Analgesic effect of Botulinum toxin in neuropathic pain is sodium channel independent.

Botulinum neurotoxin type A BoNT/A is used off-label as a third line therapy for neuropathic pain. However, the mechanism of action remains unclear. In recent years, the role of voltage-gated sodium channels (Nav) in neuropathic pain became evident and it was suggested that block of sodium channels by BoNT/A would contribute to its analgesic effect. We assessed sodium channel function in the presence of BoNT/A in heterologously expressed Nav1.7, Nav1.3, and the neuronal cell line ND7/23 by high throughput automated and manual patch-clamp. We used both the full protein and the isolated catalytic light chain LC/A for acute or long-term extracellular or intracellular exposure. To assess the toxin's effect in a human cellular system, we differentiated induced pluripotent stem cells (iPSC) into sensory neurons from a healthy control and a patient suffering from a hereditary neuropathic pain syndrome (inherited erythromelalgia) carrying the Nav1.7/p.Q875E-mutation and carried out multielectrode-array measurements. Both BoNT/A and the isolated catalytic light chain LC/A showed limited effects in heterologous expression systems and the neuronal cell line ND7/23. Spontaneous activity in iPSC derived sensory neurons remained unaltered upon BoNT/A exposure both in neurons from the healthy control and the mutation carrying patient. BoNT/A may not specifically be beneficial in pain syndromes linked to sodium channel variants. The favorable effects of BoNT/A in neuropathic pain are likely based on mechanisms other than sodium channel blockage and new approaches to understand BoNT/A's therapeutic effects are necessary.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Rt-fMRI neurofeedback-guided cognitive reappraisal training modulates amygdala responsivity in posttraumatic stress disorder.

BACKGROUND: Traumatic experiences are associated with neurofunctional dysregulations in key regions of the emotion regulation circuits. In particular, amygdala responsivity to negative stimuli is exaggerated while engagement of prefrontal regulatory control regions is attenuated. Successful application of emotion regulation (ER) strategies may counteract this disbalance, however, application of learned strategies in daily life is hampered in individuals afflicted by posttraumatic stress disorder (PTSD). We hypothesized that a single session of real-time fMRI (rtfMRI) guided upregulation of prefrontal regions during an emotion regulation task enhances self-control during exposure to negative stimuli and facilitates transfer of the learned ER skills to daily life. METHODS: In a cross-over design, individuals with a PTSD diagnosis after a single traumatic event (n = 20) according to DSM-IV-TR criteria and individuals without a formal psychiatric diagnosis (n = 21) underwent a cognitive reappraisal training. In randomized order, all participants completed two rtfMRI neurofeedback (NF) runs targeting the left lateral prefrontal cortex (lPFC) and two control runs without NF (NoNF) while using cognitive reappraisal to reduce their emotional response to negative scenes. During the NoNF runs, two %%-signs were displayed instead of the two-digit feedback (FB) to achieve a comparable visual stimulation. The project aimed at defining the clinical potential of the training according to three success markers: (1) NF induced changes in left lateral prefrontal cortex and bilateral amygdala activity during the regulation of aversive scenes compared to cognitive reappraisal alone (primary registered outcome), (2) associated changes on the symptomatic and behavioral level such as indicated by PTSD symptom severity and affect ratings, (3) clinical utility such as indicated by perceived efficacy, acceptance, and transfer to daily life measured four weeks after the training. RESULTS: In comparison to the reappraisal without feedback, a neurofeedback-specific decrease in the left lateral PFC (d = 0.54) alongside an attenuation of amygdala responses (d = 0.33) emerged. Reduced amygdala responses during NF were associated with symptom improvement (r = -0.42) and less negative affect (r = -0.63) at follow-up. The difference in symptom scores exceeds requirements for a minimal clinically important difference and corresponds to a medium effect size (d = 0.64). Importantly, 75% of individuals with PTSD used the strategies in daily life during a one-month follow-up period and perceived the training as efficient. CONCLUSION: Our findings suggest beneficial effects of the NF training indicated by reduced amygdala responses that were associated with improved symptom severity and affective state four weeks after the NF training as well as patient-centered perceived control during the training, helpfulness and application of strategies in daily life. However, reduced prefrontal involvement was unexpected. The study suggests good tolerability of the training protocol and potential for clinical use in the treatment of PTSD.

Fronto-parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing.

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty-five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed-based connectivity analyses investigated depression-specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto-parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed-to voxel analysis on the whole-brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto-parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.

Targeting Treatment-Resistant Auditory Verbal Hallucinations in Schizophrenia with fMRI-Based Neurofeedback - Exploring Different Cases of Schizophrenia.

Auditory verbal hallucinations (AVHs) are a hallmark of schizophrenia and can significantly impair patients' emotional, social, and occupational functioning. Despite progress in psychopharmacology, over 25% of schizophrenia patients suffer from treatment-resistant hallucinations. In the search for alternative treatment methods, neurofeedback (NF) emerges as a promising therapy tool. NF based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntarily change of the activity in a selected brain region - even in patients with schizophrenia. This study explored effects of NF on ongoing AVHs. The selected participants were trained in the self-regulation of activity in the anterior cingulate cortex (ACC), a key monitoring region involved in generation and intensity modulation of AVHs. Using rt-fMRI, three right-handed patients, suffering from schizophrenia and ongoing, treatment-resistant AVHs, learned control over ACC activity on three separate days. The effect of NF training on hallucinations' severity was assessed with the Auditory Vocal Hallucination Rating Scale (AVHRS) and on the affective state - with the Positive and Negative Affect Schedule (PANAS). All patients yielded significant upregulation of the ACC and reported subjective improvement in some aspects of AVHs (AVHRS) such as disturbance and suffering from the voices. In general, mood (PANAS) improved during NF training, though two patients reported worse mood after NF on the third day. ACC and reward system activity during NF learning and specific effects on mood and symptoms varied across the participants. None of them profited from the last training set in the prolonged three-session training. Moreover, individual differences emerged in brain networks activated with NF and in symptom changes, which were related to the patients' symptomatology and disease history. NF based on rt-fMRI seems a promising tool in therapy of AVHs. The patients, who suffered from continuous hallucinations for years, experienced symptom changes that may be attributed to the NF training. In order to assess the effectiveness of NF as a therapeutic method, this effect has to be studied systematically in larger groups; further, long-term effects need to be assessed. Particularly in schizophrenia, future NF studies should take into account the individual differences in reward processing, fatigue, and motivation to develop individualized training protocols.