Neurofeedback Training versus Treatment-as-Usual for Alcohol Dependence: Results of an Early-Phase Randomized Controlled Trial and Neuroimaging Correlates.

INTRODUCTION: Alcohol dependence is one of the most common substance use disorders, and novel treatment options are urgently needed. Neurofeedback training (NFT) based on real-time functional magnetic resonance imaging (rtf-MRI) has emerged as an attractive candidate for add-on treatments in psychiatry, but its use in alcohol dependence has not been formally investigated in a clinical trial. We investigated the use of rtfMRI-based NFT to prevent relapse in alcohol dependence. METHODS: Fifty-two alcohol-dependent patients from the UK who had completed a detoxification program were randomly assigned to a treatment group (receiving rtfMRI NFT in addition to standard care) or the control group (receiving standard care only). At baseline, alcohol consumption was assessed as the primary outcome measure and a variety of psychological, behavioral, and neural parameters as secondary outcome measures to determine feasibility and secondary training effects. Participants in the treatment group underwent 6 NFT sessions over 4 months and were trained to downregulate their brain activation in the salience network in the presence of alcohol stimuli and to upregulate frontal activation in response to pictures related to positive goals. Four, 8, and 12 months after baseline assessment, both groups were followed up with a battery of clinical and psychometric tests. RESULTS: Primary outcome measures showed very low relapse rates for both groups. Analysis of neural secondary outcome measures indicated that the majority of patients modulated the salience system in the desired directions, by decreasing activity in response to alcohol stimuli and increasing activation in response to positive goals. The intervention had a good safety and acceptability profile. CONCLUSION: We demonstrated that rtfMRI-neurofeedback targeting hyperactivity of the salience network in response to alcohol cues is feasible in currently abstinent patients with alcohol dependence.

Increased fractional anisotropy in the motor tracts of Parkinson's disease suggests compensatory neuroplasticity or selective neurodegeneration.

OBJECTIVE: To determine the differences in motor pathways and selected non-motor pathways of the basal ganglia in Parkinson's disease (PD) patients compared to healthy controls (HCs). METHODS: We analysed diffusion weighted imaging data of 24 PD patients and 26 HCs. We performed deterministic tractography analysis using the spherical deconvolution-based damped Richardson-Lucy algorithm and subcortical volume analysis. RESULTS: We found significantly increased fractional anisotropy (FA) in the motor pathways of PD patients: the bilateral corticospinal tract (right; corrected p = 0.0003, left; corrected p = 0.03), bilateral thalamus-motor cortex tract (right; corrected p = 0.02, left; corrected p = 0.004) and the right supplementary area-putamen tract (corrected p = 0.001). We also found significantly decreased FA in the right uncinate fasiculus (corrected p = 0.01) and no differences of FA in the bilateral supero-lateral medial forebrain bundles (p > 0.05) of PD patients compared to HCs. There were no subcortical volume differences (p > 0.05) between the PD patients and HCs. CONCLUSION: These results can inform biological models of neurodegeneration and neuroplasticity in PD. We suggest that increased FA values in the motor tracts in PD may reflect compensatory reorganization of neural circuits indicative of adaptive or extended neuroplasticity. KEY POINTS: • Fractional anisotropy was higher in motor pathways of PD patients compared to healthy controls. • Fractional anisotropy was lower in the uncinate fasciculus of PD patients compared to healthy controls. • Increased fractional anisotropy could suggest adaptive neuroplasticity or selective neurodegeneration.

Real-time functional magnetic resonance imaging neurofeedback for treatment of Parkinson's disease.

Self-regulation of brain activity in humans based on real-time feedback of functional magnetic resonance imaging (fMRI) signal is emerging as a potentially powerful, new technique. Here, we assessed whether patients with Parkinson's disease (PD) are able to alter local brain activity to improve motor function. Five patients learned to increase activity in the supplementary motor complex over two fMRI sessions using motor imagery. They attained as much activation in this target brain region as during a localizer procedure with overt movements. Concomitantly, they showed an improvement in motor speed (finger tapping) and clinical ratings of motor symptoms (37% improvement of the motor scale of the Unified Parkinson's Disease Rating Scale). Activation during neurofeedback was also observed in other cortical motor areas and the basal ganglia, including the subthalamic nucleus and globus pallidus, which are connected to the supplementary motor area (SMA) and crucial nodes in the pathophysiology of PD. A PD control group of five patients, matched for clinical severity and medication, underwent the same procedure but did not receive feedback about their SMA activity. This group attained no control of SMA activation and showed no motor improvement. These findings demonstrate that self-modulation of cortico-subcortical motor circuits can be achieved by PD patients through neurofeedback and may result in clinical benefits that are not attainable by motor imagery alone.

