• DSM-5 evaluation [ Time Frame: week 0 ]
  Structured Clinical Interview for DSM 5 Axis I Disorders (SCID)
• changes in depressive symptoms [ Time Frame: weeks 0 (T0), 2, 4, 6, 9, 12, 16 (T1), T2 ]
  Quick Inventory of Depressive Symptomatology
• changes in depressive symptoms [ Time Frame: week 0, week 16, week 40 ]
  Hamilton Depression Rating Scale (HDRS)
• changes in cognitive component of depressive syndrome [ Time Frame: week 0, week 16, week 40 ]
  Beck Hopelessness Scale (BHS)
• changes in HD-EEG [ Time Frame: week 0, week 16 ]
  HD-EEG in resting state phase and a second phase with a task
• changes in fMRI [ Time Frame: week 0, week 16 ]
  fMRI in resting state phase and a second phase with a task
• changes in HRV [ Time Frame: week 0, week 16 ]
  HRV detection during hdEEG assessment

• DSM-5 evaluation [ Time Frame: week 0 ]
  Structured Clinical Interview for DSM 5 Axis I Disorders (SCID)
• changes in depressive symptoms [ Time Frame: weeks 0 (T0), 2, 4, 6, 9, 12, 16 (T1), T2 ]
  Quick Inventory of Depressive Symptomatology
• changes in depressive symptoms [ Time Frame: week 0, week 16, week 40 ]
  Hamilton Depression Rating Scale (HDRS)
• changes in cognitive component of depressive syndrome [ Time Frame: week 0, week 16, week 40 ]
  Beck Hopelessness Scale (BHS)
• changes in feeling pleasure [ Time Frame: week 0, week 16, week 40 ]
  Snaith Hamilton Pleasure Scale (SHaPS)
• changes in HD-EEG [ Time Frame: week 0, week 16 ]
  HD-EEG in resting state phase and a second phase with a task
• changes in fMRI [ Time Frame: week 0, week 16 ]
  fMRI in resting state phase and a second phase with a task

• changes in anxiety symptmoms [ Time Frame: week 0, week 16, week 40 ]
  Hamilton Anxiety Rating Scale (HARS)
• changes in Loss-related and post-traumatic symptoms [ Time Frame: week 0, week 16, week 40 ]
  Trauma and Loss Spectrum Self Report (TALS-SR)
• changes in Quality of Life [ Time Frame: week 0, week 16, week 40 ]
  WHO-QoL-bref

Depression is one of the most common invalidating mental disorders, ranked by World Health Organization as the single largest contributor to global disability. Its occurrence and development, besides stress and other neurobiological/genetic correlates, has been significantly associated with exposure to traumatic experiences (e.g., physical and sexual abuse, emotional neglect).

Major flaws in current practice are linked to the diagnosis and treatment of this severe psychiatric disorder. Diagnosis is currently based only on semi-structured clinical interviews focused on symptoms that patients may have experienced for at least two weeks. However, this approach comes with a very low diagnostic consensus and there is no objective biomarker accurate enough to be used to support clinical decision. Currently recommended treatments for depression include antidepressant medication and psychotherapies including, according to guidelines, only the Cognitive Behavioural therapy (CBT) and Interpersonal Therapy. In spite of encouraging preliminary results Eye Movement Desensitization and Reprocessing (EMDR) is not yet recognized as an effective therapy for Depression. As a whole, while antidepressant medications have been associated with a modest advantage over placebos, psychotherapeutic treatments do not work for all patients. Typical response rate, in fact, may be less than 50%, especially for chronic depression. In summary, given the high inter-patient variability, a clinical decision support system allowing for an objective diagnosis of neurobiological markers of depression and, consequently, a personalised treatment is very missing.

