1, Mechanism of DBS for PD.
PD is due to the absence of SNc dopamine neurons, which causes symptoms such as muscle tonicity and bradykinesia through two direct and indirect pathways, resulting in an excessive increase of inhibition in the motor regulatory loop. Destruction surgery destroys the abnormally excited neurons and their fibers, thus eliminating their abnormal effects on other neurons and achieving a new state of equilibrium. In terms of clinical effects, the effect of DBS is similar to that of disruption.
As early as the 1960s, Hasslar et al. found intraoperatively that high-frequency electrical stimulation (>100 Hz) of the thalamic motor nucleus cluster inhibited tremor. This suppression disappeared after stimulation was stopped and was reversible. Subsequently, this high-frequency stimulation was used as a target confirmation method in thalamic disruption surgery.
More recent DBS implantations have further validated that high frequency electrical stimulation has similar effects to disruption, except that the effects are reversible and adjustable. At the cellular level, however, the mechanism of action of DBS is far more complex than that of disruption. Electrical stimulation can either activate peripheral neurons and fibers by depolarizing them or deactivate them by blocking the depolarization process, depending on the morphology of these neurons, the frequency of the underlying electrical activity, the distance from the stimulating electrode, and the stimulation parameters. Moreover, neuronal cytosol and fibers respond differently to stimulation. This complexity of the mechanism of action at the cellular level may cause different clinical effects of disruption and stimulation of the same target site.
The stimulation parameters currently used in clinical practice generally affect the tissue around the electrode in a 2-3 mm area, but this is not constant. carparros-Lefebvre autopsy of a patient who died 8 years after Vim nucleus DBS implantation found no abnormal changes other than a thin layer of glial hyperplasia around the electrode. However, little is still known about the long-term effects of DBS and further studies are needed.
2. Case selection.
The effectiveness of surgical treatment depends on the appropriate case selection. Generally speaking, the indications for DBS treatment are.
(1) Primary Parkinson’s disease.
(2) Effective for treatment with levodopa preparations.
(3) Diminished drug efficacy or symptom fluctuations and switching.
(4) Inability to tolerate drug therapy due to side effects.
(5) Contralateral disfiguring surgery with complications.
The contraindications are.
(1) Bleeding tendency or the presence of other serious medical conditions that cannot tolerate stereotactic surgery.
(2) With dementia, suicidal tendencies, severe apprehension, etc.
(3) Advanced Parkinson’s patients who are completely unable to take care of themselves and are bedridden. The age of surgery is not strictly limited. For Parkinson’s superimposed syndrome (ParkinsonPlus) such as Shy-Drager syndrome (SDS), striatal degeneration (SND), progressive supranuclear palsy (PSP) and olivopontocerebellar-cerebellar atrophy (OPCA), surgery should be selected with caution because their pathophysiological basis is different from that of primary Parkinson’s disease and responds poorly to treatment with DBS. These syndromes often have cone bundle symptoms such as positive pathological signs, cerebellar symptoms such as ataxia, and poor response to levodopa treatment, which can be distinguished from Parkinson’s disease.
3.Localization methods.
Surgical localization first uses imaging localization such as MRI, CT, etc., and then does target correction intraoperatively according to electrophysiological response. Traditional indirect imaging localization uses AC-PC as the reference point, but because of individual differences (such as different widths of the three ventricles, etc.), there is a certain error in the target point.
MRI has higher resolution and can directly show the contours of certain nuclei and surrounding structures, which can be localized directly and avoid the bias caused by individual differences in indirect localization methods, but MRI may produce errors due to signal drift. CT does not have signal drift and is more accurate, but it does not show the nuclei as well as MRI. If CT and MRI can be combined, localization can be more accurate. Even with very accurate image positioning, intraoperative brain displacement can still occur due to intraoperative changes in body position, cerebrospinal fluid leakage, and other factors, thus shifting the position of the target site.
Currently, the main methods of intraoperative electrophysiological target verification are microelectrode recording and stimulation, and “macrostimulation”, i.e., direct stimulation with radiofrequency electrodes or DBS electrodes. Microelectrode recording is used to identify neuronal cells in different nuclei by their different firing frequencies, while motor-related and tremor-related neuronal firing is recorded to identify motor-related nuclei. Stimulation can also help identify the location of the corresponding neuron or fiber by eliciting motor and sensory responses and visual flash responses.
Macrostimulation can determine the distance between the target site and the internal capsule and the optic tract by impedance measurement and the stimulation threshold that causes motor, sensory and visual flash responses, and use the improvement of clinical symptoms caused by high frequency electrical stimulation as the basis for target site confirmation.
4.Target selection.
At present, there are three main surgical targets for DBS treatment of PD: Vim, Gpi, and STN.
