Know your brain: Reticular formation

Where is the reticular formation?

The reticular formation is found in the brainstem, at the center of an area of the brainstem known as the tegmentum. The tegmentum is a heterogeneous section of neural tissue that extends vertically through the brainstem, making up the portion of the brainstem that sits between the ventricles and surface structures like the basal pons and the pyramids of the medulla. As the reticular formation is found at the core of the tegmentum, it too runs along the length of the brainstem.

What is the reticular formation and what does it do?

The reticular formation is a very diverse structure that contains various nuclei along with numerous ascending and descending tracts. The fibers that traverse the reticular formation give the region a net-like appearance, which is where it gets its name (reticular means net-like). Due to the heterogeneity of the structure, as well as to the fact that there are not clear boundaries between the nuclei within the reticular formation, it was originally thought to lack organization. However, it is now clear that the reticular formation is highly organized, just very intricate and complex. Of the numerous cell groups and tracts found throughout the reticular formation or connected to reticular formation neurons, some worth noting are nuclei involved in neurotransmitter production, nuclei associated with the cranial nerves, descending tracts involved in modulating sensory and motor functions, and ascending tracts integral to arousal and consciousness.

The reticular formation is home to several groups of cells that produce neurotransmitters; these neuronal populations have extensive connections throughout the central nervous system and are involved in the regulation of activity throughout the brain. One of the largest dopamine-producing areas in the brain, the ventral tegmental area, is located in the reticular formation, as is the locus ceruleus, which is the largest collection of noradrenergic neurons in the brain. The primary sites of serotonin release in the brain, the raphe nuclei, are found near the midline of the brainstem in the reticular formation. And, some of the largest sites of acetylcholine production in the brain, the pedunculopontine nucleus and laterodorsal tegmental nucleus, are found in the midbrain reticular formation. Neurotransmitters are produced in all of these areas and sent throughout the central nervous system to modulate sensory perception, motor activity, and behavioral responses.

Reticular formation neurons also form circuits with the motor nuclei of the cranial nerves; these nuclei contain neurons that are responsible for motor movements in the face and head, as well as motor movements related to autonomic functions of the visceral organs. Reticular formation circuitry helps to coordinate the activity of neurons in these cranial nerve nuclei, and thus is involved in the regulation of simple motor behaviors. For example, reticular formation neurons in the medulla facilitate motor activity associated with the vagus nerve. This activity involves functions of the gastrointestinal system (e.g. swallowing, vomiting), respiratory functions (e.g. coughing, sneezing, breathing rhythm), and cardiovascular functions (e.g. maintenance of blood pressure). Reticular neurons in the medulla and pons also contribute to orofacial motor responses by coordinating activity in motor nuclei for the trigeminal, facial, and hypoglossal nerves. This activity, for example, allows for movements of the jaw, lips, and tongue that lead to the movements required for chewing and eating. Reticular formation neurons are also important for facilitating the operation of muscles that allow for emotional facial expressions, like laughing or crying, as well as for coordinating eye movements.

The reticular formation contains long ascending (i.e. traveling to the brain) and descending (i.e. traveling from the brain to the body) tracts. The descending projections are primarily involved with the modulation of sensory and motor pathways. For example, projections extend from the raphe nuclei down to the dorsal horn of the spinal cord and can act to inhibit pain sensations. This is thought to be a major component of descending pain control systems that allow us to suppress pain in certain situations (e.g. during a traumatic event). Other descending projections from the reticular formation are involved in the control of posture and movement. These fibers are mainly found in the reticulospinal tract, which extends from the reticular formation to help maintain posture, facilitate stereotyped movements like stepping, and modulate muscle tone to either aid or inhibit movement.