The project aims to bridge this gap increasing treatment efficacy, especially for depression from trauma, through an assessment of Central and Autonomic Nervous System dynamics (CNS, ANS). A study involving 40 patients with major depression will be carried out. Patients will be randomly assigned to a given psychotherapy (CBT or EMDR) for a total of 20 session during 16 weeks. At the beginning and at the end of the psychotherapy, a comprehensive CNS-ANS dynamics signature will be retrieved through concurrent functional Magnetic Resonance Imaging (fMR), High Definition Electroencephalography (hd-EEG) and Heart Rate Variability (HRV) analyses.

Recently defined measures of sympathetic autonomic outflow from heartbeat dynamics will be applied. Complexity measures will also be derived from EEG and fMRI series, along with other indices including power spectra and functional connectivity, and quantifiers of brain-heart interplay (e.g., mutual information, transfer entropy [Valenza 2016]).

To significantly improve on the specificity of ANS-related estimates, measures of brain-heart interplay will be used as a reference point for further evaluations.

From a clinical perspective, this will be the first study to evaluate specific effects of EMDR in comparison to the golden standard psychotherapy of Depression as assessed by several neurobiological methods as well as neuropsychological tests. The results of this study will allow to evaluate the possibly most useful approach for a specific patient, personalizing the treatment plan.

As regards the mechanism of EMDR, it will increase the knowledge about the process monitoring the ANS during all EMDR sessions, about 400 in the whole research project, allowing to analyze with Machine Learning algorithm the association between specific EMDR practices (e.g. stabilization techniques, processing with EM and Tapping, verbal interventions) and neurovegetative correlations.

Depression is one of the most common invalidating mental disorders, ranked by World Health Organization as the single largest contributor to global disability. Diagnosis is currently based only on semi-structured clinical interviews focused on symptoms that patients may have experienced for at least two weeks. However, this approach comes with a very low diagnostic consensus and there is no objective biomarker accurate enough to be used to support clinical decision. Antidepressant medications have been associated with a modest advantage over placebos, psychotherapeutic treatments do not work for all patients. Typical response rate, in fact, may be less than 50%, especially for chronic depression. Given the high inter-patient variability, a clinical decision support system allowing for an objective diagnosis of depression and, consequently, a personalised treatment throughout EMDR therapy is very missing.

This study has the following aims:

1. To compare the effects of different therapeutic interventions (CBT and EMDR) on emotion processing and on autonomic response in adult patients with depression, as assessed through hd-EEG, fMRI and HRV recording during administration of images expressing the emotions of sadness, anger, fear, joy, or neutral images, in order to investigate specific potential of each treatment.
2. To compare the efficacy of different interventions on clinical symptoms, as assessed by psychological questionnaires, and their correlation with neurobiological changes.
3. To investigate the correlation between hd-EEG, fMRI and autonomic responses.

4. To deepen the understanding of autonomic changes in different mood states, assessing the capability of HRV recordings to evaluate changes in mood states during therapy sessions, through videotaping sessions with identification of the following states through percentage variation of sympatho-vagal indices of HRV, as compared to resting-state baseline acquisitions:

   1. Emotional distress and resolution through therapeutic intervention
   2. Expression of resources and recovery of enriching emotions
   3. States of hyper and hypo arousal
   4. Correlations with specific practices of the EMDR process of therapy (Stabilization, Processing, Cognitive interwaves) The evaluation of EEG and fMRI alterations and autonomic nervous system dynamics across the clinical trial proposed in this project is the primary outcome of the experimental design and results.

Moreover, autonomic biomarkers will be correlated with EEG-derived measures, providing a unique assessment of the EMDR effects on the so-called brain-heart axis during depression.

