Deep Brain Stimulation (DBS)

Localization of DBS electrodes
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Post operative X ray image showing the location of DBS electrodes
(indicated by arrows) in the patient’s cranium. Image source: Sclaepfer, TE et al, 2008 [5]

Deep Brain stimulation (DBS) is a new technique that is being considered an effective line of treatment for people suffering from severe depression. This intervention is thought to be particularly effective for a third of the total number of patients who seem to be having a relatively poor prognosis than others and are considered to be suffering from Treatment Resistant Depression (TRD) [1].TRD patients fail to respond to adequate courses of at least two different anti depressant medications[2]

Deep Brain stimulation is currently being thought to be useful in stimulating certain anatomical structures of the brain that are implicated in Major Depression. These structures include: The Subgenual Cingulate (Brodmann Area 25), Nucleus Accumbens and Anterior Limb of the Internal Capsule (ALIC) [1]. Moreover, new evidence suggests that the Lateral Habenula[1], the Medial Forebrain Bundle[1] and Ventral Striatum[3] also might serve as potential targets for stimulation and there are clinical trials being conducted at present to confirm this. Another interesting observation that has been made with respect to these brain structures is that some are seen to be overactive (eg: ALIC, Lateral Habenula and Area 25) while others are underactive (eg: Nucleus Accumbens) and these observations are mostly consistent with some of the symptoms seen in depressed individuals[1].

The Food and Drug Administration (FDA) has not yet approved DBS as a treatment strategy that can be used to clinically treat patients because of certain limitations that are evident from clinical trials - including variability in positive responses from patients[4], small sample sizes in research studies[4] and other side effects of DBS including suicidal tendencies & agitation observed among patients and possible wound infections[1].

1.1 Timeline

DBS has been considered as an effective method of treatment for movement disorders like Parkinson’s disease (PD) and Dystonia since 1997[6] and was officially approved by the Food and Drug Administration (FDA) as a method of treatment for Parkinson’s disease in 2002[7].

However, the idea that DBS can be used to stimulate the white matter in the subgenual cingulate (Area 25) was introduced by Dr. Helen Mayberg in 1999 after she observed that this portion of the brain was active in patients suffering from Depression (including those suffering from Treatment Resistant Depression)[6]. The subgenual cingulate is an area of the brain that serves as a junction (circuitry) in mood control and becomes activated when the person is sad or when they see someone else appearing to be sad[6].

The first surgical DBS experiment was conducted by Dr. Mayberg in collaboration with neurosurgeon Dr. Andres Lozano in Toronto Western Hospital[6]. Six Treatment Resistant Depression ( TRD) patients volunteered to be subjects in this surgical study[6]. This surgery was conducted to mainly test for safety rather than with the intention of treating these patients[6]. However, four out of six patients reported that they felt significantly better and happier after the surgery[6]. The results of this very first DBS surgery were later published in 2005[6]. Since then Dr. Mayberg has reported positive results for approximately 31 patients[6].

Currently, there are studies being conducted in various labs to improve the efficacy of DBS with respect to alleviating the symptoms shown by patients suffering from Major Depression and reducing the side effects. The FDA has not yet approved this surgery as a treatment option for Major depression [4].

1.2 Treatment Resistant Depression (TRD)

Patients are generally considered to be suffering from Treatment Resistant Depression if they fail to respond to adequate courses of at least two different anti depressant medications[2] (eg: Selective Serotonin Reuptake Inhibitors - SSRIs).

1.2a Prognosis of patients and relevance to DBS

TRD seems to be affecting 30-40% of the patients suffering from Major Depression and is considered a burden to public health[8]. Although relapse preventing therapeutics like combination pharmacotherapy and continuous Electroconvulsive therapy (ECT) can potentially reduce the relapse rates, at least 40% of the patients experience a recurrence in episodes of Major Depression[8]. Therefore, the prognosis for these patients is usually not thought to be very positive[8]. A treatment option that seems to be having the potential to improve the prognosis of these patients is DBS. Since many brain targets including Area 25, Nucleus Accumbens and Anterior Limb of the Internal Capsule are known to be involved in mood regulation, and Depression is primarily an affective disorder that influences mood, it is now thought that stimulating these brain targets via DBS might potentially ameliorate some of the clinical features of depression including Anhedonia (lack of interest in activities that are normally considered pleasurable)[1].