The reticular formation may be best known for its role in promoting arousal and consciousness. This function is mediated by the reticular activating system (RAS), also known as the ascending arousal system. The reticular activating system contains circuits that originate in several areas of the brainstem, including the midbrain reticular formation, and ascend to the cerebral cortex and thalamus. These pathways are predominantly associated with the neurotransmitters acetylcholine and norepinephrine, both of which are thought to play important roles in regulating arousal and wakefulness. The cholinergic neurons originate in the pedunculopontine nucleus and laterodorsal tegmental nuclues, while the noradrenergic neurons originate in the locus coeruleus. The fibers that arise from these locations combine with other pathways that ascend to the cerebral cortex and thalamus to promote wakefulness, vigilance, and overall arousal. These pathways from the reticular formation must be functional for normal attentional abilities and sleep-wake cycles to be preserved. Lesions to major pathways of the reticular activating system can thus impair consciousness, and severe damage can cause coma or a persistent vegetative state.

Kandel ER, Schwartz JH, Jessell TM 2000. Principles of Neural Science, 5th ed. McGraw-Hill, New York.

2-Minute Neuroscience: Pain and the Anterolateral System

In this video, I discuss pain and the anterolateral system. I describe the three main pathways of the anterolateral system: the spinothalamic, spinoreticular, and spinomesencephalic tracts. I follow the route pain information takes along each of these tracts, from nociceptors to the somatosensory cortex, reticular formation, or periaqeuductal grey (depending on the tract).

The powerful influence of placebos on the brain

The term placebo effect describes an improvement in the condition of a patient after being given a placebo--an inert substance (e.g. sugar pill) the patient expects may hold some benefit for him. The placebo effect has long been recognized as an unavoidable aspect of medical treatment. Physicians before the 1950s often took advantage of this knowledge by giving patients treatments like bread pills or injections of water with the understanding that patients had a tendency to feel better when they were given something--even if it was inactive--than when they were given nothing at all. In the years following World War II, it became recognized that the placebo effect is more than just a medical curiosity--it is an extremely potent influence on patient psychology and physiology. With this realization came the determination that a condition where participants are given a placebo is a necessary component of an experiment designed to assess the effectiveness of a drug; for, if just the act of receiving treatment makes patients feel better, then that improvement must be subtracted from the overall strength of a drug's action to determine the true efficacy of the substance. This awareness led to the use of placebo conditions in clinical trials of pharmaceutical drugs being commonplace, and to the modern conception of the placebo effect as an important component of drug effects.

While many of us are aware of the use of placebos to test the effectiveness of drugs, we may be less likely to realize that some fraction of the benefit of any drug we take is likely due to the placebo effect. Because we expect the medications we take to help us feel better, they generally do to some extent; this influence is added to the efficacy of the mechanistic action of the drug to produce its overall effect. The magnitude of the contribution of the placebo effect can range from minor to the majority of the drug effect, depending on the medicine in question. Thus, the placebo effect in medicine is something that influences many of us on a daily basis, and all of us at some point or another.

The potency of the placebo effect

The magnitude of the placebo effect is often under-appreciated. Although placebos have no active ingredients, they have been shown to influence both psychology and physiology, and in some cases the effects of a placebo have been found to be stronger than the effects of the medication being compared against it. Placebos can improve quality of life, mitigate the burden of a disability, and--amazingly--have even been associated with decreased mortality. For example, in studies of patients with congestive heart failure, those who adhered to taking placebos regularly were 50% less likely to die than those who were in the placebo group but didn't adhere to taking their "medication." Those who faithfully took placebos were also less likely to experience cardiovascular events like stroke or heart attack.

The effects of placebos on a number of physiological systems have now been well documented. Placebos have been found to influence the activity of the autonomic nervous system, such as heart rate, gastrointestinal activity, and respiration. Placebos can elicit changes in hormone levels across various functional systems; effects have ranged from reducing stress hormone levels based on expectation alone to decreasing levels of appetite-stimulating hormones by convincing participants they had just eaten a very calorie-rich food (even though they hadn't). Researchers have even found that placebos can affect the activity of the immune system. In one study, investigators elicited immunosuppression as a placebo-induced response, and in another study it was found that watching advertisements for the antihistamine drug Claritin led to the drug being more effective than it was in participants who didn't receive any pro-drug messages.

