Distribució de la polvorització en el tractament general a la vegeta-

Previous neuroimaging studies on animals and humans identified the fear circuit which consists of the PFC and the amygdala (Shin & Liberzon, 2009). This PhD project

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focuses on the prefrontal part of the fear circuit. In human neuroscience the PFC is usually divided into three main subregions:

• Medial PFC which consists of BA (Brodmann Area) 24, 25, 32 and 10.BA 10 is the foremost located brain region in the prefrontal cortex. In the literature the neuroanatomical nomenclature for this brain area vary, being labelled as the ventromedial prefrontal cortex, frontopolar prefrontal cortex, lateral frontopolar cortex or anterior prefrontal cortex (Burgess 2007). The medial PFC plays a role in the top-down regulation of a fear response, suppression of fear response when the threat is no longer present, attention to the emotional states of the self and others, and the guidance of response selection by emotional states (Davidson et al., 2002; Siddiqui et al., 2008).

• Orbitofrontal PFC consists of BA 11, 12, 13 and 47. It plays a role in the modulation of behavioural and automatic responses in fear-relevant situations (Davidson et al., 2002). Moreover, it plays a significant role in emotional-social behaviour and interactions (Siddiqui et al., 2008).

• Dorsolateral PFC consist of BA 9 and 46 (Cieslik et al., 2013). Dorsolateral functions relevant to fear regulation are believed to include involvement in working memory, response preparation, response selection, and top-down emotional regulation (Davidson, 2002). Emotional regulation can be modulated by the DLPFC using top-down executive control over emotional stimuli through processes of cognitive reappraisal, which is a psychological ability to assess the meaning of an emotional response through rationalising (Goldin et al., 2008).

A meta-analysis performed by Ipser (2013) on functional brain imaging of anxiety studies identified a role of the PFC, amygdala, right thalamus, left insula and cerebellum in specific phobia (Ipser, Singh, & Stein, 2013). The PFC plays a critical role in emotional regulation and fear inhibition. Neuroimaging connectivity studies showed thatregions of the PFC have reciprocal connections with the amygdala, in particular, the medial PFC (MPFC) and orbitofrontal cortex have direct connections, and the dorsolateral prefrontal cortex (DLPFC) has indirect connections to the amygdala. Therefore prefrontal regions modulate amygdala activity via an inhibitory connection from regions of the prefrontal cortex which are activated during exposure to fear-evoking stimuli after extinction learning (Davidson, 2002; McGarry & Carter, 2016).

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The neural bases of response inhibition in healthy participants have been widely investigated in neuroimaging studies. Those studies involved both motor and emotional inhibition. Approaches that examine brain activity during motor response inhibition usually implement tasks in fMRI scanner that involve a routine response, which requires effortful withdrawal or cancellation of the already initiated response when an occasional “stop” cue or instruction occurs. Two experimental paradigms that create withdrawal/cancellation responses are called the “Go/no-go task” (GNG) and the Stop Signal Task (SST), and these are commonly used in cognitive neuroscience. In this paradigm, participants are instructed to press a left or right button quickly in response to a “Go” cue. In randomly generated trials, a “Stop” cue is presented quickly, instructing the participant to inhibit the already planned response. The assumption is that having more “Go” than “Stop” trials involves responding rather than inhibiting the response, which leads to the development of a routine which can be later disrupted (Verbruggen & Logan, 2008). Aron and colleagues employed the Stop Signal Paradigm in order to investigate the neural bases of inhibition and demonstrated higher brain activity in the right prefrontal cortex during successful inhibition (Aron & Poldrack, 2006). Lesions in prefrontal regions result in an impaired ability to control motor inhibition (Hodgson et al., 2002).

The PFC also plays a crucial role in emotional inhibition and cognitive reappraisal of emotion. In particular, neuroimaging studies performed on healthy participants found increased activity in medial prefrontal cortex (MPFC) and dorsolateral prefrontal cortex (DLPFC) during perception offearful pictures (Lange et al., 2003), fearful faces (Nomura et al., 2004), emotional reappraisal (Ochsner et al., 2002), or suppressing negative mood during decision making (Beer, Knight, & D’Esposito, 2006). Moreover, studies found that increased activity in the DLPFC and MPFC has an inverse relationship with decreased amygdala activity in the regulation of emotions.Transcranial magnetic stimulation (TMS) studies demonstrated that the DLPFC plays a role in the recovery from anxiety (Balconi & Ferrari, 2013) and trauma (Karsen, Watts, & Holtzheimer, 2014). Boggio et a.l (2010) showed that repetitive TMS of the bilateral DLPFC reduces symptoms of PTSD, however, applying TMS on the right DLPFC has even better results, including at 3-months follow-up.

