**1. Introduction**

Longevity is increasing and consequently triggering a surge in age-related, multimorbid neurodegenerative diseases [1,2]. One of these diseases is Parkinson's disease (PD). PD is the second most common neurodegenerative disorder worldwide and typically occurs after 50 years of age [3]. This is a multi-systems disease primarily characterized by symptoms that affect movement control, such as bradykinesia, tremor, rigidity, postural instability, and gait difficulties [3].

Drug treatments for PD are symptomatic in nature and function to replace the dopamine deficiency within the brain that occurs due to loss of nigrostriatal dopamine neurons [4–6]. While dopaminergic medications relieve the motor-related symptoms of PD, they do not address non-motor symptoms, further complications, or disease progression [6]. Moreover, drug therapy in PD is associated with side e ffects that include but are not limited to nausea and vomiting, sleep disorders, hallucinations, and delusions. Furthermore, as the disease progresses, initially beneficial drug treatments become less e ffective in about 40% of patients. At this stage, the therapeutic window begins to narrow and the medication may wear o ff faster, resulting in the re-emergence or worsening of motor fluctuations [7,8]. Chronic drug treatment and disease progression are also associated with levodopa-induced dyskinesias, which refer to involuntary, uncontrolled movements that occur when medications are most e ffective [7–9]. Increasing the dosages in response to reduced durability of levodopa or dopamine agonists is not always feasible. Alternative treatments such as device-aided therapies may then be considered.

The next step for a subset of patients is neurosurgery intervention by means of deep brain stimulation (DBS) of the subthalamic nucleus (STN) [10–13]. The STN is a small, glutamatergic, biconvex structure with a high iron content that is located within the subcortex [14,15]. DBS involves the implantation of electrodes that emit persistent high frequency stimulation in this nucleus [11–13]. The STN is a viable target for DBS as it modulates output of both the indirect and hyper-direct cortico-basal pathways, whose functions are assumed to suppress undesirable motor behavior and inappropriate movements, respectively [16,17]. In PD, dopaminergic degradation of the substantia nigra (SN) is thought to result in inhibition of direct pathways, as well as disinhibition of indirect and hyper-direct pathways. Collectively, this leads to the functional disinhibition of output to motor-related areas of the cortex, which is thought to produce impaired movement and reduced movement control [16]. However the exact mechanisms underlying DBS are still poorly understood, although the general consensus is that DBS results in a functional normalization of pathologically overactive circuits [17–19].

While DBS may ameliorate between 60 to 90% of the motor-related symptoms of PD, it can produce neuropsychiatric side e ffects and emotional or associative disturbances, with side e ffects ranging from hypomania; apathy; hallucinations; and, as well as general changes in moral competency, personality and reckless behavior [20–23]. A fraction of patients will fail to exhibit a long-term clinical benefit in the reduction of parkinsonian symptoms [24,25]. Revisions or removals of the DBS system occur in between 15 and 34% of operated patients, 17% of which are attributed solely to electrode misplacement [26,27]. Additional risks can arise from the surgery itself, with implantation posing a 15% risk of "minor and reversible problems", and a 2–3% risk of fatal or hemorrhagic events, infection, lead fracture, and dislocation [28]. Between 2013 and 2017, there were 711 bilateral DBS placement surgeries in The Netherlands, a subset of which were su ffering from PD. Of those 711 surgeries, 169 patients required the DBS system to be either replaced or removed entirely [29]. These side e ffects and adverse outcomes can partially be attributed to suboptimal placement of the DBS lead, which is dependent on the accuracy of the preoperative planning procedures [30,31].

### **2. Using MRI to Target the STN in PD for DBS**

As noted, the success of DBS treatment is partly determined by the accuracy of targeting the STN. Further, targeting is dependent on stereotaxic precision, neuroimaging methods, and electrophysiological mappings [32]. Identification of the STN can be achieved in two ways: indirectly or directly. Indirect targeting refers to identification of the DBS target via application of reformatted anatomical atlases, formulae coordinates, and distances from anatomical landmarks. These standard targets can be applied to a patient's individual magnetic resonance imaging (MRI), or can be used as a coordinate for navigation with a stereotaxic reference system (see next paragraph). Additionally, intra-operative microelectrode recordings, macrostimulation, and intraoperative behavioral feedback are commonly used for verification with indirect targeting [32,33]. Direct targeting refers to visualization of the STN on patient-specific MRI images [34,35].

For indirect targeting, the most common landmarks are the mid-way point between the anterior and posterior commissure (AC and PC, respectively), which are visualized and marked on a T1-weighted (T1w) MRI, computer tomography (CT), or ventriculography [33,36]. The native brain is commonly realigned to the AC-PC with a Euclidean transform [37,38]. This transform provides an augmented matrix with a 3D homogenous coordinate system, allowing for application of formulae coordinates and distances. The standardized STN coordinates are defined as 12 mm lateral, 4 mm posterior, and 5 mm inferior to the mid commissural point [39]. Some centers may utilize their own reference points, such as the top of the red nucleus [40–42].

Direct targeting with patient-specific MRI is generally preferred as the STN is known to shift with both age and disease, as well as vary in size, shape, and location across individuals [43–47]. Clinical MRI typically visualizes the STN using T2-weighted (T2w) images, which present the nucleus as a hypointense region relative to surrounding tissue. The optimal part of the STN is considered to be the ventral dorsolateral portion, also termed the somatosensory region, and is assumed to have direct connections with pre-motor cortical areas [48]. As with indirect targeting, direct targeting also incorporates AC-PC alignment, which provides the common reference system required for frame-based stereotaxic surgeries. Additionally, AC-PC alignment allows for comparisons between planned target location, actual target location, and postoperative verification. Therefore, clinical identification of the STN is usually achieved with a combination of both direct and indirect targeting methods.

The presence of extreme side e ffects and lack of clinical e ffect that can occur with DBS may arise from either direct or indirect targeting. One method for increasing the success and e fficacy of DBS is to optimize preoperative planning procedures via neuroimaging techniques. For instance, advanced MRI can be used to increase visualization and understanding of anatomy, connectivity, and functioning of the STN. This information can then be used to inform on optimal electrode placement on a patient-specific basis.

The goal of this paper is to explain the current procedures for structural target identification of the STN for DBS in PD using MRI. We identify limitations that may contribute to suboptimal identification of the STN and provide alternatives for optimizing MRI in order to visualize the STN. The organization of topics is as follows: field strength; current procedures for intra and post-operative verification with microelectrode recordings; SAR limitations; shimming and magnetic field corrections; sequence types and contrasts; voxel sizes; motion correction; registration and image fusion; quantitative maps; complications unrelated to pre-operative planning; and conclusions. The suggestions are presented with the underlying expectation that more accurate visualization can translate into targeting and implantation with increased precision.
