Tuning decisions with deep brain stimulation

‘All right, Mr. Glas*, we’ll switch you on now.’ The young neurologist is carrying an old-fashioned electronic device the size of a first-generation mobile phone. ‘I’m just going to check your battery status.’ Mr. Glas nods. The 68-year old man is exhausted. He travelled all the way to Berlin from a village in Brandenburg. Now, the doctor is moving closer, with the device still in his hand. Mr. Glas knows what’s coming and slightly bends forward to meet the neurologist half way. The doctor presses a button on the device. ‘You’re back on.’

Mr. Glas has Parkinson’s disease. He was diagnosed ten years ago after noticing a stiffness and slight shaking of his right hand. He was given Levodopa, a dopamine replacement drug commonly prescribed to alleviate the symptoms. It worked, but only for a while. After only a couple years the effect of the drug seemed to come in waves and Mr. Glas started noticing twitches in his arm that he couldn’t control. This was when he first came to the university hospital to be seen by experts of the movement disorders clinic. This was when he first heard about deep brain stimulation.

Deep brain stimulation electrodes are implanted to tune neuronal activity of structures deep down in the brain. Retrieved from Wikipedia Commons, credit: Andreas Horn.

Deep brain stimulation (DBS) has become one of the most exciting and rapidly expanding fields in neurosurgery. Today, it is applied as therapy for a growing range of neurological and psychiatric disorders like Parkinson’s disease, dystonia, chronic pain, Tourette’s syndrome, obsessive-compulsive disorder and depression. However, the mechanisms underling it’s functioning are still only poorly understood. Leading neuroscientists all over the world are working full-speed to help decipher the neural network and hierarchies underlying this powerful treatment. But neuroscience can learn more from DBS: the treatment provides a unique opportunity to study the brain from the inside rather than from its surface or through a low-resolution 3D MRI-image, opening a rare window to the deepest structures of the brain. In patients with Parkinson’s, neural recordings of DBS electrodes are now used to inform about the representation and processing of movement, motivation and emotion in the brain.

DBS electrodes shown in X-ray of the skull. Retrieved from Wikipedia Commons, credit: Hellerhoff

How to switch on movement: DBS as a treatment for Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disease. Around 1 in 1000 people is affected in Europe, the majority of cases being male. It manifests in core symptoms such as bradykinesia (general slowness of movement), postural instability (difficulties to maintain balance), rigidity or tremor. Often one side of the body is affected first and symptoms spread to the other side as disease progresses.

In Parkinson’s, dopamine neurons are lost progressively in a structure deep down in the brain, the substantia nigra pars compacta. Dopamine generated by these neurons is crucially important, as it is supplied to an assembly of deep brain nuclei called the basal ganglia. The basal ganglia modulate voluntary movements and integrate action plans ordered by higher cortical areas. That is, if there is demand for action, the basal ganglia release the brake and step on the accelerator to initiate the movement. In the basal ganglia, accelerator and brake are represented by two neural pathways called the ‘direct’ and ‘indirect’ pathway. Importantly, for these pathways to function correctly, a supply of dopamine from the substantia nigra is crucial. If there is a lack of dopamine supply to the basal ganglia, like in Parkinson’s, direct and indirect pathways are out of balance. In particular, activation of the indirect (braking) pathway is increased, whereas activation of the direct (accelerating) pathway is decreased. Due to this imbalance, movements become slow, shaky or stiff.

However, the dopamine deficit in Parkinson’s also leads to functional impairments outside the basal ganglia motor network. Patients often display a “Parkinsonian facial expression”, a face lacking emotive expression and articulateness. Most also develop a flat affect, a sort of apathic, depressive mood affecting their life just as bad as their motor problems do. Such non-motor symptoms can also be attributed to the lack of dopamine liberation in prefrontal or limbic emotion-processing areas, and subsequently its unstable interaction with other neurotransmitters.

Medication that balances out the dopamine deficit in the brain is thus the first choice to relieve the symptoms of Parkinson’s disease. Unfortunately, as the disease progresses, especially the frequently used dopamine precursor drug Levodopa can lose its primary effectiveness and induce unwanted side effects. Patients start to move involuntarily, twitching and abruptly jerking a limb or the entire body. Not all patients develop such dyskinesias, but those who do, like Mr. Glas, are in need for an alternative treatment of their symptoms. This is when DBS therapy may be considered.

Typical deep brain stimulation setup. The electrodes are placed in the brain connected to a pacemaker permanently placed under the skin of the chest. Retrieved from Wikipedia commons, credit: R.Shamir, A. Noecker and C. McIntyre.

In DBS, a neurostimulation device with electrode leads in each hemisphere is implanted in the patient’s brain. Its purpose is to alter brain activity in the target brain region, where the electrodes are placed. In Parkinson’s disease, one of the most common targets for the electrodes is the six millimetre small subthalamic nucleus (STN). It sits deep down in the brain below the thalamus, a central hub for cognition, motion and emotion. In fact, the STN is part of the indirect (braking) pathway in the basal ganglia. Presumably, in DBS, the high-frequency electrical stimulation inhibits the STN’s braking function and thus releases movement.

