Deep brain stimulation, the practice of placing electrodes deep into the brain to stimulate subcortical structures with electrical current, has been increasing as a neurosurgical procedure over the past 15 years. Originally a treatment for essential tremor, DBS is now used and under investigation across a wide spectrum of neurological and psychiatric disorders. In addition to applying electrical stimulation for clinical symptomatic relief, the electrodes implanted can also be used to record local electrical activity in the brain, making DBS a useful research tool.
Since its approval by the FDA (Food and Drug Administration) in 1997 for the treatment of essential tremor, deep brain stimulation (DBS) has revolutionized functional neurosurgery.
Electrical current has been known to be critical for biological signal transduction since Luigi Galvani's work in the 18th century, and reports from the middle of the previous century detail first attempts to harness the effects of electrical stimulation of the CNS. However, the use of chronic electrical stimulation to directly alter brain function was not shown to be safe or effective until pioneering publications by Alim Benabid . Soon after the approval of DBS for essential tremor, approvals for applications in Parkinson disease (PD) and dystonia followed. The last decade has seen remarkable progress in the development of new applications for DBS, such as in the Anorexia Nervosa, and other psychiatric disease.
Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation, and other methodological advances that even more selectively activate specific groups of neurons, can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective.
Deep Brain Stimulation - A Mechanistic and Clinical Update - 2013
Mechanism of action of DBS
Naturally, if we know how it works, we may be able to make it work better: to optimize motor benefit, to minimize adverse effects (cognitive, psychiatric, visual …), to look for tentative new DBS targets for other disorders.
Early theories focused on depolarization block of efferent activity and local γ-aminobutyric acid (GABA)-mediated inhibitory effects. These notions were supported by acute stimulation experiments in animals, but paired electrode recordings and other advanced techniques complicated this picture.
Proposed mechanisms of DBS can be grouped into 4 main categories:
- inhibition of the target, the classic reversible functional lesioning paradigm
- activation of the target
- combined inhibition and activation
- disruption of pathological oscillations to restore rhythmic activity and synchronization, the "noisy signal hypothesis".
Part of the difficulty in identifying a mechanism for the physiological effect of DBS is due to the incomplete understanding of the pathophysiology of the diverse array of movement, neuropsychiatric, and cognitive disorders currently under investigation for DBS intervention.
In Parkinson’s Disease
Most of the studies about the DBS mechanisms of action has been conducted in relation to Parkinson's disease. In experimental animals , with depth electrodes implanted in the subthalamic nucleus ( STN ) and subjected to high-frequency stimulation ( HFS ) , electrophysiological recordings show a reduction in the substantia nigra pars reticulata ( SNR ) discharge and the globus pallidus interna ( GPI ) and, at the same time, that the activity of the ventral nucleus of the thalamus is increased. These observations suggest that inhibition of the subthalamic nucleus by HFS reduces the glutamatergic excitatory activity towards the SNR and the GPI , disinhibiting the thalamus by GABAergic influence of these two nuclei. The inhibition of the STN is instead evident by the reduced activity of discharge of the nucleus, that persists for several seconds after the HFS interruption. The stimulation by electrodes placed in the depth of the brain can act through the modulation of the activity of the nearby cells and through interaction with afferent fibers.
For some authors the HFS can achieve this inhibitory effect by inducing a depolarization, during which the STN neurons are incapable of producing action potentials, and so, block depolarizing. Other authors have proposed a hyperpolarization rather than depolarization, as mechanism of inhibition, based on the observation that in patients subjected to HFS STN stimulation was able to produce an early inhibition followed by a new occurrence of excitation, on its way to a permanent inhibition. Another hypothesis for the HFS’s mechanism of action is called neural traffic. The high-frequency activity would interfere with the activity of the pathological circuit.
Recent data finally allow to hypothesize the existence of other mechanisms of action. For exemple, it’s possible that the DBS , in addition to inhibiting , stimulate some neuronal subtalamic populations. Probably more than a mechanism determine the therapeutic effect of DBS of the subthalamic nucleus although, so far, is not available a unique model of interpretation about the mechanism of action . The final effect of DBS of the subthalamic nucleus is a disinhibition of the thalamus by activation of the cerebral cortex, demonstrated by PET (Positron Emission Tomography) and SPECT ( computed tomography single photon emission ) in humans.
In a study, conducted by P.Stanzione and A.Stefani in 2012, biochemical effects of STN-DBS have been assessed in putamen ( PUT ), internal pallidus, and inside the antero-ventral thalamus ( VA ), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP (Cyclic Guanosine Monophosphate) , an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC (High Performance Liquid Chromatography). During clinically effective STN-DBS, they found a significant decrease in GABA extracellular concentrations in VA, −30% . Simultaneously,
cGMP* extracellular concentrations were enhanced in PUT, +200% and GPi, +481%. These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy.
So, what are we stimulating and/or inhibiting?
Stimulating axons with monopolar stimulation:
- Nearby axons may be blocked (by high currents)
- Distant axons are unlikely affected by stimulation
- Intermediately located axons may be activated (“shell of activation”)
High-frequency stimulation in Parkinson’s disease:
more or less?
Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus
Neuroscience - Mechanism of BDS - 2011
Focus on Anorexia Nervosa
Anorexia nervosa ( AN ) is a potentially fatal eating disorder characterized by self-starvation, where an individual’s weight is, by arbitrary definition, <85% of expected levels. The syndrome is approximately tenfold more common in females than in males, with a typical age of onset during adolescence. Today, roughly 0.3% of females in the United States develop anorexia nervosa.
Although its causes are virtually completely unknown, there is evidence of an important genetic component, despite there having been no disease-causing genes identified so far. Several environmental and psychological factors have also been implicated, but they have provided little insight into causative mechanisms. