Deep Brain Stimulation for the Treatment of Aggressive Behaviour: Considerations on Pathophysiology and Target Choice

emotional response to stimuli and aggressive behaviour expression [17, 21] . The experimental low-frequency (8 Hz) stimulation of the posteromedial hypothalamus led to autonomic system arousal and defence-like behaviour in cats [22] . Following these observations, Miyazaki et al. [23] and Sano et al. [13] , in the 1960s, popularized with success the technique of pHyp lesioning in patients with severe aggressive behaviours. Given these considerations, both the pHyp region and the VC/ VS probably belong to the brain systems involved in the processing and expression of emotions. In order to further define the anatomical regions involved in the generation of aggressive behaviour, DBS-related literature data are of paramount relevance, even though they are not often considered. The reported efficacy of both the VC/VS and the pHyp targets led us to consider the possible structure connecting the 2 above-mentioned DBS target regions. The only well-described anatomical bundle of fibres connecting these 2 areas is the mesolimbic pathway, a dopaminergic pathway primarily connecting the VTA (located in the so-called “posterior hypothalamic region” defined by Starr [14] ) with the nucleus accumbens, part of the VS complex. This pathway is also known as the “reward pathway” because it is activated during the processes of rewarding, by which appetitive and consummatory behaviours are induced. This pathway has been extensively studied in addiction, and it is supposed to have a role in the positive symptoms of schizophrenia [24, 25] . Animal studies have already shown a role of this pathway in the pathophysiology of aggressive behaviour, but this was never delineated in humans (also given the obstacles in performing invasive studies). Panksepp and Zellner [26] hypothesized 2 distinct categories of aggression, RAGE and SEEKING, the former describing offensive/defensive rage and the latter predatory and methodical aggression. The rage response is mediated by the corticomedial amygdala, the medial hypothalamus, and the periaqueductal grey. Periaqueductal grey would generate the autonomic arousal, thanks to its brainstem nuclei connections, by means of the dorsal longitudinal fasciculus. The core of this system seems to be glutamatergic. The SEEKING response is mediated by the lateral hypothalamus and the mesolimbic dopaminergic system (VTA and nucleus accumbens). Panksepp and Zellner [26] also proposed interrelations between these 2 systems, mediated by an intrahypothalamic system between the medial and the lateral part. Both animals and humans would react with rage (RAGE system involvement) when an expected reward was not received (SEEKING system involvement), generating frustration. So, the electrical stimulation of DBS targets in the mesolimbic pathway could introduce a “noise” in the rewarding system, blocking an aggressive behaviour. These observations on the pathogenesis of IED led us to consider the disease as a circuitopathy or a system disease, in which the mesolimbic “reward” system has a central role. This observation allows clarifying the possible reason why both VC/VS and pHyp targets are successfully used in the DBS of aggressive behaviour. The experience of Giordano et al. [1] contributes to shedding a light in the field of the neurosurgical treatment of aggressive behaviour (hereby called “intermittent explosive behaviour, IED,” following the DSM-V). The case of a patient presenting with IED, intellectual disabilities, and obsessive ritualistic behaviours is described.