During surgery, the one-millimetre electrodes of the DBS device are placed in the dorsal part of the nucleus (the part of the STN pointing towards the back of the head), which is involved in the control of movement. Since the STN is positioned in close proximity to brain circuits modulating cognition, emotion, language and sensorimotor skills, DBS surgery is a delicate intervention that requires accuracy and precision. The surgeon uses a stereotactic procedure, to place the electrodes at their target region. During surgery, the patient is woken up in order to be responsive for the neurologist’s examination, who determines which stimulation position is most effective to ameliorate motor symptoms. A couple of days after both electrodes have been placed successfully, the pacemaker will be implanted in the patients torso with cables running under the skin at the side of the head. During the following consultations with the neurologist, the stimulation of each electrode can be adjusted to best meet the patients needs and to provide the best therapeutic effect.

Insertion of DBS electrodes during surgery. Retrieved from Wikipedia Commons, credit: Thomasbg

DBS is proven to have wonderful success. In many occasions it ameliorated patients’ life for many years and helped them to live an almost unimpaired life. However, in recent years the application of DBS has extended even further: it has transformed from being solely a treatment to being one of the most exciting research methods to study the brain.

What DBS can teach us about decision-making

Reconstrucion of DBS electrodes penetrating the STN (dark orange) surrounded by other basal ganglia including red nucleus (green), substantia nigra (yellow), internal (cyan) and external pallidum (blue) and striatum (red). Colour-coded white matter fibres traverse this volume and terminate in cortical regions. Retrieved from Wikipedia Commons, credit: Andreas Horn.

It did not take long for neuroscientists to realise that treating Parkinson’s in this new way also provides an outstanding chance to investigate whether the STN is also involved in cognitive processes such as decision-making. Scientists have started to access the externalized DBS electrodes to directly record neural activity from the STN while patients conduct a decision-making task. With this method, neural signatures in response to or in anticipation of reward, errors, ambiguous information, or movement inhibition  could be identified. Recently, a third pathway has been discovered within the basal ganglia, through which the STN receives direct input from prefrontal cortical brain regions. Bypassing the other basal ganglia nuclei, this ‘hyperdirect’ pathway represents a quicker way for action demands to be processed: it can mediate inhibition of movement right before the time of response. It turns out this function is crucial for decision-making.

Studies recording STN neural activity during tasks, where subjects have to decide between two or more choice options, have found STN activity to increase with the number of options. Consequently, the STN has been ascribed the function to hold back the response until enough evidence is collected in favour of one option over the others. This mechanism is especially vital during difficult decisions.

Whenever we are faced with difficult decisions, the ability to slow down and think is vital. If there was no brake signal, our choices in scenarios where weighing the options is important would be impulsive, premature, and disadvantageous. There would be no time to weigh pro’s and con’s. Thus, the brake signal of the STN is something all humans take advantage of in everyday life. This signal holds back the action until enough information has been accumulated to decide which option is the best. How exactly the STN determines when to hold back action execution is a heatedly debated question in cognitive neuroscience. Current models of decision-making assume that input of the medial prefrontal cortex mediates STN activity during cautious choices.
Adequate STN functioning seems thus not just important for movements to be fluidly initiated but also for adequate decision-making, especially during difficult choices. But does stimulation of the STN in Parkinson’s patients with DBS cause impairments?

It turns out that aberrant STN activity induced through DBS can indeed have detrimental effects on decision-making. Patients under STN DBS make more premature and impulsive choices because their response cannot be slowed down in difficult choice scenarios. Hence, a substantial number of patients treated with STN DBS shows impaired inhibitory control, executive deficits, and experiences making more faulty or risky choices. When taking a bad decision slips from being an occasional fault to being the rule, this has considerable impact on a person’s life. Together with the effects on mood that DBS sometimes has, such as hypomania, depression, or suicidal thoughts these side effects severely affects the patients mental health and quality of life. Research addressing these issues is thus a crucial step towards the optimization of DBS therapy. But also beyond Parkinson’s disease, a better comprehension of the role of the STN in decision-making has striking impact.

We all make hundreds of choices every day. Understanding how the brain orchestrates decisions is necessary to answer questions like: why do we make the wrong choices now and then. Why do some decisions take longer than others. And ultimately, which strategies can be applied to make decisions faster without increasing the number of errors. Further, this knowledge is required for on-going development of interventions for patients with decision-making problems, such as those with impulsive control disorders, gambling disorders, hypersexuality or obsessive compulsive disorders, to name a few. Applying a comprehensive approach alterations within the multilevel dynamic network of brain regions guiding cognition, affect, motivation and motor behaviour can be translated into therapeutic interventions. By adding to the comprehension of STN function and its role in the basal ganglia-cortical network, future research will be able to fill a small yet substantial niche contributing to the understanding of human decision-making.

* Name and situation represent a fictional case.



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