Depression is one of the most common mental disorders, with more than 300 million people affected and it is ranked by World Health Organization as the single largest contributor to global disability [WHO 2017]. The occurrence and development of major psychiatric disorders including depression, in addition to stress and other neurobiological/genetic correlates [Nemeroff 2016], has been significantly associated with the exposure to adverse childhood experiences (e.g., physical and sexual abuse, emotional neglect [Felitti 1998; Norman 2012; Infurna 2016]. Note that the standard diagnosis of psychiatric pathological conditions is based on clinical evaluations through interviews and questionnaire scores only, completely disregarding any specific physiological or biochemical markers [APA DSM-5]. Current recommended treatments for depression include antidepressant medication, counselling, interpersonal therapy, and psychotherapy [UK NICE 2010]. However, despite the efficacy of these interventions [Butler 2006; Olfson 2006], they do have important limitations. Regarding antidepressant medications, several meta-analyses have concluded that they have only a modest advantage over placebos [Kirsch 2008; Khan 2015], though with greater benefits in the case of severe depression [Fournier 2010].

Several studies have shown that patients with depression who have had adverse childhood experience (ACE) have a poorer clinical course of depression, including earlier age of onset, greater symptom severity, more comorbidity, episode persistence and recurrence, and a poor treatment response [Wiersma 2009; Scott 2012; Teicher 2013; Tunnard 2014; Paterniti 2017]. To this end, two psychotherapeutic strategies that could be of interest are Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitization and Reprocessing (EMDR). CBT is one of the best-known, empirically supported treatments for depression [UK NICE 2010], while EMDR is currently being used as a treatment for a wide range of disorders that follow distressing life experiences [Valiente-Gomez 2017] and has been recently evaluated as effective as CBT in treating depression [Ostacoli 2018]. Recent randomized controlled studies suggest that EMDR is effective in improving depressive symptomatology and quality of life of patients, especially in the presence of psychological traumas in their personal history (Ostacoli et al., 2018; Minelli et al., 2019; Hase et al., 2018). Therefore, it's essential to continue to evaluate EMDR as an evidence-based treatment for depression, in order to have EMDR recognized in the international treatment guidelines for depression.

Moreover, it is known that depression has significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain, and both drugs and psychotherapy have effects through different mechanisms on patients. Recent studies on the neurobiology of depression highlight the potential to customize on neurobiological basis in order to make even more effective psychotherapy treatments (Maletic et al., 2007). In fact, in recent years neuroimaging studies have investigated the neurobiological abnormalities associated with Major Depression Disorder (MDD). In particular, several prefrontal and limbic structures and their interconnected circuits have been implicated in affective regulation. These neuroanatomical areas include the ventromedial prefrontal cortex (VMPFC), lateral orbital prefrontal cortex (LOPFC), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), ventral striatum (including nucleus accumbens), amygdala and the hippocampus. Abnormalities in these areas have been shown in patients with MDD compared with healthy controls and thus suggesting a foundation for the symptomatic expression of MDD. Findings from several studies that examined resting-state electroencephalograms (EEGs) suggest that there is a decreased left prefrontal activity in depressed individuals, relative both to depressed participants' right frontal EEG activity and to EEG measures taken from the left prefrontal regions of healthy individuals (Davidson, 2003). Researches that investigate neurobiological effects of psychotherapies show that different psychotherapy methods lead to metabolism and activity changes in the direction of recovery especially in the cingulate cortex, prefrontal cortex and amygdala (Sözeri-Varma and Karadağ, 2012; Roffman et al., 2005). The neurobiological processing of emotions can also be a parameter for evaluating and measuring the effectiveness of therapies that integrates, increasing the reliability, clinical rating scales that are influenced by contingent factors such as recent life events and social conditions (Trentini et al., 2015). Furthermore, depression and, in particular, MDD strongly affects the Autonomic Nervous System (ANS) dynamics in a manner characterised by a reduced parasympathetic and increased sympathetic tone. Features extracted from Heart Rate Variability (HRV) have been demonstrated to allow quantitative estimates of Autonomic Nervous System (ANS) dynamics, also characterizing mental disorders (Valenza et al., 2014; Valenza and Scilingo, 2014; Nardelli et al., 2014; Lanata et al., 2015). Agelink et al. studied the HRV frequency parameters in MD patients observed a decrement of HF power and an increment of LF/HF ratio (Agelink et al, 2002). Decreased HRV in depressed patients, reflecting dysregulation of the ANS, explains the increased risks for mortality and morbidity (Carney et al, 1995-2001). The loss of complexity and variability in physiological systems in general, and in the cardiovascular system in particular, has recently been linked with a number of diseases and dysfunctions (Leistedt et al, 2011, Valenza et al, 2014).