1.3 Surgical procedure of DBS

1.3a Equipment and methodology

Animation of DBS
An animation showing the placement of electrodes and effect of stimulation.
Image source: Cleaveland clinic, Ohio. http://www.youtube.com/watch?v=B6sqV7bEPo0

A pulse generator (similar to an implanted heart pacemaker) and two electrodes each having four contacts are the main equipments employed in a DBS surgery[6]. The first step in the surgery involves creating two Burr holes on specific locations on the skull of the patient who is given a mild local anesthetic prior to sending the electrodes to specific target areas of the brain (eg: Area 25)[6]. The coordinates are demarcated on the skull before the surgery so that the two holes can be created in accurate locations[6][9]. The symptoms shown by the patients will determine whether one or two electrodes have to be implanted inside the brain[9]. A stereotactic surgery that uses a stereotactic frame is used in some institutions to identify and demarcate the coordinates on the skull and the target structures deep inside the brain[6][9]. The surgeon then introduces cannulas through the holes created on the skull (one cannula per hole) which serve as pathways for the DBS electrodes[6].These lead electrodes are typically around 1.27mm in diameter and are implanted into a specific target area of the brain[6]. The other end of each lead electrode is connected to extension wires that in turn are connected to the pulse generator that is eventually implanted under the patient's skin - usually under the collar bone[6].

The surgeon is aided by a computerized brain mapping technology (eg: Magnetic Resonance Imaging - MRI) to locate the location of the brain that is responsible for the symptoms seen in patients[9]. Sophisticated technology is used to map the physical structure and functioning of these brain areas[9] and the doctors are also able to monitor the sound of neuronal firing[6]. The gray matter makes a raspy sound while the white matter appears to be silent[6]. Stimulation of Area 25 involves stimulating the silent white matter area[6]. Each contact on the electrodes can be independently turned on or off with various (suitable) levels of electricity and these electrodes generally stimulate approximately 1 cubic centimeter of brain tissue[6]. Which contact works best for the patient is determined mostly by the response given by patients during the surgery[6][9]. This requires the patient to be awake and responsive during the surgery[6]. In order to determine which contact works best, the surgeon will ask the patient to rate their feeling of dread (eg on a scale of 1-10) when they stimulate a particular area of the brain using a contact[6]. Taking the patient’s response into account, the surgeon will then determine the contact that would potentially produce the most optimal positive result in the patient[6].

The pulse generator is implanted under the collar bone either during surgery or post-surgery depending on the protocols followed by the different institutions that carry out DBS surgery[9]. Adjustments to the electrical pulse generated by the implanted pulse generator will be made over the next few weeks following surgery[9]. The patient’s feedback on changes in their mood is the most important factor that determines the optimal pulse rate[9]. The pulse generator is usually turned on after determining the pulse rate that would be optimal to the patient and this is usually done within a few weeks post surgery[9].

1.3b Pre and Post DBS surgery - A patient's perspective

The Neurosurgeons in the Cleaveland Clinic in Ohio have used DBS to treat certain patients who were suffering from Treatment Resistant Depression (TRD) and Diane was one of the first Depression patients to be treated using this procedure[9]. Diane’s experiences pre and post her DBS surgery and a recap of the surgical procedure are reproduced in the following video.

Diane's experiences - Pre and Post DBS surgery
A video that shows the process of DBS surgery for TRD
Image source: Cleaveland clinic, Ohio. http://www.youtube.com/watch?v=rGYAByJnDn0

1.4 Targeted brain structures

1.4a Currently known & newly identified targets

A number of key brain structures have been identified as targets for DBS. The most common example and the first target to be implicated in DBS as a treatment for Major Depression is the subgenual cingulate, also known as Area 25 of the brain (according to the Brodmann numbering system)[1]. Although other targets have currently been identified, the strongest evidence till date exists for Area 25 - as the target for DBS in TRD[11]

