The recent technical progresses in PET have the potential to broaden the spectrum of applications of nuclear medicine for both research and clinical investigations.

Dynamic scans at rest, assessing 18F-FDG uptake in the first minutes after bolus injection, allow to capture the cortical and subcortical distribution occurring at the same time. In these first minutes, in which the most of the radiopharmaceutical is extracted by the brain before reaching a plateau after about thirty minutes, 18F-FDG uptake, representing neuronal and glial activity, is consistently couple with brain perfusion [1]. The substantial advancements improving the sensitivity and time resolution of the cameras have paved the way to the implementation of the so-called functional PET, a new methodology implying a slow and constant infusion allowing to monitor tracer uptake during time and to measure within the same session its distribution at rest and while performing a task [2]. Furthermore, dual-phase amyloid-PET scans exploiting the high lipophilicity of the radiopharmaceuticals make of the early dynamic acquisition phase a good perfusion surrogate and a topographical/functional biomarker reflecting disease progression, while the late-phase corresponds to the pathophysiological state [3].

It is in this frame that, in the August 2019 issue of the European Journal of Nuclear Medicine and Molecular Imaging, it is reported an original and well-conducted study aiming at describing in fifteen soldiers suffering from post-traumatic stress disorder (PTSD) following war combat the functional changes occurring before and after eye movement desensitization and reprocessing (EMDR), a trauma-focused psychotherapy promoting the reprocessing of dysfunctionally stored information in traumatized patients [4]. In order to disclose such neurobiological changes, they were exposed from 10 minutes before to 7 minutes after 18FDG injection to a virtual reality war scene with strong autobiographic connotations. Therefore, the PET images acquired thirty minutes after injection represented the distribution of metabolism in the minutes peri-injection in which the emotional stimulus was administered. This procedure, performed during the symptomatic phase, was repeated after EMDR therapy, thus allowing to detect the metabolic changes associated with symptoms remission. Applying this elegant methodology, they were able to speculate on the role of the precuneus in reprocessing traumatic memories. After EMDR therapy, its modulation of anxious and fearful states made patients perceiving their traumatic event at a cognitive level without overwhelming emotionality.

In order to elicit an emotional response and to investigate in real time the regions hyper- or hypo-activated in association with symptoms, most of neuroimaging studies in psychiatry have been performed by administering during the recording of the functional activity the so-called script [5, 6]. When investigating PTSD, the script is either an autobiographical narrative of the traumatic event to be read from a written text or, more frequently, to be listened by an audiotape or, as in the Rousseau et al. study, the exposure of the patient to stimuli (images or sounds) correlated to the event itself. Aiming at disclosing the neurobiological correlates of PTSD, the first PET studies were performed in Vietnam veterans and in women abused during childhood by injecting 15O-water upon script listening [7, 8]. Subsequently, the same methodology was successfully implemented in SPECT studies in which the script was administered away from the camera gantry a few minutes pre- and post-injection assessing the blood flow distribution by 99Tc-HMPAO [9, 10] or 99Tc-ECD [11]. All these studies consistently reported in association with symptoms of hyperarousal, avoidance and re-experiencing (i.e. the typical clinical feature of PTSD), a hyperactivation of limbic system structures, i.e. amygdala, and a hypoactivation of cortical structures, i.e. prefrontal cortex [12, 13]. In the recent past, it has been reported by SPECT [14,15,16] and EEG [17,18,19] that trauma-focused psychotherapies, among which EMDR, reverse the functional changes caused by PTSD and normalize the activity in cortical and subcortical structures.

The successful outcome of the Rousseau et al. study replicated the methodology implemented by Chiaravalloti et al. investigating patients with multiple chemical sensitivity (MCS) [20]. They injected 18FDG in MCS patients and healthy controls (HCs) three minutes after the inhalation of either neutral or pure olfactory stimuli, prolonging the procedure for six more minutes. Also in this case, PET images acquired thirty minutes after injection represented the metabolic status at the time of the stimulation identifying several cortical regions in which metabolism, evaluated in the two different experimental conditions, differed between MCS patients and HCs.

The innovative PET methodologies described above overcome the disadvantages of functional magnetic resonance imaging (fMRI), the most used methodology in resting-state and functional activation studies in psychiatry [21, 22]. Some of these drawbacks have recently been discussed by Verger and Guedj [23], who pointed out that at single subject level the reproducibility of the studies could be impaired by the low and variable between runs signal-to-noise ratio and by the need of multiple runs. Furthermore, fMRI is sensitive to ferromagnetic artefacts deriving from implantable devices. Also the noise deriving by the coils may bias the experimental inputs and outputs and the tight space within the camera gantry may prevent scanning subjects suffering from claustrophobia. Beyond these technical drawbacks of fMRI, the main advantage of activation studies by 18FDG-PET is the possibility to perform the investigations outside the camera gantry. This will allow to run the experiments in a more ecological environment with the subjects comfortably positioned, less distracted by all camera-related variables and more focused of the task to be performed.

Moreover, the possibility to run functional neuroimaging investigations by 18FDG-PET makes them easier to be carried out and more approachable by nuclear medicine departments when compared with the ones performed producing 15O, the radioisotope extensively utilized in the past in the seminal activation studies on the neurobiology of PTSD [24]. In fact, the mandatory proximity of an in-house cyclotron, the equipment needed for 15O gas inhalation or continuous injection, and the need of an operator beside the bed to collect repeated arterial sampling restrict the possibility to perform the experiments to a very limited amount of centres.

PET activation studies in psychiatry may in the next future also benefit from the introduction of cameras with a temporal resolution of seconds. In fact, performing dynamic scans upon the neuronal activation elicited by the emotional stimuli will add to the information about metabolic distribution also the details about blood inflow enabling to explore the neurometabolic and neurovascular coupling in normal and pathological conditions.

All these potential advantages have to be carefully taken into account by the members of the nuclear medicine community. In a moment in which PET, beyond oncology, is gaining more and more space in neurology [25, 26], functional imaging might contribute to the renaissance of this methodology also in psychiatry. The possibility to perform activation studies with reliable spatial and temporal resolution will attract psychiatrist and psychologist not only for research purposes but, in a near future, also to discriminate between the different psychiatric disorders and to predict the outcome of psychotherapeutic and pharmacological treatments [27,28,29].