(1) Vim: It is the first DBS treatment target used in clinical practice, located in the posterior 1/4 of AC-PC line, 12~15mm next to AC-PC line, 0~2mm on AC-PC plane. intraoperative microelectrode recording can see motor related electrical activity and tremor synchronous discharge. the outer side of Vim nucleus is the internal capsule, the posterior side is VC nucleus, low threshold stimulation that causes muscle contraction suggests that the electrode is biased outward into the Low-threshold stimulation causes numbness in the contralateral limb, suggesting that the electrode is biased posteriorly into the VC nucleus, and the target location can be determined intraoperatively based on this stimulation response. In the Vim nucleus, there are corresponding torso localizations, which are arranged from the face to the lower extremities from inward to outward, and the corresponding target sites can be selected clinically according to the main sites of tremor.
Vim’s DBS treatment is effective in suppressing tremor in PD patients and has been approved by the FDA in 1995. Its common stimulation parameters are 60-120цs, 130-200 Hz, and 1-3 V. In a 6-month-8-year follow-up of 80 PD patients treated with VimDBS, Benabid et al. showed complete or almost complete control of tremor in 88% of patients. Other authors have reported similar results. It has been suggested that Vim stimulation is effective for drug-induced casual dyskinesia but is less effective for myotonia and bradykinesia.
The most common complication of DBS treatment with Vim is dysarthria, especially in patients who have undergone thalamic disruption contralaterally or are treated with bilateral VimDBS. However, it is less risky compared to bilateral thalamic disruption because it can be reversed or alleviated by adjusting stimulation parameters. Others, such as contralateral hemianesthesia, mild hemiparesis, intracranial hemorrhage, and infection, also have a certain incidence.
(2) Gpi: Gpi is the most commonly selected target of disruption surgery for PD, which is located 2 mm before the midpoint of AC-PC, 18-22 mm below the midline, and 3-6 mm below the plane of AC-PC. neuronal firing is characteristic in the nucleus accumbens, Gpe, Gpi, and the boundary plate, and microelectrode recording can be used to assist in target identification, and the threshold of stimulus-evoked responses in the internal capsule and optic tract can be judged. The distance between the target site and the internal capsule and optic beam can be determined from the stimulus-evoked response threshold. Stimulation electrodes alone can also be used to adjust the target location according to the stimulation threshold. In the Gpi nucleus, there is also an anterior-to-posterior somatic positioning sequence from the lower extremities to the head, and the clinical target can be selected according to the patient’s main symptomatic areas.
DBS treatment of Gpi can effectively improve tremor, tonicity, bradykinesia and drug-induced hyperactivity in the contralateral limb of PD patients, and prolong the “open phase” state, but less improve the gait, posture and other mid-axis symptoms. Levodopa dose cannot be reduced in most patients. There is a lack of clinical data on the cost-efficacy evaluation of Gpi disruption and stimulation treatment, and further research is needed.
Complications of Gpi stimulation include visual impairment and dysarthria, but they can be reversed with adjustment of stimulation parameters and are therefore relatively safer than disruption. The safety of bilateral Gpi stimulation is greater than that of bilateral disruption. For patients who have undergone pallidum disruption on one side, contralateral Gpi stimulation may be a safer and more effective method.
(3) STN: It is a newly selected stimulation target for the treatment of PD, located 12 mm next to the midpoint of AC-PC and 2-3 mm below the plane of AC-PC. it appears as a flat pallid nucleus on MRI images, located ventral to the thalamus, medial to the posterior limb of the internal capsule, lateral to the red nucleus, and superior to the external side of the substantia nigra, and can be directly image localized. There are characteristic multicellular discharges with high background noise during microelectrode recording. Because STN disruption is prone to more serious complications such as deviated body throwing, disruption in the STN nucleus is generally not advocated for the treatment of Parkinson’s disease. However, the STN has a modulatory effect on both Gpi and SNr in the indirect pathway of the motor loop, and is therefore a more ideal target for stimulation in the treatment of Parkinson’s disease.
Benabid et al. reported that STN stimulation was effective for myotonicity, bradykinesia, and tremor, and that STN stimulation, especially bilateral STN stimulation, was effective in improving mid-axis symptoms such as gait, posture, and freezing phenomenon compared with Gpi, but less effective than Gpi for drug-induced casual dyskinesia. The incidence of complications of STN stimulation is not high, but if the stimulation voltage is too high, it may cause deviated throwing phenomenon and dystonia, and adjusting the stimulation parameters can reverse these side effects.
5. Summary.
With the gradual understanding of the pathophysiological mechanisms of PD, surgical treatment of drug-refractory PD has been further developed. Currently, the main surgical targets used in clinical practice are Vim, Gpi and STN, and DBS treatment has the following advantages over destructive treatment due to its reversible and adjustable characteristics.
(1) The STN can be chosen as the target, and DBS treatment of the STN nucleus can reduce the patient’s levodopa dosage, which may have a slowing or reversing effect.
(2) It can be used bilaterally or in patients who have been treated with destruction on one side.
(3) It does not interfere with the patient’s subsequent access to new, more effective treatments. Therefore, DBS is becoming an emerging treatment for PD. The long-term efficacy of DBS treatment (whether the long-term electrical stimulation will gradually lose its efficacy due to the formation of gelatinous scar around the electrodes) and its cost- efficacy comparison with disfigurement treatment are yet to be further clinically proven. In addition, with a better understanding of the pathophysiological mechanisms of PD, more appropriate surgical approaches and surgical targets will be explored.