Despite all of the experiments that have documented placebo effects, there is still a great deal to be learned about which neurobiological systems are necessary for creating the placebo effect. It may be that the neurobiology of the placebo effect is different depending on the type of stimulus or the expectancies involved. In other words, it is not clear if there is a group of brain regions and/or pathways that are activated whenever the placebo effect occurs--regardless of the circumstances--or if there are different regions activated depending on the context of the placebo administration. Recent research has used neuroimaging to attempt to unravel the mechanism underlying the placebo effect and, while the effect is complex and still poorly understood, these studies have provided some insight into which areas of the nervous system may be important to mediating it.

Neuroimaging of the placebo effect

Much of the experimental evidence regarding the placebo effect comes from studies of the impact of placebos on pain. This is due in part to the early recognition that the experience of pain is amenable to manipulation by the use of placebos. Pain is also useful to study because it is a ubiquitous problem that has relevance for clinical practice; additionally, we have a fairly good understanding of the components of the nervous system that are involved in pain sensations.

There are several brain regions that receive direct innervation from pathways that carry nociceptive (i.e. pain-related) information from the body to the brain. These include: the thalamus, through which pain signals must pass as they travel to the cortex; the somatosensory cortex, which is the cortical area where sensory signals from the body are initially processed; the insula, which is thought to be involved in mediating the intensity and emotional response to pain; and the anterior cingulate cortex, which is also believed to be involved in emotional responses to pain. Treatment with a placebo has been found to decrease activity in all of the above areas, and several studies have found that larger placebo responses were associated with a greater reduction of activity in these regions.

In addition to affecting these pain "centers" in the brain, placebos have also been found to activate pathways that travel down from the brainstem to the spinal cord to inhibit pain responses. The best known of these pathways runs from an area in the midbrain called the periaqueductal grey, down to the spinal cord. Activation of the periaqueductal grey can be initiated by a variety of cortical areas, and leads to increases in levels of natural painkillers known as endogenous opioids, which act to suppress pain. Endogenous opioids are part of an adaptive mechanism that allows us to tolerate pain, presumably to ensure we can extricate ourselves from an acutely dangerous situation before we become preoccupied with pain sensations.

Placebos can activate these descending pain modulatory pathways involving the periaqueductal grey to cause increases in levels of endogenous opioids. Some studies have found that increased activity in the periaqueductal grey is associated with the degree of placebo analgesia experienced. Additionally, administering a drug called naloxone that blocks the receptors where endogenous opioids normally exert their effect causes a decrease in placebo-induced analgesia. Thus, it seems that activity in the periaqueductal grey is an important component of placebo-induced pain relief. 

Placebos also affect activity in higher brain regions like the prefrontal cortex, amygdala, and striatum. Changes in activity in these areas may cause alterations in levels of endogenous opioids and/or may involve changes in affective and anticipatory states, which may influence the perception of pain. Connections between the prefrontal cortex and periaqueductal grey seem to be important for placebo analgesia, as placebos can cause increased activity in areas of the prefrontal cortex; this activity is associated with increased periaqueductal grey stimulation and endogenous opioid release. Placebo treatments also elevate levels of endogenous opioids in the amygdala, and reduce activity there. The role most commonly attributed to the amygdala involves the detection of threats in the environment and the generation of anxiety about those threats, and thus reduced activity in the amygdala may mitigate the anxiety-producing impact of pain. Placebo treatments also cause increases in both dopaminergic and endogenous opioid activity in the striatum. Dopamine activity in the striatum is generally associated with learning, motivation, and emotion; it has been hypothesized that the striatum may be involved in encoding information about the rewarding nature of pain relief and the aversive aspects of pain itself, and thus in the learning and behavior associated with pain avoidance.