On the contrary, studies comparing patients with phobias, anxiety and PTSD with healthy controls demonstrated decreased activation in the DLPFC and the MPFC

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inversely correlated with increased activity in the amygdala when exposed to anxiogenic stimuli, in those who suffered phobia, anxiety or PTSD (Duval, Javanbakht, & Liberzon, 2015; Etkin & Wager, 2007; Ipser, Singh, & Stein, 2013). The amygdala, which is a part of the limbic system, plays a crucial role in the detection of potentially threatening stimuli. A vast number of studies on rodents and humans have demonstrated that activity in the amygdala increases as a response to fear-relevant cues. Increased activity was found in the amygdala during viewing of negative pictures (Irwin et al., 1996), fearful faces (Morris et al., 1996) or aversive stimuli (Buechel et al.,1998). Conversely, in phobic patients, this amygdala activity is exaggerated due to abnormalities in the amygdala-prefrontal circuit (Rauch et al., 2003). Some researchers suggested that hypoactivation and hyperactivation in these areas may be associated with different symptom severity (Weber et al., 2013). Therefore patients who score high on symptom measurement scales in clinical assessment will show greater activity in the amygdala, and lower activity in prefrontal areas, which are correlated with symptom severity. Hypoactivation in the MPFC and DLPFC could indicate deficits in emotional regulation, while hyperactivation in the amygdala could indicate an abnormally exaggerated response to the threat (Duval et al., 2015). Therefore, modulation of the amygdala by the PFC could be one of the neural mechanisms which underlie the efficacy of ET and VRET in anxiety disorders, specific phobias and PTSD.

Despite evidence showing how ET changes the fear circuit, little is known about what is happening within the session (Åhs, Gingnell, Furmark, and Fredrikson, 2017). Within-session brain imaging would help therapists objectively monitor patient’s response in real time, and determine the optimal level of exposure for the treatment to occur (Brouwer, Neerincx, Kallen, van der Leer, and ten Brinke, 2011). Treatment effects have been observed during ET sessions in patients with specific phobias, as measured by self-reports (see Zlomke and Davis, 2008 for a review). However, there has been little research on the neural basis of within-session inhibitory learning during ET. So far, two brain imaging studies have investigated the effects of ET sessions on the brain by measuring within-session changes in neural activity in phobic participants during repeated exposure to fearful stimuli. The study conducted by Veltman et al., (2004) compared brain activity from arachnophobic participants to healthy controls employing a symptom provocation paradigm which involved a

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continuous presentation of series of pictures of either spiders or butterflies. They found habituation effects in the bilateral anterior medial temporal lobe, including the amygdala, reflected in the decline of Regional Cerebral Blood Flow (rCBF) in phobic participants during repeated exposure to pictures of spiders. In particular, right amygdala activity showed habituation effects after 5–15 minutes of exposure. More recently, the study conducted on patients with social anxiety disorder found a within- session reduction in amygdala rCBF, as well as decreased anxiety ratings and heart rate during the stressful speech in front of an audience– from one speech to another (after 2.5 minutes) (Åhs et al., 2017). However, both of those studies employed Positron Emission Tomography (PET) to measure brain response. PET has a low temporal resolution, therefore, limits the accuracy of data acquisition in the temporal domain (Varvatsoulias, 2013). Alternative brain imaging methods give better temporal resolution, theoretically making them more relevant for monitoring within-session changes. Such technologies include Functional Near-Infrared Spectroscopy (fNIRS) or Electroencephalography (EEG). Although fNIRS has a lower spatial resolution, it offers a better temporal resolution that would allow better insight into what is happening in the brain during the treatment session (Ohtani, Matsuo, Kasai, Kato, and Kato, 2009). Two studies have employed fNIRS to measure temporal changes in the brain during Eye Movement Desensitisation and Reprocessing (EMDR) treatment for PTSD, showing a potential of using fNIRS as a tool for within-session brain monitoring during a treatment (Amano et al., 2016; Ohtani et al., 2009). Although the aforementioned studies have provided some insight into the neural activity during ET session, so far there are no studies which investigated within-session brain activity during VRET.

Measuring within-session brain activity during VRET would help to understand what changes occur, and when they occur in the brain during a single session. Previous studies demonstrated that VRET has a potential to trigger inhibitory response and emotional regulation after the treatment (described in details in Chapter 3 – Systematic Review), however they did not demonstrate on which stage of VRET these changes occur, what is the minimal amount and duration of VRET to achieve a therapeutic effects as measured from the neural activity.

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