**5. Rationale and mechanisms of action**

Although the exact mechanisms of action of DBS are still elusive in spite of extensive research, several theories have been put forward. These proposed mechanisms can be divided according to the latency of onset of the effects from the time of stimulation into acute (seconds to hours) and chronic (days to months). The two major proposed mechanisms are as follows:


However, there is a considerable overlap among the proposed mechanisms and one group of mechanisms has effects over the other, as described in detail in the following sections. Furthermore, depending on the methods used to investigate the mechanisms of action, different aspects of stimulation effects are tested. With an integrative approach combining investigations employing different modalities, one can understand the general effects of DBS.

### **5.1 Modalities used to study the mechanisms of DBS**

Different methods have been used to quantify the changes produced by the DBS at the cellular, tissue and system levels to study the mechanisms of action of DBS. These modalities can be broadly classified into electrophysiological, imaging, biochemical, and molecular methods. Imaging techniques such as positron emission tomography (PET) and functional MRI (fMRI) provide information on both localand system-level changes. These are complementary methods: functional imaging studies have high spatial resolution, whereas electrophysiological methods have high temporal resolution. Moreover, electrophysiological methods directly measure neuronal activities rather than indirect measures of neural activities using bloodflow changes measured by imaging methods [13].

There are several hypotheses proposed by different schools of thought, to explain the processes by which DBS works. Accepted and popular hypothesis relied on the alteration of pathological brain circuit activity induced by stimulation [12, 14]. The stimulating impacts that are accountable for this disturbance occur at protein, ionic, cellular, and network levels to produce symptom improvements [15]. While it is presently unclear that which of the DBS' wide-ranging impacts are needed and adequate to generate therapeutic results, it is evident that highfrequency (~100 Hz) pulse stations (~0.1 ms) produce network reactions that are essentially distinct from low-frequency (~10 Hz) stimulation. The electrodes implanted into the brain redistribute the charged particles (such as Na+ and Cl−ions) throughout the extracellular space, which generates electric field and ultimately leads to the manipulation of sodium channel protein's voltage sensor embedded in the neuron membrane [16]. The opening of sodium channels at the cellular level may generate a potential action for initiation of axons and can propagate in both orthodromic and antidromic directions. DBS causes, activated axons are able to follow very high fidelity stimulus rates at ~100 Hz, but these highfrequency synaptic transmissions are less robust and much complex than that of axonal transmission [17, 18].

Under such high-frequency activity, postsynaptic receptors can be depressed and axon terminals can exhaust their released pool of neurotransmitters [19, 20]. Even though these synapses appear to be active in DBS, theories of information processing suggest that they could become low-pass filters that can block lowfrequency signal transmission [21]. This general mechanism, defined as "synaptic filtering," may play a crucial role in DBS, hampering the transmission of oscillatory activity patterns throughout the related networks of brain via neurons [22].

DBS' simple biophysical consequences offers a background where the patterns of network activity observed in patients can begin to be interpreted. The oscillation frequency of the stimulation signal is virtually zero as stimulation intensity remains unchanged during DBS, which could produce what is known as an "information lesion" in stimulated neurons [23]. According to this theory, action potential induced by DBS essentially bypasses some endogenous activity directly within the stimulated nerves and therefore slows down the transmission of oscillatory activity via the network. Nonetheless, not too many researches support the statement that high-frequency DBS causes lesion. Research with asleep and behavioral primates indicates how DBS can serve as a filter, which allows certain sensorimotor-related regulation of neuronal activity in the activated area, whereas specifically suppressing pathological low-frequency oscillation propagation [24, 25]. Certain basal ganglia activities, like those of reward-based decision-making or motor sequence learning, can often be retained during STN DBS or globus pallidus [26].

Certain factors may also have significant roles in treatment mechanism of DBS for PD like high-frequency DBS could provide an appropriate information lesion that inhibits the propagation of low-frequency oscillations, unlike low-frequency synchronization, could have no impact on broader network function [27, 28]. One of the advantages of this system is that high-frequency DBS is a standard device that can overcome various forms of clinical low-frequency excitations, like mobile tremor, dystonia, and akinesia rigidity [29].

The above proposed mechanism of DBS goes some way to explain only the acute effects of DBS in movement disorders, but this would not explain long-latency, chronic-adaptive alterations, which arise in individuals with dystonia following DBS and it may describe the psychological response to DBS. There might be possibility that low oscillating frequencies are strongly enhanced by long-term potentiation, while stimulation of high-frequency seems to have smaller plasticity effect. Therefore, replacing low-frequency patterns with high frequency can reverse

**35**

*Deep Brain Stimulation Approach in Neurological Diseases*

those symptoms associated with chronic disease [30]. DBS often takes months to get maximum benefit in various disorders, such as dystonia, depression, and

Nowadays, the open-loop system is embedded in many cases for DBS in which related parameters such as frequency, amplitude, and duty cycle can be adjusted by trained physicians. Stimulation, in this method, is fixed for initial months of treatment, then later can be adjusted based on patient's symptoms and overall conditions. A closed-loop system receives continuous feedback from the patient's neuronal circuits of brain by a present and programmed algorithm and thus appears to be an effective stimulation, and the parameters are adjusted real time. The implanted device causes physiological changes, both over long and short term, via automatic therapeutic parameter delivery with the ability to sense brain signals. Though there are no randomized controlled trials, comparing the therapeutic effect of open- vs. closed-loop system, few researchers opine that closed-loop method are more effective than the open-loop system. Through their novel closed-loop method, to compare the effectiveness of open-loop systems using two neurons, they demonstrated that closed-loop system with implantable electrodes in GPi region has better results on the disease motor symptoms in PD patients than the open-loop and

The common form of dementia, AD, treated with lesser efficiency of success in treatment via this technique has been used to modulate nonfunctional neuronal circuits with abnormalities seen in cortical and subcortical areas of the brain. Treatment helps in altering cholinesterase inhibitors and NMDA receptor antagonist [31]. DBS is a significant option for treatment of movement disorders that are intractable to drugs namely Parkinson's disease, essential tremors, dystonia, and have recently shown to be effective against treatment of OCDs, depression, and Tourette syndrome [5, 31].

DBS became the standard therapy refractory over the last 25 years for individuals with motor circuit disabilities, most notably PD, dystonia, and essential tremor. DBS use has now been confined to high-income and developing countries [34]. Hospital-discharge-based studies of US database has showed that >30,000 DBS surgeries were performed during 2002 and 2011, and the publications on DBS have

Over the last 10 years, STN is used as a target for DBS in PD [36]. GPi is also used as a target, but the choice between STN and GPi is often guided by the bio-

degenerative disorder [37]. In PD diagnosis, DBS is called the "second honeymoon"

Multiple studies have already shown that STN DBS produces continuous symptom relief even after 5–10 years of treatment, although with cognition and gait regression due to the unremitting development of the underlying

*DOI: http://dx.doi.org/10.5772/intechopen.91756*

**5.2 Open- vs. close-loop stimulation system**

high-frequency systems [32, 33].

**7. DBS in movement disorders**

**7.1 Parkinson's disease**

also risen over the same period of time [35].

medical group based on the medical context of the patient.

**6. DBS in different neurodegenerative diseases**

epilepsy [31].

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

axonal transmission [17, 18].