Investigating the Anatomy and Microstructure of the Dentato-rubro-thalamic and Subthalamo-ponto-cerebellar Tracts in Parkinson's Disease.

Cerebellar-thalamic connections play a central role in deep brain stimulation-based treatment of tremor syndromes. Here, we used diffusion Magnetic Resonance Imaging (MRI) tractography to delineate the main cerebellar peduncles as well as two main white matter tracts that connect the cerebellum with the thalamus, the dentato-rubro-thalamic tract (DRTT) and the subthalamo-ponto-cerebellar tract (SPCT). We first developed a reconstruction protocol in young healthy adults with high-resolution diffusion imaging data and then demonstrate feasibility of transferring this protocol to clinical studies using standard diffusion MRI data from a cohort of patients with Parkinson's disease (PD) and their matched healthy controls. The tracts obtained closely corresponded to the previously described anatomical pathways and features of the DRTT and the SPCT. Second, we investigated the microstructure of these tracts with fractional anisotropy (FA), radial diffusivity (RD), and hindrance modulated orientational anisotropy (HMOA) in patients with PD and healthy controls. By reducing dimensionality of both the microstructural metrics and the investigated cerebellar and cerebellar-thalamic tracts using principal component analyses, we found global differences between patients with PD and controls, suggestive of higher fractional anisotropy, lower radial diffusivity, and higher hindrance modulated orientational anisotropy in patients. However, separate analyses for each of the tracts did not yield any significant differences. Our findings contribute to the characterization of the distinct anatomical connections between the cerebellum and the diencephalon. Microstructural differences between patients and controls in the cerebellar pathways suggest involvement of these structures in PD, complementing previous functional and diffusion imaging studies.

Dopamine boosts memory for angry faces in Parkinson's disease.

The influence of emotional context on cognitive operations is of fundamental importance for the evolution of higher cognitive functions and their disturbance in neuropsychiatric disorders. The dopamine pathways projecting to prefrontal cortex and the basal ganglia are assumed to play a major role in such emotion-cognition interactions. Here we provide evidence for such a role by studying working memory for emotional faces in patients with Parkinson's Disease. We studied 25 patients with Parkinson's disease during their on and off medication states. Faces with emotional expressions (happy, angry, sad, neutral or fearful) were shown and the participants had to remember and later recall the identity of the faces ignoring the expressions. We found that dopaminergic medication enhances working memory for angry faces and suppresses it for sad faces. The results elucidate neurochemical mechanisms for the saliency of threatening information and support cognitive explanations of the antidepressant effects of dopamine. They also suggest a role for dopamine in changing emotional-cognitive biases rather than as a generic cognitive enhancer.

Current practices in clinical neurofeedback with functional MRI-Analysis of a survey using the TIDieR checklist.

BACKGROUND: A core principle of creating a scientific evidence base is that results can be replicated in independent experiments and in health intervention research. The TIDieR (Template for Intervention Description and Replication) checklist has been developed to aid in summarising key items needed when reporting clinical trials and other well designed evaluations of complex interventions in order that findings can be replicated or built on reliably. Neurofeedback (NF) using functional MRI (fMRI) is a multicomponent intervention that should be considered a complex intervention. The TIDieR checklist (with minor modification to increase applicability in this context) was distributed to NF researchers as a survey of current practice in the design and conduct of clinical studies. The aim was to document practice and convergence between research groups, highlighting areas for discussion and providing a basis for recommendations for harmonisation and standardisation. METHODS: The TIDieR checklist was interpreted and expanded (21 questions) to make it applicable to neurofeedback research studies. Using the web-based Bristol Online Survey (BOS) tool, the revised checklist was disseminated to researchers in the BRAINTRAIN European research collaborative network (supported by the European Commission) and others in the fMRI-neurofeedback community. RESULTS: There were 16 responses to the survey. Responses were reported under eight main headings which covered the six domains of the TIDieR checklist: What, Why, When, How, Where and Who. CONCLUSIONS: This piece of work provides encouraging insight into the ability to be able to map neuroimaging interventions to a structured framework for reporting purposes. Regardless of the considerable variability of design components, all studies could be described in standard terms of diagnostic groups, dose/duration, targeted areas/signals, and psychological strategies and learning models. Recommendations are made which include providing detailed rationale of intervention design in study protocols.

