Baseline effective connectivity predicts response to repetitive transcranial magnetic stimulation in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has become a popular treatment option for treatment-resistant depression (TRD). However, suboptimal response rates highlight the need for improved efficacy through optimisation of treatment protocol and patient selection. We investigate whether the limbic salience network and its connectivity with prefrontal stimulation sites predict immediate and longer-term responsiveness to rTMS. Twenty-seven patients with TRD were randomly allocated to receive 16 sessions of either conventional rTMS or intermittent theta-burst (iTBS) over 4 weeks; delivered using connectivity profiling and neuronavigation to target person-specific dorsolateral prefrontal cortex (DLPFC). At baseline and 3-month follow-up, patients underwent clinical assessment and scanning session, and 1-month clinical follow-up. Resting-state fMRI data were entered into seed-based functional and effective connectivity analyses between right anterior insula (rAI) and DLPFC target, and independent components analysis to extract resting-state networks. Cerebral blood flow (CBF) was also assessed in the rAI. All brain measures were compared between baseline and follow-up, and related to treatment response at 1- and 3-months. Baseline fronto-insular effective connectivity and salience network connectivity were significantly positively correlated, while baseline rAI CBF was negatively correlated, with early (1-month) response to rTMS treatment but not sustained response (3-months), suggesting persistence of therapeutic response is not associated with baseline features. Connectivity or CBF measures did not change between the two time points. We demonstrate that fronto-insular and salience-network interactions can predict early response to rTMS in TRD, suggesting that these network nodes may be key regions toward developing rTMS response biomarkers.

Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain?

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.

Abnormalities in the effective connectivity of visuothalamic circuitry in schizophrenia.

BACKGROUND: Sensory-processing deficits appear crucial to the clinical expression of symptoms of schizophrenia. The visual cortex displays both dysconnectivity and aberrant spontaneous activity in patients with persistent symptoms and cognitive deficits. In this paper, we examine visual cortex in the context of the remerging notion of thalamic dysfunction in schizophrenia. We examined specific regional and longer-range abnormalities in sensory and thalamic circuits in schizophrenia, and whether these patterns are strong enough to discriminate symptomatic patients from controls. METHOD: Using publicly available resting fMRI data of 71 controls and 62 schizophrenia patients, we derived conjunction maps of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) to inform further seed-based Granger causality analysis (GCA) to study effective connectivity patterns. ReHo, fALFF and GCA maps were entered into a multiple kernel learning classifier, to determine whether patterns of local and effective connectivity can differentiate controls from patients. RESULTS: Visual cortex shows both ReHo and fALFF reductions in patients. Visuothalamic effective connectivity in patients was significantly reduced. Local connectivity (ReHo) patterns discriminated patients from controls with the highest level of accuracy of 80.32%. CONCLUSIONS: Both the inflow and outflow of Granger causal information between visual cortex and thalamus is affected in schizophrenia; this occurs in conjunction with highly discriminatory but localized dysconnectivity and reduced neural activity within the visual cortex. This may explain the visual-processing deficits that are present despite symptomatic remission in schizophrenia.