Figure highlighting the Subgenual Cingulate
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Area 25 is overactive in depression but its activity decreases post DBS surgery.
Image source:http://www.shockmd.com/2008/09/22/potential-surgical-targets-
for-deep-brain-stimulation-in-treatment-resistant-depression/[11]

MRI images of electrode placement in the white matter
of Area 25
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A and B are images of Area 25 localized on the Atlas; C and D illustrate
the localization of DBStarget before surgery & E and F illustrate the electrode
placement positions post surgery. Image source: Mayberg, H et al, 2005[10]
http://www.shockmd.com/2008/01/20/6-different-locations-for-deep-brain-
stimulation-in-depression/

Furthermore, the Anterior limb of the Internal capsule and the Nucleus Accumbens are also thought to be targets that can be stimulated via DBS in order to ameliorate some of the symptoms seen in TRD patients[1]

Nucleus Accumbens
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The Nucleus Accumbens is highlighted in red.
Image source: http://upload.wikimedia.org/wikipedia/commons/5/5e/Nucleus_
accumbens_sag.jpg

Internal capsule
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The Anterior limb of the Internal capsule is indicated by the red arrow.
Image source: http://www.studyblue.com/notes/note/n/ns-10-the-brain-in-sections/
deck/9467147

In addition to the three targets mentioned above, several other brain structures are currently thought to play a role in Depression and therefore are considered to be potential targets for DBS. These structures include the Lateral Habenula[1][11], Ventral Striatum (especially Ventral caudate nucleus which is part of the striatum)[11], Inferior Thalamic Peduncle[11] and the medial forebrain bundle[1]. These structures however are only tentative at this point, and further studies must be done before they can be considered actual targets for DBS.

Lateral Habenula
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The Lateral Habenula in each of the four images is indicated by arrows.
Image source:[11]http://www.shockmd.com/
2008/09/22/potential-surgical-targets-for-deep-brain-stimulation-
in-treatment-resistant-depression/

Caudate nucleus - including the Ventral Caudate nucleus
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The caudate nucleus (depicted in green) is part of the striatum.
Image source:[11] http://www.shockmd.com/2008/01/20/6-different-locations-for-deep-
brain-stimulation-in-depression/

Inferior Thalamic Peduncle
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The Inferior Thalamic peduncle is indicated by the blue circle.
Image source:[11] http://www.shockmd.com/
2008/01/20/6-different-locations-for-deep-brain-stimulation-in-depression/

Diffusion Tensor Image of electrode placement in the
Medial Forebrain Bundle (MFB)
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MFB refers to the Medial Forebrain Bundle and
VTA refers to the Ventral Tegmental Area. Image source:http://neuroautomaton.com/
new-targets-for-deep-brain-stimulation-of-treatment-resistant-depression/

1.4b Variation in the levels of activation

Although several brain structures (as mentioned in 1.4a) are implicated in Depression, they seem to vary in their levels of activation. Neurons in some brain structures seem to be firing at a rapid rate (above basal levels) and are considered overactive whereas others fire below normal levels and are underactive in Depressed individuals[1][11] Overactive targets include the Subgenual Gyrus[1], Anterior Limb of the Internal Capsule[1], the Lateral Habenula[1][11] and the Inferior Thalamic Peduncle[11]. Nucleus Accumbens on the other hand seems to be underactive in patients who suffer from Depression[1]. DBS therefore is thought to bring back the firing rates to equilibrium (to their basal firing levels).

Varying levels of activation in Area 25 - Pre and Post DBS surgery
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scC25 refers to sub calossal Cingulate (Area 25); Pre-op refers to "before surgery" and Post-op refers to "after surgery". Figure A is a Pre-op MRI image showing the DBS target - Area 25; Figure B is a Pre-op PET scan image of an overactive Area 25; Figure C is a Post-op MRI image that confirms DBS electrode placement & Figure D is a patient's PET scan image taken 6 months post surgery - Area 25 is no longer overactive in this image. Image source: http://archive.sciencewatch.com/dr/erf/2008/08decerf/08decerfMaybergET/

1.4c Newly proposed mechanims underlying DBS

Area 25 has been implicated in Depression because it is known to be a channel that transmits neural information between the frontal cortex or forebrain (involved in many tasks including thinking) and the central limbic region that plays a role in feeling emotions[11]. Area 25 seems to be an area that fires rapidly when one is sad and depressed[11]. Therefore, starting with Dr. Mayberg, it’s now thought by many scientists that this structure might be a key switch to lift Depression[11]. Since stimulating this region via DBS seems to bring down its firing to base line levels and consequently make people feel better, this structure is considered an effective target in alleviating Depression.

