Using neuromodulation of specific brain networks to treat psychiatric disorders is gaining interest, with both selective lesions and deep brain stimulation (DBS). Even though encouraging results have been obtained using neuromodulation of limbic brain networks, around half of patients remain poor responders or even treatment resistant without any clear explanations. From an anatomical point of view, therapeutic targets remain poorly defined and no surgical tool seems to be precise enough to reach the individually defined targets. This is especially true for the subthalamic area which comprises the subthalamic nucleus (STN) and its adjacent medial subthalamic region (MSR) which extends to the wall of the third ventricle. Three different surgical targets for psychosurgery have been proposed within the MSR,: the anteromedial STN, used to treat severe obsessive compulsive disorders (OCD) (Mallet et al. 2008; Chabardes et al. 2020), the medial forebrain bundle (MFB) to treat resistant depression (Schlaepfer et al. 2013; Coenen et al. 2019) and recently OCD (Coenen et al. 2016), and the so-called “Sano triangle” to treat pathological aggressiveness (Sano 1962; Sano et al. 1966, 1970, Torres et al. 2013, 2020; Micieli et al. 2017). These three regions are anatomically close to each other with no clear-cut boundaries, and their different neuronal and fibre types remain largely unknown in humans. This may explain the difficulty in interpreting psychiatric effects of neuromodulation in this area and to formulate physiological hypotheses regarding the effects obtained.
High frequency stimulation of the STN in some patients with Parkinson’s disease (PD) has been reported to induce psychiatric symptoms such as hypomania (Welter et al. 2014), and to alleviate significantly OCD when stimulating the anteromedial part of the nucleus (Mallet et al. 2007). Following this finding in PD, an initial randomised double-blind trial was done in refractory OCD patients that demonstrated the ability for STN-DBS to significantly alleviate obsessions and compulsions. However, about a quarter of patients were unresponsive without obvious predictive factors (Mallet et al. 2008; Chabardes et al. 2020), whereas roughly half of the patients had a significant alleviation that surprisingly necessitated only a very small volume of activated tissue within the anteromedial STN. One possible explanation for these unpredictable results was that the optimal target is so small that DBS placement is very difficult to achieve, especially in the light of individual anatomical variability. Moreover, at present, no imaging tools could answer this question with high enough accuracy and especially if the goal is to reach neurons and pathways that could only be identified at the microscopic level.
Anatomically, the STN is not a homogeneous nucleus, with the highest density of its glutamatergic neurons being observed in its ventromedial part with a small population of GABAergic interneurons (Lévesque and Parent 2005). The STN receives two main projections from the cortex and from the external pallidum, with the anteromedial STN receiving mainly inputs from the limbic ventral pallidum (Karachi et al. 2005; Haynes and Haber 2013). The STN also receives multiple sources of innervation, with a sparse dopaminergic projection from the substantia nigra pars compacta and the ventral tegmental area as reported in monkeys (Lavoie et al. 1989; François et al. 2000) and humans (Augood et al. 2000), and an important serotoninergic and cholinergic innervation (Parent et al. 2011; Eid et al. 2014). Whether these different modulatory inputs homogeneously innervate the whole extent of the STN or are restricted to specific functional territories of the nucleus, is still to be determined and has important relevance for the understanding of the clinical effects observed following DBS, and would shed some light on the physiology basis of OCD.
Lying between the STN and the third ventricle, the MSR is poorly defined anatomically with numerous fibres of passage and sparse cell bodies (Temiz et al. 2019; Barbier et al. 2021). The MFB constitutes the biggest fibre bundle of the MSR, and contains both ascending and descending fibres of the mesolimbic pathways. These fibres are mainly dopaminergic and serotoninergic and lie along the dorsal border of the STN (Parent et al. 2011). The MFB, and especially its supero-lateral branch, is a relatively new target and its stimulation seems efficacious to alleviate depression (Schlaepfer et al. 2013; Coenen et al. 2016, 2019) and has shown interesting recent results in bipolar disorders (Gippert et al. 2017) and resistant OCD (Coenen et al. 2016; Oldani et al. 2021). The hypothetical mechanism of such therapy is that MFB high frequency stimulation activates basal forebrain structures and prefrontal cortex and may explain the clinical benefit obtained. Whether DBS of the MFB also modulates other neurotransmitters such as descending glutamatergic projections from the PFC remains to be determined (Schlaepfer et al. 2013).
In the most medial part of the MSR, the Sano triangle has been used as a target to treat pathological aggressiveness in schizophrenic and autism-spectrum disorders patients with stereotactic lesions in the 70’s (Sano 1962; Sano et al. 1966, 1970), and more recently with DBS (Torres et al. 2013, 2020; Micieli et al. 2017; Yan et al. 2022). The target first defined by Sano was within the posterior hypothalamus (Sano 1962; Sano et al. 1966, 1970). However, anatomically the Sano triangle is located posterior to the mammillary body which is actually defined as the posterior limit of the hypothalamus (Swaab 2003; Schaltenbrand et al. 2005; Nieuwenhuys et al. 2008). Due to this discrepancy and to the lack of clear boundaries, defining the Sano triangle is challenging. Its morphological organisation is not well-known in primates but roughly located between surrounding structures such as the posterior hypothalamus and the midbrain Periaqueductal Grey (Nauta et al. 1969; Carpenter 1991).
All these data highlight the fact that improved targeting for treatment-resistant psychiatric disorders needs a precise characterisation of the morphological organisation of targets within the subthalamic area in the primate brain. In this study, we aim to identify the main neuronal and fibre types present in the primate MSR. By using immunohistochemistry and fluorescent in situ hybridisation (FISH) in regularly spaced sections, we provide 2D and 3D maps of labelled fibres and cell bodies to allow precise delineation of the three targets: the anteromedial STN, the MFB and the Sano triangle. Our final aim is to be able to identify the neuronal populations, the axon terminals and the fibre bundles included in lesions or volume of activated tissue (VTA) induced by DBS in order to better understand the physiology basis of the effects of neuromodulation in these severe and resistant psychiatric diseases in a given patient.