**6. How to perform connectomic analyses in patients with DBS implanted**

Assuming that there is no significant difference between the patient's brain and an average brain, normative connectomic analysis can be conducted to study the patient's connectivity profile that his neurostimulator may modulate. Unlike individual connectomic analysis, either structural or functional MRI data is enough for normative connectomic analysis. In other words, either diffusion-weighted MRI with tractography or functional MRI is required for normative connectomic analysis. With this network analysis, the precision of pre-operative targeting and post-operative programming can be enhanced [23, 60, 61].

The approach to conduct connectomic analysis in a patient with DBS implanted is described as follows (**Figure 2**) [23, 60, 61].

#### **Step 1: co-registration.**

Before DBS surgery, structural MRI brain, as well as diffusion-weighted or functional MRI brain is performed. After surgery, a computed tomography (CT) of the brain is done. The post-operative CT brain is then co-registered to the pre-operative MRI brain, preferably with brain shift correction and spatial normalization.

#### **Step 2: electrode localization.**

After co-registration of pre-operative and post-operative neuroimages, the electrodes can be localized while the adjacent neuroanatomical structures are identified.

#### **Step 3: estimation of volume of tissue activated (VTA).**

The VTA is an estimate of the volume and shape of the distribution of electrical signal stimulating brain tissues when the contact on a DBS electrode is activated. It depends on the composition of settings of the electrode contacts and implanted pulse

#### **Figure 2.**

*The approach to perform connectomic analysis in a patient with DBS implanted.*

generator, e.g., the number and locations of activated contacts, impedance, voltage, pulse width, or frequency [62, 63].

After the localization of DBS electrode, the VTA is estimated with the activated contact(s) on the DBS electrode identified. The physician can choose the electrode contact(s) stimulated with monopolar stimulation and decide the stimulation programming setting. The VAT will be estimated according to the DBS programming parameters.

#### **Step 4: calculation of connectivity profile from seed region.**

When a region-of-interest (ROI) has been identified, it can be used as a seed within specific functional or structural normative connectomes to work out its functional or structural connectivity, respectively. Usually, the VTA of a specific DBS electrode is selected as the seed.

## **Step 5: analysis of the relationship of DBS site connectivity with clinical outcome.**

Finally, a statistical analysis is conducted to investigate if there is a relationship between DBS site connectivity and clinical outcome, which can be symptom improvement or side effects.