Targeting the affective brain-a randomized controlled trial of real-time fMRI neurofeedback in patients with depression.

Functional magnetic resonance imaging neurofeedback (fMRI-NF) training of areas involved in emotion processing can reduce depressive symptoms by over 40% on the Hamilton Depression Rating Scale (HDRS). However, it remains unclear if this efficacy is specific to feedback from emotion-regulating regions. We tested in a single-blind, randomized, controlled trial if upregulation of emotion areas (NFE) yields superior efficacy compared to upregulation of a control region activated by visual scenes (NFS). Forty-three moderately to severely depressed medicated patients were randomly assigned to five sessions augmentation treatment of either NFE or NFS training. At primary outcome (week 12) no significant group mean HDRS difference was found (B = -0.415 [95% CI -4.847 to 4.016], p = 0.848) for the 32 completers (16 per group). However, across groups depressive symptoms decreased by 43%, and 38% of patients remitted. These improvements lasted until follow-up (week 18). Both groups upregulated target regions to a similar extent. Further, clinical improvement was correlated with an increase in self-efficacy scores. However, the interpretation of clinical improvements remains limited due to lack of a sham-control group. We thus surveyed effects reported for accepted augmentation therapies in depression. Data indicated that our findings exceed expected regression to the mean and placebo effects that have been reported for drug trials and other sham-controlled high-technology interventions. Taken together, we suggest that the experience of successful self-regulation during fMRI-NF training may be therapeutic. We conclude that if fMRI-NF is effective for depression, self-regulation training of higher visual areas may provide an effective alternative.

Functional Magnetic Resonance Imaging Neurofeedback-guided Motor Imagery Training and Motor Training for Parkinson's Disease: Randomized Trial.

OBJECTIVE: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient's own brain activity to self-regulate brain networks which in turn could lead to a change in behavior and clinical symptoms. The objective was to determine the effect of NF and motor training (MOT) alone on motor and non-motor functions in Parkinson's Disease (PD) in a 10-week small Phase I randomized controlled trial. METHODS: Thirty patients with Parkinson's disease (PD; Hoehn and Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with MOT. Group 2 (MOT: 15 patients) received MOT alone. The primary outcome measure was the Movement Disorder Society-Unified PD Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention "off-medication". The secondary outcome measures were the "on-medication" MDS-UPDRS, the PD Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. RESULTS: Patients in the NF group were able to upregulate activity in the supplementary motor area (SMA) by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the "off-medication" state (95% confidence interval: -2.5 to -6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to -6.8). The improvement in the intervention group meets the minimal clinically important difference which is also on par with other non-invasive therapies such as repetitive Transcranial Magnetic Stimulation (rTMS). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. INTERPRETATION: This Phase I study suggests that NF combined with MOT is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions.

Neurofeedback training for alcohol dependence versus treatment as usual: study protocol for a randomized controlled trial.