The reward circuitries of Nucleus Accumbens (NAC) and Ventral Striatum have been implicated in Depression for a number of years[12]. More specifically, the densities of dopaminergic receptors in these structures are linked to stress and learned helplessness in animal models for Depression[12]. It has been observed in mouse models that various factors including genetic predisposition can decrease metabolism and dopamine release in the NAC and thus give rise to depression[12]. Moreover, data suggests that an increase in meso-limbic dopamine within the NAC can help in neuromodulation for depression[12]. The shell of the NAC mainly receives input from the subgenual and pre genual cingulate cortices[12]. The NAC and ventral striatum in turn project to the thalamus which then projects to the cortices (orbitofrontal, prefrontal etc), amygdala and hypothalamus forming the limbic loop of the basal ganglia[12]. Since NAC is connected to many affective brain structures that are involved in Depression, it is considered an effective target for DBS (for TRD)[12].

Since the NAC (dopaminergic pathway) receives information from the Subgenual cingulate (Area 25) and because stimulation of Area 25 seems to alleviate many symptoms of Depression including Anhedonia, it was previously thought that stimulation of Area 25 might be alleviating these symptoms by altering the faulty Dopaminergic pathway[12]. However, a recent paper by Rea, E et al, 2014 disproved this idea[13].

Rea, E et al (2014) used rats as rodent model organisms in their experiments. Rats of the Flinders Sensitive Line (FSL) are a validated genetic model for depression while the Flinders Resistant Line (FRL) of rats are known to be resistant to depression[13]. The Ventromedial Pre frontal cortices (vmPFC) of these rats were stimulated and these rats were tested in the Forced swim test, Sucrose consumption test and Intracranial self stimulation paradigm[13]. The vmPFC of rodents are known to be analogous to the human Subgenual cingulate and therefore the results from this study can potentially be relevant to humans as well[13]. The Forced swim test is a measure of behavioral despair and involves placing the animals in a cylinder of water followed by stimulating their vmPFC and recording the length of time spent immobile (immobility results from depression)[13]. The sucrose preference test involved measuring the preference of animals to condensed milk before and after the forced swim test and stimulation[13]. This is a test for stress induced Anhedonia[13]. The Intracranial self stimulation involved placing the animals in an operant conditioning box containing a lever[13]. Pressing the lever elicited stimulation of the Medial Forebrain Bundle (passes information between the ventral tegmentum and NAC) and this is usually considered a rewarding stimulation for rodents[13]. The rates of Intracranial self stimulation were assessed before and after stimulating the vmPFC of rats[13]. Results from these experiments showed that chronic intermittent stimulation of vmPFC (vmPFC-DBS) reduced both despair (as shown by the reduction in the time spent immobile by FSL rats post vmPFC-DBS relative to before stimulation – See figure A below) and Anhedonia (as shown by the increase preference of FSL rats to milk post vmPFC-DBS relative to before stimulation – See figure B below) in FSL rats[13].
Note: In the figures below, Sham refers to the rats that were not stimulated and DBS refers to vmPFC-DBS[13]. Also, the gray bars refer to FSL rats and the white bars refer to the FRL rats[13].