Although the placebo effect has been explored most comprehensively in regards to pain, it is not confined to mitigating painful sensations; placebos have been found to affect experiences ranging from emotion to movement in Parkinson's disease. In many cases, the same systems discussed above in the context of pain are thought to be involved. For example, being given a placebo anti-anxiety medication led to decreased activity in the amygdala in response to a series of negative images; participants also rated the images as less unpleasant after taking the placebo. Studies in Parkinson's disease patients have found that taking a placebo that is expected to facilitate movement can cause increased dopamine levels in the striatum, which is associated with improvements in mobility.

Thus, it seems that the brain areas mentioned above may not be specific to the type of placebo effect explored, and may be part of some underlying neural circuitry that mediates the placebo effect in general. However, it is also likely true that we are just scratching the surface with the identification of these common areas. The full neural circuitry of the placebo effect is probably more complex than the collection of regions outlined above, and presumably includes a more intricate neurochemical basis than just endogenous opioids and dopamine. For example, recent research has identified roles for hormones like cholecystokinin and oxytocin in the placebo response as well.

Additionally, it is unclear if brain regions like the prefrontal cortex, which are activated in different types of placebo responses, are activated to serve the same purpose in each context. For example, in a pain context the prefrontal cortex may be involved in activating the periaqueductal grey; in a situation where someone is given a placebo anti-anxiety drug, however, the prefrontal cortex may be involved with regulation of areas like the amygdala. Thus, it is uncertain if this shared neural circuitry is actually working in the same manner in different placebo situations.

Research will therefore continue into the phenomenon of the placebo effect, for more than just the sake of curiosity. For, if we can learn more about the placebo effect and how it is mediated by the brain, we can use that knowledge to better predict which patients might be likely to experience a large placebo effect, and which would not. An ability to predict placebo response in patients could be immensely valuable, and could turn the placebo effect from a quirky aspect of medical care to something that can be directly manipulated in order to improve the effectiveness of treatment. And, while we may not return to the days of giving bread pills without consent, we may be able to better evaluate the efficacy of medications if we are able to better understand the contribution the placebo effect is having.

Wager, T., & Atlas, L. (2015). The neuroscience of placebo effects: connecting context, learning and health Nature Reviews Neuroscience, 16 (7), 403-418 DOI: 10.1038/nrn3976

2-Minute Neuroscience: The Cochlea

In this video, I discuss the cochlea. I describe the passage of sound waves through the ear, which leads to the depression of the oval window, a structure found in the wall of the cochlea. I cover the three main cavities in the cochlea: the scala vestibuli, scala media, and scala tympani. Then I describe how the movement of fluid in the cochlea causes movement of the basilar membrane, which activates hair cells in the organ of Corti. The hair cells transmit the auditory information to the vestibulocochlear nerve, which carries it to the brain to be processed.

Read more about the cochlea: Know your brain: Cochlea

Know your brain: Default mode network

Where is the default mode network?

The default mode network (sometimes called simply the default network) refers to an interconnected group of brain structures that are hypothesized to be part of a functional system. The default network is a relatively recent concept, and because of this there is not yet a complete consensus on which brain regions should be included in a definition of it. Regardless, some structures that are generally included are the medial prefrontal cortex, posterior cingulate cortex, and the inferior parietal lobule. A few of the other structures that may be considered part of the network are the lateral temporal cortex, hippocampal formation, and the precuneus.

What is the default mode network and what does it do?

The concept of a default mode network was developed after researchers inadvertently noticed surprising levels of brain activity in experimental participants who were supposed to be "at rest"--in other words they were not engaged in a specific mental task, but just resting quietly (often with their eyes closed). Although the idea that the brain is constantly active (even when we aren't engaged in a distinct mental activity) was clearly expressed by Hans Berger in the 1930s, it wasn't until the 1970s that brain researcher David Ingvar began to accumulate data showing that cerebral blood flow (a general measurement of brain activity) during resting states varied according to specific patterns; for example, he observed high levels of activity in the frontal lobes of participants at rest.