In recent years the personalization of care has become a primary goal (Cuijpers et al., 2012). This is of fundamental importance in the context of depression, because many patients do not respond adequately to treatments, with substantial economic and social costs. Personalized medicine aims at identifying which characteristics of an individual predict the outcome of a specific treatment in order to get a better match between the individual and treatment received. These characteristics may include sociodemographic characteristics and clinical characteristics of the depressive disorder, as well as biological markers, such as neuroimaging or biological variation (Cuijpers et al., 2012).

• Eye Movement Desensitization and Reprocessing
• Cognitive Behavioral Therapy
• Neurobiological Processing
• Emotions
• Functional Magnetic Resonance Imaging
• High Definition Electroencefalography
• Heart Rate Variability

• Behavioral: EMDR
  CBT and EMDR treatments will be provided for 16 weeks. CBT and EMDR comprise 20 individual sessions in 16 weeks and were conducted according to published treatment manuals. Psychotherapy visits are to be scheduled twice a week for weeks 1-4, then once a week for 12 weeks. All treatment sessions will be video-recorded for fidelity rating and supervision. Safety criterion: If a severe worsening of symptoms is observed patients would be withdrawn from their assigned treatment arm.
  Other Name: Eye Movement Desensitization and Reprocessing
• Behavioral: CBT
  CBT and EMDR treatments will be provided for 16 weeks. CBT and EMDR comprise 20 individual sessions in 16 weeks and were conducted according to published treatment manuals. Psychotherapy visits are to be scheduled twice a week for weeks 1-4, then once a week for 12 weeks. All treatment sessions will be video-recorded for fidelity rating and supervision. Safety criterion: If a severe worsening of symptoms is observed patients would be withdrawn from their assigned treatment arm.
  Other Name: Cognitive Behavioral Therapy

• Experimental: Eye Movement Desensitization and Reprocessing
  EMDR manualized protocol is DEPRend (Hofmann, Ostacoli, et al., 2015), based on the eight-phase protocol by Shapiro (2001) adapted for the treatment of Depression by the European Depression EMDR Network and used in previous studies (Hase et al., 2015; Hofmann et al., 2014). EMDR targets were selected following the Adaptive Information Processing model that looks for stressful events linked with the depression and for specific developments of resources.
  Intervention: Behavioral: EMDR
• Active Comparator: Cognitive Behavioral Therapy
  CBT is based on the principles described by Beck (Beck et al., 1979) and included behavioral activation and cognitive restructuring according to a session-by- session protocol with homework assignments.
  Intervention: Behavioral: CBT

Inclusion Criteria:

• 17-item Hamilton Rating Scale for Depression (HRSD) score of 8 or more;
• age 18 to 70 years;
• Italian speaking;
• willingness and ability to give informed consent.;
• if the person is following and Antidepressant medication, the treatment must be stable for at least two months before the enrollement.

Exclusion Criteria:

• history of brain injury;
• history of severe neurological illness, including epilepsy, cerebrovascular diseases, Parkinson disease and neurodegenerative disorders (as Alzheimer disease, Frontotemporal dementia);
• history of schizophrenia spectrum disorder and bipolar disorder;
• unipolar melancholic and psychotic depression;
• history of substance dependence in the past year;
• other disorders poorly suited to study treatments (e.g. antisocial, borderline, and schizotypal);
• severe suicidality warranting immediate intensive treatment or hospitalization;
• medical condition precluding the participation in the study;
• current pregnancy.