Monitoring pain response with deep brain stimulation

Abstract

The following is a review on monitoring pain response with deep brain stimulation.  Deep brain stimulation (DBS) has been clinically proven to be successful for various forms of chronic pain however further research is required since specific mechanisms of actions are not understood. Techniques such as beamforming and artefact rejection can be used to understand the whole brain activity and newer techniques such as null beamforming easily outscores normal beamforming since it works even in presence of artefacts such as DBs electrodes. Also, long term effects of DBs can also be observed and these have helped to better understand the brain activity as well help surgeons get specific targets for surgery.

Introduction

The most common neurodegenerative disorder after Alzheimer’s is Parkinson’s disease (PD), which is increasing its social and economic burden on society as the general population ages (LM & MM, 2006). According to some recent surveys the incidence of PD especially in industrialized countries is about 0.3% for the entire general population, 1% in people who are over 60 and increasing to 4% in people above 80 years (CA, 2008).

In PD, the substantia nigra pars compacta is mainly affected which leads to an inadequate formation of dopamine, which in turn affects the normal transmission of impulses originating from the basal ganglia (BG) (J, 2008). The basal ganglia are the main area responsible for conducting various cortical functions through the limbic and occulomotor loops (BG-thalamo-cortical loops) (AP et al., 2005). Mainly in the motor as well as occulomotor circuits the BG is deemed responsible for selecting which initiated actions will be carry forwarded and allowed to be expressed that act through the brain stem motor networks as well as thalamo cortical networks (J, 2008). Motor dysfunctions are one of the main One of the main indicators of PD and form a big part of its clinical diagnosis.

Background

Deep brain stimulation (DBs)

In the early 1990’s usage of deep brain stimulation (DBs) for Parkinson’s disease started being widely accepted by the general population with the popularity increasing exponentially. The teams of scientists and doctors form Grenoble (Benabid et al., 1987) and Lille (Benabid et al., 1991). Blond and Siegfried (1991) published data and findings which was the main reason for reigniting an interest in this technique especially after various earlier publications (IS et al., 1982) had failed to generate any interest or acceptance for using DB for PD. The main appealing thing about this reinvented technique was creating a beneficial effect on the affected tissue without destroying it. Prior to this technique neurosurgeons would only be partly or not successful whilst destroying the tissue in the process. Also, the early experiences (before 1960) with this technique were burdened with mortality and morbidity (Benabid et al., 2009). Recent advances in neuroimaging etc. have aided this technique further. It has been documented that during thalamotomy there is macrostimulation of the Vim i.e., ventral intermediate. The stimulation is a relatively high frequency (100 Hz) that helps block the contralateral tremors whereas it was noted that a low frequency (50hz) actually drove tremor (Benabid et al., 2009).  Permanently implanting the electrode to the area that chronically stimulates Vim at high frequency was a proposition put forth to suppress the tremors that also avoids any complications that may arise from a thalamotomy. On increasing the stimulation voltage beneficial effects were observed including blocked tremors whereas adverse effects were also avoided on reducing the voltage.

Reviewing the potential risks involved in DBs forms an essential and big part of patient’s preoperative assessment. Still the mechanisms by which DBs exerts its effects is still controversial (R et al., 2007). On comparison with high frequency DBs in thalamus that gave promising results for lesions it was assumed that DBs works by inhibiting neuron firing. This was one of the main reasons supporting the surgeon’s decision to target the STN, which has been known to be extremely reactive in primate models of PD (Benabid et al., 2009). But recent studies have proven that more complex mechanisms might be involved (Benabid et al., 2009). One theory is that it may be working by desynchronizing pathological rhythms located in the basal ganglia (Wilson et al., 2011). Deep brain stimulation also brings a host of problems concerned with the management of PD. For e.g., there are various complication arising out of brain surgery (infection, hemorrhage), neuropsychiatric issues arising due to stimulation are also present, hence intensive follow-up sessions are required to monitor and adjust the stimulation accordingly (Benabid et al., 2009). But the machines for these are really expensive however the patient on track considering all these drawbacks gets stunning results nonetheless (S et al., 2010) and can all fall into place upon selection of the correct patient (S et al., 2010).

Targets for DBs in Parkinson’s

The following are the two targets used for DBs in Parkinson’s 1) Sub thalamic Nucleus (STN) and 2) Globus Pallidus pars interna (GPi)

STN: – The most common site for DBs for Parkinson’s is STN. It is localized in the brain stem just beneath the thalamus. Stimulating this site especially in patients suffering from stiffness, tremors and bradykinesia can easily treat motor symptoms of PD. Hence it is a very popular site of stimulation. But STN is located exactly behind the corticospinal and coticotubular tracts and any damage may cause loss of control of muscles hence some patients suffer from speech and swallowing problems. Some instances patients have reported double visions this is due to enrollment of the occulomotor nerve which is just below the STN and this nerve is responsible for the movement of the eye as well. Apart from the side effects caused by stimulation of the neighboring structures along with STN, DBs of STN will also interact with DBs medication causing it to remain in the system and not get excreted as a normal drug would (S et al., 2010).

GPi: – A recent study by Follett et al., 2010 proved that DBs of STN and GPi are equally effective which contradicts earlier findings and preset rules. Patients who suffer from dystonia mostly opt for deep brain stimulation of GPi. Since immediate remission of the normal painful consequences of this disease such as cramping and posturing occurs. Also, stimulation of GPi has been documented to be very useful and effective to counter the motor symptom associated with Parkinson’s disease (KA et al., 2010). The globus pallidus is a region of the brain, which is concerned with regulating voluntary movements. It is located within the basal ganglia that with various other functions are also concerned with regulating movements occurring subconsciously. If GPi is damaged it can greatly hamper movement control leading to movement disorders. In so many patient cases this damage is caused deliberately during a procedure known as pallidotomy in which a lesion is deliberately created to decrease muscle tremors of involuntary nature.

DBs targets for pain

Other possible targets are also being evaluated. It is still not clinically validated however a study carried out at Oxford gave about 60% success rate with almost 50% reduction in pain. With further experimentations these new sites could well be integrated with the current methodology for DBs. The possible new sites are as follows

1) VPL (ventroposterior lateral nucleus): – The cortical information processing in the somatosensory system happens in between the spatially distributed and interconnected regions. The thalamus has been known to hold an important position in this network. The various signals emerging from the peripheries is constantly being relayed into the ventroposterior lateral nucleus (VPL) and information from the facial areas is being relayed into the ventroposterior medial nucleus (VPM) ultimately ending into the primary somatosensory cortex (SI) (W & PW, 2003). It has been documented that electrical stimulation of the contralateral nerve (phrenic) leads to the activation of VPL. It had also been observed in the same study that a direct stimulation of the diaphragm also increased activity of the VPL neurons that were earlier activated via phrenic nerve electrical stimulation, while some VPL neurons responded to afferent phrenic nerve stimulation as well as shoulder probing (W & PW, 2003).  Since this region modulates pain reception it can potentially act as a target for DBs.

2) Periaqueductal/periventricular regions (PAG/PVG): – The PAVG (periaqueductal and periventricular gray) region (of the midbrain) is an important are for the modulation of pain as well as autonomic signals (Sillery et al., 2005).  The PAVG region has been the target of DBs in response to increasing intractable pain persisting for longer than two decades. The effects of DBs on this region have known to release endorphins but since the connectivity of this region is poorly understood the exact mechanisms are still unclear (Sillery et al., 2005).

3) Anterior cingulate cortex (ACC): – It has been documented that deep brain stimulation of the subgenual sACC results in noticeable reduction in symptoms of depression in patients, which were deemed resistant to treatment (Johansen-Berg et al., 2008). SACC is actually a part of ACC that is located below the corpus callosum and parallels mainly to Brodmann’s area (BA) as well as percentages of BA32 and BA24. It has been implicated that ACC is the main hub dictating control over mediation of symptoms relating to depression. Also, recent brain studies have implicated its role in mediating being in a negative mood/state (Johansen-Berg et al., 2008).

Monitoring Brain activity

The most commonly used equipment is the Electroencephalography, or EEG, which actually records the electrical activity in the brain. This helps in the diagnosis of many neurological issues such as headaches, strokes, epilepsy, and degenerative brain diseases (Benabid et al., 2009). During this procedure extremely sensitive monitoring equipment is used to record the patient’s brain activity using electrodes that are placed on the scalp at specific intervals. Being non-invasive this test is pain free. The head is first measured, and the electrodes are placed on the scalp supported with a paste like substance. Whereas the deep brain stimulation consists mainly of three components that are the pulse generator implanted (IPG) inside the brain, the lead and finally the extension. IPG is basically a battery-powered stimulator that sends pulses to the brain at the target site. The surgeon, neurologist or trained technician optimizes the IPG to the exact calibration (Sillery et al., 2005).

The normal activity observed In the EEG is normally described as rhythmic activity and transients. The rhythmic activity if further divided into bands based on frequency. They are alpha, beta, gamma, and theta (Towle et al., 1993). Alpha is in between the range of 8-12 Hz and regarded as the first rhythmic EEG activity. A diffused alpha wave occurs in conditions such as coma. A beta frequency is observed between 12-30Hz and is closely associated with all motor behaviors. It is reduced during cortical damages. Gamma is in the range of 30-100Hz and represent network of neurons carrying out specific motor function. Theta is in the range of 4-7Hz and normally seen in children and mainly during meditation (Towle et al., 1993).

With the introduction of above-mentioned non-invasive techniques such as EEG examination of the brain during the clinical pain conditions was possible and significant progress has been made over the years in this field of study. Early hemodynamic studies made a good attempt to identify brain activity and tried to differentiate clinical pain from acute pain stages.  It has been documented that pain conditions (chronic clinical) more frequently involves PFC almost 81% as compared to normal subjects (only 51%).  It has also been noted that normal patients’ perception of pain more frequently than so involves S1, S2, Th and ACC (Apkarian et al., 2004). These findings were also consistent with the fact that ACC activity in normal subjects correlated with pain perception/intensity was due to distention of the rectum and this correlation was absent during conditions such as irritable bowel syndrome (Apkarian et al., 2004). On the other hand, pain that was experimentally induced in normal test subjects had a diminished baseline activity as well as diminished stimuli. Another study proved the correlation between the complex regional pain syndrome (CRPS) and thalamus, and that the thalamus undergoes a lot of changes during the CRPS. Thus, it was proven that brain activity during normal chronic condition is very different from the one observed upon experimental induction of painful stimulus in normal subjects (Apkarian et al., 2004).

Various techniques are used to study the brain activity and according to their set standards the electrodes are placed on the skull. For e.g., fMRI is another good technique which helps to detect changes in blood flow and oxygenation in the brain, while it has a good spatial resolution its temporal resolution is not good while EEG has moderate spatial but excellent temporal resolution so with its merits and faults placing electrodes at the local pain centers can prove beneficial.

Magneto encephalography (MEG) Imaging: – MEG is a technique developed which maps brain activity by recording magnetic fields which are caused by electric currents present naturally in the brain using extra sensitive magnetometers. There are two types, one most common SQUID (superconducting quantum interference devices) and SERF (spin exchange relaxation-free (SERF) magnetometer) currently being tested. It directly measures brain activity and has high spatial and temporal resolutions, completely noninvasive and it is combined with MRI to give a complete picture of the brain called magnetic source imaging (MSI) (Towle et al., 1993).

Artefact Rejection: – Normally the EEG software always subtracts a baseline before any stimulus takes place from every trial, detecting and eliminating the electrode whose value exceeds some set threshold (G et al., 2004). The rest of the electrodes located on the scalp record brain activity, frontal as well as parietal electrodes may contain artifacts such as muscle artifacts and eye movements hence it is necessary to omit such artifact contaminating events. There are various methods of detecting trials with artefacts 1) extreme values 2) linear trends 3) improbability 4) kurtosis (K) activity and 5) spectral patterns. Analysis is carried out as principal and independent component (G et al., 2004).

Beamforming: – Ultrasound applied in medicine has the spectrum of 1-50 MHz as combination of good resolution and good penetration is required together. Hence a Beamformer is utilized which provides transducer directivity along with defining a focal point from within the body.  A more commonly used approach is digital beamforming. A constant high resolution is required in this process mainly to avoid the deteriorating effects the delay quantization lobes might induce mainly on the dynamic range of image and signal to noise ratio (SNR). Maximizing SNR is extremely difficult but new options such as null beamforming can be used to detect specific regional activity in spite of presence of DBs electrodes. Both these techniques can be further validated using phantom validations, clinical data and computer models.

Applications and conclusion

All the above-mentioned techniques have proven to provide novel insights into the brain activity during normal and pain induced conditions. Studies have also proven null beamformer to suppress excess noise and provide a far better reconstructed image as compared to the normal beamformer. Also, combination of these with various known techniques has helped in identifying complex networks in the brain. Studies have also helped identify the importance of the various regions in the brain such as the ACC that is central to the whole aspect of experiencing pain. Techniques such as MEG have identified the continuous changes the brain undergoes upon continued DBs for over a year. Overall combinations of non- invasive techniques have helped to understand mechanisms of the DBs in addition to exposing optimized surgical targets.

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