As neuroimaging methods became more accurate, data continued to accumulate that suggested activity during resting states followed a certain order; this data was easy to come by because in many neuroimaging studies, asking participants to rest in a quiet state is considered the control condition. In the early 2000s, Raichle, Gusnard, and colleagues published a series of articles that attempted to more specifically define the areas of the brain that were most active during these rest states. It was in one of these publications that they used the term default mode to refer to this resting activity, phraseology which led to the brain areas that exhibited default mode activity being considered part of the default mode network.

Thus, the default mode network is a group of brain regions that seem to show lower levels of activity when we are engaged in a particular task like paying attention, but higher levels of activity when we are awake and not involved in any specific mental exercise. It is during these times that we might be daydreaming, recalling memories, envisioning the future, monitoring the environment, thinking about the intentions of others, and so on--all things that we often do when we find ourselves just "thinking" without any explicit goal of thinking in mind. Additionally, recent research has begun to detect links between activity in the default mode network and mental disorders like depression, anxiety, and schizophrenia. Furthermore, therapies like meditation have received attention for influencing activity in the default mode network, suggesting this may be part of their mechanism for improving well-being.

The concept of a default mode network is not without controversy. There are some who argue that it is difficult to define resting wakefulness as constituting a unique state of activity, as energy consumption during this state is similar to energy consumption during other waking states. Others have asserted that it is unclear what the patterns of activity during these resting states mean, and thus what the functional importance of the connections between the regions in the default mode network really are.

These caveats are worth keeping in mind when you come across research on the default mode network, as--especially due to its relationship with meditation--it is becoming a frequently-used term in popular neuroscience descriptions of brain activity. The idea of a default mode network, however, is not universally accepted; even those who endorse the idea concede there still is a lot of work left to do to figure out the network's exact functions. Regardless, at the very least the concept of a default mode network has sparked interest in understanding what the brain is doing when it is not involved in a specific task, and this line of research may help us to gain a more comprehensive understanding of brain function.

Buckner RL, Andrews-Hanna JR, & Schacter DL (2008). The brain's default network: anatomy, function, and relevance to disease. Annals of the New York Academy of Sciences, 1124, 1-38 PMID: 18400922

2-Minute Neuroscience: The Retina

In this video, I cover the retina. I discuss the five major types of neurons found in the retina: photoreceptor cells (i.e. rods and cones), bipolar cells, ganglion cells, horizontal cells, and amacrine cells. I also briefly describe the fovea, our area of highest visual acuity, and the optic disc, which creates a natural blind spot in our visual field.

Deep brain stimulation in Parkinson's disease: Uncovering the mechanism

Parkinson's disease (PD) belongs to a group of diseases that are referred to as neurodegenerative because they involve the degeneration and death of neurons. In PD a group of structures called the basal ganglia, which play a role in facilitating movement, are predominantly affected. The substantia nigra, one of the basal ganglia nuclei as well as one of the most dopamine-rich areas in the brain, is severely impacted; by the end stages of the disease patients have often lost 50-70% of the dopamine neurons in this region. This excessive loss of dopamine neurons and the accompanying depletion of dopamine levels in the basal ganglia are associated with increasingly debilitating movement-related symptoms, such as rigidity, tremor, bradykinesia (slow movement), and postural impairment.

The most common method of treating PD involves the administration of L-DOPA. L-DOPA is a precursor to dopamine that the brain can use to synthesize more of the neurotransmitter; thus, it works to increase the dopamine levels that are being continuously reduced by the disease. PD, however, is progressive, meaning that neurodegeneration will continue once it has begun. L-DOPA isn't capable of halting neurodegeneration, and eventually the dopamine synthesized from L-DOPA is not enough to replace all that has been lost due to the disorder; with time L-DOPA begins to lose its effectiveness. Especially in the later stages of PD, L-DOPA provides diminishing returns, and the side effects of chronic L-DOPA treatment start to make its continued use more detrimental than beneficial.

