, we test the hypothesis that the properties of these neuroimaging metrics are related to individual levels of cortical inhibition by combining magnetic resonance spectroscopy to quantify resting GABA concentration in the visual cortex, MEG to measure stimulus-induced visual gamma oscillations and fMRI to measure the BOLD response to a simple visual grating stimulus. Our results demonstrate that across individuals gamma oscillation frequency is positively correlated with resting GABA concentration in visual cortex (R = 0.68; P < 0.02), BOLD magnitude is inversely correlated with resting GABA (R = -0.64; P < 0.05) and that gamma oscillation frequency is strongly inversely correlated with the magnitude of the BOLD response (R = -0.88; P < 0.001). Our results are therefore supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individual's cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.

Stimuli of varying spatial scale induce gamma activity with distinct temporal characteristics in human visual cortex.

Gamma activity to stationary grating stimuli was studied non-invasively using MEG recordings in humans. Using a spatial filtering technique, we localized gamma activity to primary visual cortex. We tested the hypothesis that spatial frequency properties of visual stimuli may be related to the temporal frequency characteristics of the associated cortical responses. We devised a method to assess temporal frequency differences between stimulus-related responses that typically exhibit complex spectral shapes. We applied this methodology to either single-trial (induced) or time-averaged (evoked) responses in four frequency ranges (0-40, 20-60, 40-80 and 60-100 Hz) and two time windows (either the entire duration of stimulus presentation or the first second following stimulus onset). Our results suggest that stimuli of varying spatial frequency induce responses that exhibit significantly different temporal frequency characteristics. These effects were particularly accentuated for induced responses in the classical gamma frequency band (20-60 Hz) analyzed over the entire duration of stimulus presentation. Strikingly, examining the first second of the responses following stimulus onset resulted in significant loss in stimulus specificity, suggesting that late signal components contain functionally relevant information. These findings advocate a functional role of gamma activity in sensory representation. We suggest that stimulus specific frequency characteristics of MEG signals can be mapped to processes of neuronal synchronization within the framework of coupled dynamical systems.

Neuroimaging in human amblyopia.

Functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and magnetoencephalography (MEG) have been the principal neuroimaging tools used to assess the site and nature of cortical deficits in human amblyopia. A review of this growing body of work is presented here with particular reference to various controversial issues, including whether or not the primary visual cortex is dysfunctional, the involvement of higher-order visual areas, neural differences between strabismic and anisometropic amblyopes, and the effects of modern-day drug treatments. We also present our own recent MEG work in which we used the analysis technique of synthetic aperture magnetometry (SAM) to examine the effects of strabismic amblyopia on cortical function. Our results provide evidence that the neuronal assembly associated with form perception in the extrastriate cortex may be dysfunctional in amblyopia, and that the nature of this dysfunction may relate to a change in the normal temporal pattern of neuronal discharges. Based on these results and existing literature, we conclude that a number of cortical areas show reduced levels of activation in amblyopia, including primary and secondary visual areas and regions within the parieto-occipital cortex and ventral temporal cortex.

Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity.

RATIONALE: MDMA is a popular drug of abuse in adolescents which causes serotonergic neurotoxicity in adult but not young rodents. However, few studies have examined the long-term behavioural consequence of MDMA and it is unclear whether such changes occur in the absence of neurotoxicity. OBJECTIVES: The present study examined whether treatment of young rats with MDMA produced long-term behavioural alterations without accompanying serotonergic neurotoxicity. METHOD: Male Lister hooded rats ( n=36, postnatal day (PND) 39) received MDMA (7.5 mg/kg i.p., twice daily for 3 days) or saline (l ml/kg i.p.) and the acute effect on open field behaviour and body temperature was monitored. Following drug withdrawal, social interaction in pre-treatment- and weight-matched rat pairs, cortical [(3)H]paroxetine binding and hippocampal and frontal cortical serotonin and dopamine levels (PND 53, n=12) and conditioned place preference (PND 70, n=24) to cocaine (5 mg/kg IP) were analysed. RESULTS: MDMA elicited the expected immediate serotonin syndrome with significant hyperlocomotion, decreased rearing and hypothermia. Twelve to 29 days after the last MDMA injection social interaction was significantly attenuated (by 41%) and the sub-threshold conditioned place preference to cocaine was significantly enhanced compared with that in saline controls, although no significant side preference to cocaine occurred in the latter. MDMA pre-treatment did not alter 5-HT levels or cortical [(3)H]paroxetine binding. CONCLUSION: MDMA administration to adolescent rats reduced social interaction and enhanced the sub-threshold rewarding effect of cocaine at adulthood, despite an absence of accompanying serotonergic and dopaminergic neurotoxicity.