Results from the Forced swim test
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The results show that FSL rats had lower floating times (were less depressed) post vmPFC-DBS
relative to FSL rats that didn't recieve the stimulation. Image source: Rea, E et al, 2014

Results from the Sucrose consumption test
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Results show that the FSL rats that had vmPFC-DBS done on them liked
sweetened milk much more than FSL rats that didn't recieve stimulation. Image source: Rea, E et al, 2014

Results from Intra Cranial Self Stimulation (ICSS)
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The ICSS rates before and after vmPFC-DBS in FSL rats were not significantly different.
Note: this image is modified to only include the results that are most relevant to this neurowiki.
LFS and HFS refer to Low Frequency Stimulation and High Frequency Stimulation respectively.
Image source: Rea, E et al, 2014

However, there was no significant change in Intracranial self stimulation rates post vmPFC-DBS (relative to pre - stimulation) in FSL rats (see Figure C below)[13].Results from this paper suggest that it is unlikely that the anti-anhedonic effect of DBS stimulation of Area 25 (vmPFC-DBS) is mediated by changes in the Dopaminergic reward pathway that involves the Medial Forebrain Bundle, NAC and Ventral Striatum[13]. However, other studies have shown that stimulating each of these targets individually will still result in a reduction in symptoms of Depression[1][11] but the actual mechanisms are still unclear.

1.5 Side effects of surgery

The side effects of DBS surgery include wound infections, erythema (redness of skin) due to stimulation[1], brain hemorrhage (low probability of occurrence)[14], breaks in the extension wires[14] and movement of the stimulating electrodes[14]. In previous clinical trials it was noticed that some patients showed signs of hypomania, anxiety, agitation, suicidal tendencies and elevation of mood post DBS stimulation[1]. Adverse events that were associated with this procedure were trivial in younger psychiatric patients but were more severe in much older movement disorder patients[4]. However, DBS is considered a fairly safe method of brain stimulation and the risks associated with it occur at a fairly low frequency.

1.6 Limitations in current research

The DBS procedures followed in various studies differ to a certain extent making the results quite unreliable[4]. Moreover, the number of patients is usually too small to do meaningful statistics on[4]. Therefore, it is quite hard for researchers to make valid inferences from the data they obtain[4]. These might be reasons why there is a variability in the total number positive responses to DBS in any given trial[4]. It is quite evident from most studies that not everyone feels better after the surgery[4]. There is always an element of uncertainty in the results and variability in patient response to DBS. Furthermore, the exact biological mechanisms behind stimulation of certain brain targets are also not known yet[4]. These are reasons why the FDA has not yet approved DBS as a treatment for TRD[4].

1.7 The future of DBS

DBS definitely is a promising treatment strategy for people suffering from Treatment Resistant Depression. However, outstanding questions about selection of patients and placement of electrodes (along with other modifications in the procedure and side effects of surgery) must be potentially resolved by studies that involve a large sample size, genetic studies that focus on DBS and imaging studies that use techniques like Magnetic Resonance Imaging (MRI), functional Magnetic Resonance Imaging (fMRI), Positron Emission Topography (PET) and tractography[4]

Bibliography
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3. Taghva, AS, Malone, DA & Rezai, AR. Deep Brain Stimulation for Treatment Resistant Depression. World Neurosurg. (2013). 80(3/4): S27.e17 – S27.e24 (ePub)
4. Lakhan, SE & Callaway, E. Deep Brain Stimulation for Obsessive Compulsory Disorder and Treatment Resistant Depression: systematic review. BMC Research Notes. (2010). 3: 60
5. Sclaepfer, TE et al. Deep Brain Stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. (2008). 33: 368-377
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11. Dr Shock – A neurostimulating blog. Potential surgical targets for deep brain stimulation. http://www.shockmd.com/2008/09/22/potential-surgical-targets-for-deep-brain-stimulation-in-treatment-resistant-depression/
12. Hauptman, JS et al. Potential surgical targets for Deep Brain Stimulation in Treatment Resistant Depression. Neurosurg focus. (2008). 25(1): E3 (Medscape).Online Source: http://www.medscape.com/viewarticle/581634_3
13. Rea, E et al. Anti-anhedonic effect of deep brain stimulation of the prefrontal cortex and the dopaminergic reward system in a genetic rat model of depression: an intracranial self-stimulation paradigm study. Brain Stimul. (2014). 7(1): 21-28
14. Clements, IP. How Deep Brain Stimulation works. How stuff works. Web source:http://science.howstuffworks.com/life/inside-the-mind/human-brain/deep-brain-stimulation6.htm

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