Therefore, we continue to seek out treatments for PD that will be more effective in the advanced stages of the disease (while maintaining a manageable side effect profile). In the early 1990s, it was observed in non-human primates that lesions of the subthalamic nucleus (STN) appeared to effectively eradicate Parkinsonian symptoms. Although the reason for this was not fully understood, a hypothesis was formulated based on the understanding that one of the functions of the STN seems to be to inhibit unwanted movements. Normally, this suppression of movement should only occur when a movement is not desired, and thus the interference should be removed with the attempt to initiate movement. In PD, decreased dopamine levels may prevent another structure in the basal ganglia, the globus pallidus, from moderating activity in the STN. This can lead to excessive STN activity, which serves to overly-inhibit movements and may cause the difficulty in making movements that characterizes PD. Based on this rationale and related experimental evidence, the STN was identified as a potential therapeutic target in PD. At that point, though, the only way to reduce activity in the STN was through a surgical procedure that irreversibly destroyed the nucleus.

However, not long after the STN was identified as playing a role in PD symptoms, a new method of influencing activity in the STN (and other brain areas) was developed: deep brain stimulation (DBS). This method was tested in patients with PD for the first time in the mid-1990s. The results were encouraging, as in some cases symptoms improved drastically and the patients were able to reduce their dose of L-DOPA and related drugs significantly. An example of the marked improvements that can occur after DBS is initiated can be seen in the video to the right. Since the first experimental DBS procedures, the method has been used with thousands of patients, making it an established therapeutic approach for the treatment of advanced PD.

Deep brain stimulation procedure

DBS involves the insertion of an electrode into the brain. Thus, it requires an invasive surgical procedure that necessitates making one or two holes in the skull. An electrode is placed in the desired region of the brain (in the case of PD usually the STN but also sometimes the globus pallidus); the electrode is connected to a wire that runs under the skin to a device called a pulse generator, which is usually implanted under the collar bone.

When the pulse generator is turned on, it emits electrical impulses that seem to disrupt neural functioning. This can be used to cause changes in brain activity that resemble what happens when a lesion has been created. Thus, implanting an electrode near the STN and turning on the pulse generator reduces excessive activity in the STN; the abatement of STN activity is associated with an improvement of symptoms.

Although the DBS procedure has seen some success in alleviating symptoms in patients with advanced PD, the mechanism by which it achieves those effects is still unclear. DBS in the STN does reduce STN activity in patients with PD, but it is uncertain why stimulation of a brain region would have effects similar to the ablation of that brain region. Several hypotheses have been put forth to explain the mechanism of DBS, ranging from the assertion that DBS causes changes in neurotransmitter and hormone levels to the proposition that DBS disrupts abnormal neural oscillations in the brains of PD patients. This latter hypothesis has perhaps received the most research attention as a mechanism of DBS, and is considered by some to be the most viable explanation.

Neural oscillations and phase-amplitude coupling

The term neural oscillations describes rhythmic changes in the electrical activity of neurons and can involve fluctuations in the membrane potential of an individual neuron (i.e. action potential) or a small population of neurons (i.e. local field potential). These neural oscillations in certain areas of the brain tend to exhibit patterns of synchronization, which means that the activity of different neural populations becomes regulated on a similar timescale. In other words, synchronized neural populations may (on average) fire action potentials at the same time, then be at rest at the same time. It is thought that these synchronized patterns of neural activity are used to facilitate communication and integrate activity among groups of neurons from different parts of the brain, and thus normal oscillatory behavior may be essential for diverse functions ranging from sensory perception to motor movements

There are several different rhythms of oscillatory activity that can be detected throughout the brain; they range from low frequency delta oscillations (1-4 Hz) to high frequency gamma oscillations (>30 Hz). What makes understanding the effects of neural oscillations even more complicated is that these different frequencies of oscillations can be linked, or coupled, together in such a way that different areas of the brain with different patterns of oscillatory activity seem to work in concert with one another by coordinating their disparate oscillatory behavior. For example, a peak in the activity in one region might coincide with a valley in the activity of another. This mechanism, known as phase-amplitude coupling (PAC) may allow for the syncing of activity across a variety brain regions in a dynamic manner, and is becoming recognized as a key feature of healthy cognition.