BACKGROUND: Real-time functional magnetic resonance imaging (rtfMRI) is used for neurofeedback training (NFT). Preliminary results suggest that it can help patients to control their symptoms. This study uses rtfMRI NFT for relapse prevention in alcohol dependence. METHODS/DESIGN: Participants are alcohol-dependent patients who have completed a detoxification programme within the past 6 months and have remained abstinent. Potential participants are screened for eligibility, and those who are eligible are randomly assigned to the treatment group (receiving rtfMRI NFT in addition to treatment as usual) or the control group (receiving only treatment as usual). Participants in both groups are administered baseline assessments to measure their alcohol consumption and severity of dependence and a variety of psychological and behavioural characteristics that are hypothesised to predict success with rtfMRI NFT. During the following 4 months, experimental participants are given six NFT sessions, and before and after each session various alcohol-related measures are taken. Participants in the control group are given the same measures to coincide with their timing in the experimental group. Eight and 12 months after the baseline assessment, both groups are followed up with a battery of measures. The primary research questions are whether NFT can be used to teach participants to down-regulate their brain activation in the presence of alcohol stimuli or to up-regulate their brain activation in response to pictures related to healthy goal pursuits, and, if so, whether this translates into reductions in alcohol consumption. The primary outcome measures will be those derived from the functional brain imaging data. We are interested in improvements (i.e., reductions) in participants' alcohol consumption from pretreatment levels, as indicated by three continuous variables, not simply whether or not the person has remained abstinent. The indices of interest are percentage of days abstinent, drinks per drinking day, and percentage of days of heavy drinking. General linear models will be used to compare the NFT group and the control group on these measures. DISCUSSION: Relapse in alcohol dependence is a recurring problem, and the present evaluation of the role of rtfMRI in its treatment holds promise for identifying a way to prevent relapse. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02486900 , registered on 26 June 2015.

Real-time self-regulation of emotion networks in patients with depression.

Many patients show no or incomplete responses to current pharmacological or psychological therapies for depression. Here we explored the feasibility of a new brain self-regulation technique that integrates psychological and neurobiological approaches through neurofeedback with functional magnetic resonance imaging (fMRI). In a proof-of-concept study, eight patients with depression learned to upregulate brain areas involved in the generation of positive emotions (such as the ventrolateral prefrontal cortex (VLPFC) and insula) during four neurofeedback sessions. Their clinical symptoms, as assessed with the 17-item Hamilton Rating Scale for Depression (HDRS), improved significantly. A control group that underwent a training procedure with the same cognitive strategies but without neurofeedback did not improve clinically. Randomised blinded clinical trials are now needed to exclude possible placebo effects and to determine whether fMRI-based neurofeedback might become a useful adjunct to current therapies for depression.

Sad benefit in face working memory: an emotional bias of melancholic depression.

Emotion biases feature prominently in cognitive theories of depression and are a focus of psychological interventions. However, there is presently no stable neurocognitive marker of altered emotion-cognition interactions in depression. One reason may be the heterogeneity of major depressive disorder. Our aim in the present study was to find an emotional bias that differentiates patients with melancholic depression from controls, and patients with melancholic from those with non-melancholic depression. We used a working memory paradigm for emotional faces, where two faces with angry, happy, neutral, sad or fearful expression had to be retained over one second. Twenty patients with melancholic depression, 20 age-, education- and gender-matched control participants and 20 patients with non-melancholic depression participated in the study. We analysed performance on the working memory task using signal detection measures. We found an interaction between group and emotion on working memory performance that was driven by the higher performance for sad faces compared to other categories in the melancholic group. We computed a measure of "sad benefit", which distinguished melancholic and non-melancholic patients with good sensitivity and specificity. However, replication studies and formal discriminant analysis will be needed in order to assess whether emotion bias in working memory may become a useful diagnostic tool to distinguish these two syndromes.

Emotion-cognition interactions in schizophrenia: Implicit and explicit effects of facial expression.

Working memory (WM) and emotion classification are amongst the cognitive domains where specific deficits have been reported for patients with schizophrenia. In healthy individuals, the capacity of visual working memory is enhanced when the material to be retained is emotionally salient, particularly for angry faces. We investigated whether patients with schizophrenia also have an enhanced WM capacity for angry faces. We compared 34 inpatients with schizophrenia and 34 age-, handedness- and gender-matched control participants in three separate tasks. In the WM task, participants saw two faces with angry, happy or neutral emotional expressions for 2s and had to decide whether a probe face presented after a 1s delay was identical to one of them. In the emotion classification task, they had to assign these faces to the appropriate categorical emotion. They also rated faces for valence and arousal. Although patients performed generally worse on the working memory task, they showed the same benefit for angry faces as control participants. However, patients were specifically impaired for angry faces on the emotion classification task. These results indicate preserved implicit emotion processing in schizophrenia patients, which contrasts with their impairment in explicit emotion classification. With regard to clinical practice, our findings underline the importance of assessing responsiveness to emotions in patients with schizophrenia, with a view possibly to utilize preserved implicit emotion processing in cognitive remediation programs.