There are several hypotheses proposed by different schools of thought, to explain the processes by which DBS works. Accepted and popular hypothesis relied on the alteration of pathological brain circuit activity induced by stimulation [12, 14]. The stimulating impacts that are accountable for this disturbance occur at protein, ionic, cellular, and network levels to produce symptom improvements [15]. While it is presently unclear that which of the DBS' wide-ranging impacts are needed and adequate to generate therapeutic results, it is evident that highfrequency (~100 Hz) pulse stations (~0.1 ms) produce network reactions that are essentially distinct from low-frequency (~10 Hz) stimulation. The electrodes implanted into the brain redistribute the charged particles (such as Na+ and Cl−ions) throughout the extracellular space, which generates electric field and ultimately leads to the manipulation of sodium channel protein's voltage sensor embedded in the neuron membrane [16]. The opening of sodium channels at the cellular level may generate a potential action for initiation of axons and can propagate in both orthodromic and antidromic directions. DBS causes, activated axons are able to follow very high fidelity stimulus rates at ~100 Hz, but these highfrequency synaptic transmissions are less robust and much complex than that of

Under such high-frequency activity, postsynaptic receptors can be depressed and axon terminals can exhaust their released pool of neurotransmitters [19, 20]. Even though these synapses appear to be active in DBS, theories of information processing suggest that they could become low-pass filters that can block lowfrequency signal transmission [21]. This general mechanism, defined as "synaptic filtering," may play a crucial role in DBS, hampering the transmission of oscillatory

DBS' simple biophysical consequences offers a background where the patterns of network activity observed in patients can begin to be interpreted. The oscillation frequency of the stimulation signal is virtually zero as stimulation intensity remains unchanged during DBS, which could produce what is known as an "information lesion" in stimulated neurons [23]. According to this theory, action potential induced by DBS essentially bypasses some endogenous activity directly within the stimulated nerves and therefore slows down the transmission of oscillatory activity via the network. Nonetheless, not too many researches support the statement that high-frequency DBS causes lesion. Research with asleep and behavioral primates indicates how DBS can serve as a filter, which allows certain sensorimotor-related regulation of neuronal activity in the activated area, whereas specifically suppressing pathological low-frequency oscillation propagation [24, 25]. Certain basal ganglia activities, like those of reward-based decision-making or motor sequence

activity patterns throughout the related networks of brain via neurons [22].

learning, can often be retained during STN DBS or globus pallidus [26].

tremor, dystonia, and akinesia rigidity [29].

Certain factors may also have significant roles in treatment mechanism of DBS for PD like high-frequency DBS could provide an appropriate information lesion that inhibits the propagation of low-frequency oscillations, unlike low-frequency synchronization, could have no impact on broader network function [27, 28]. One of the advantages of this system is that high-frequency DBS is a standard device that can overcome various forms of clinical low-frequency excitations, like mobile

The above proposed mechanism of DBS goes some way to explain only the acute

effects of DBS in movement disorders, but this would not explain long-latency, chronic-adaptive alterations, which arise in individuals with dystonia following DBS and it may describe the psychological response to DBS. There might be possibility that low oscillating frequencies are strongly enhanced by long-term potentiation, while stimulation of high-frequency seems to have smaller plasticity effect. Therefore, replacing low-frequency patterns with high frequency can reverse

**34**

those symptoms associated with chronic disease [30]. DBS often takes months to get maximum benefit in various disorders, such as dystonia, depression, and epilepsy [31].

### **5.2 Open- vs. close-loop stimulation system**

Nowadays, the open-loop system is embedded in many cases for DBS in which related parameters such as frequency, amplitude, and duty cycle can be adjusted by trained physicians. Stimulation, in this method, is fixed for initial months of treatment, then later can be adjusted based on patient's symptoms and overall conditions.

A closed-loop system receives continuous feedback from the patient's neuronal circuits of brain by a present and programmed algorithm and thus appears to be an effective stimulation, and the parameters are adjusted real time. The implanted device causes physiological changes, both over long and short term, via automatic therapeutic parameter delivery with the ability to sense brain signals. Though there are no randomized controlled trials, comparing the therapeutic effect of open- vs. closed-loop system, few researchers opine that closed-loop method are more effective than the open-loop system. Through their novel closed-loop method, to compare the effectiveness of open-loop systems using two neurons, they demonstrated that closed-loop system with implantable electrodes in GPi region has better results on the disease motor symptoms in PD patients than the open-loop and high-frequency systems [32, 33].