Deep brain stimulation as a correction to abnormal oscillatory activity

Patients with PD display abnormally increased oscillatory activity in the STN in the beta frequency (13-30 Hz), which has been hypothesized to disrupt the normal functioning of the basal ganglia in such a way as to impair movement. And, some studies have found that the reduction of this oscillatory activity may be one mechanism by which DBS alleviates the symptoms of PD. However, the signal for voluntary movement originates in the motor areas of the cerebral cortex, and it remains unclear how abnormal beta oscillations in the basal ganglia might influence the motor cortex in such a way as to produce the movement-related symptoms of PD. Thus, it is also unknown how the stimulation provided by DBS might affect the motor cortex to alleviate those symptoms.

In a recent study published in Nature Neuroscience, de Hemptinne et al. (2015) explored the hypothesis that DBS helps to improve the symptoms of PD by reducing excessive coupling of neural oscillations in the motor cortex. In non-PD patients, PAC between high- and low-frequency oscillations in motor areas of the brain occurs when at rest and is reduced when movements are made. It has been suggested that this coupling may inhibit neural activity until movement is initiated; at that point the coupling is diminished so movement can occur. de Hemptinne et al. hypothesized that in PD patients, the PAC is exaggerated and continues to inhibit movement even when a movement is desired. DBS, however, may act to reduce PAC and increase the possibility of movement execution. To test this hypothesis, they used a procedure called electrocorticography in PD patients before, during, and after DBS stimulation of the STN.

Electrocorticography (ECoG), also sometimes called intracranial electroencephalogram (iEEG), involves the placement of electrodes directly on the surface of the brain to record the electrical activity of neurons. Although this is an invasive surgical procedure, the patients in the study by de Hemptinne et al. were already undergoing surgery for the placement of the DBS electrode and thus an additional surgical procedure wasn't required. In this study, the electrodes for ECoG were placed directly on the sensorimotor cortex.

As the authors hypothesized, the ECoG recording before the DBS device was turned on showed excessive beta frequency activity in the STN as well as exaggerated coupling of beta activity with gamma frequency oscillations in the motor cortex. Patients at this point displayed characteristic PD symptoms like rigidity, tremor, and bradykinesia. When the DBS device was turned on, however, the abnormal PAC in the motor cortex was reduced and symptoms were alleviated. Additionally, the degree to which PAC was reduced was associated with the degree to which the patients' symptom severity was mitigated. Thus, it appears plausible that DBS reduces PD symptoms in part by reducing PAC in the motor cortex.

DBS is still considered a last-resort option for most PD patients, as it does involve invasive surgery and all the associated risks, and it is not successful for everyone. However, if we can come to fully understand the mechanism by which it works, we may be able to refine the method and improve its success rate. For example, if PAC in the motor cortex is to blame for the severity of some of the symptoms of PD, future DBS devices could incorporate real-time monitoring of PAC and the automatic adjustment of stimulation to most effectively reduce it.

As we uncover more information about the mechanism of DBS, it may become a treatment for PD that can eventually replace L-DOPA which, despite its therapeutic value, remains a temporary solution to the problem. Regardless of the improvements we make to DBS, however, it still does not seem it will be capable of permanently arresting the neurodegeneration that occurs in PD. Thus, the search will continue for a therapeutic approach to treating the symptoms of PD that can at the same time either slow or stop the relentless loss of basal ganglia neurons that defines the disease.

de Hemptinne, C., Swann, N., Ostrem, J., Ryapolova-Webb, E., San Luciano, M., Galifianakis, N., & Starr, P. (2015). Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease Nature Neuroscience, 18 (5), 779-786 DOI: 10.1038/nn.3997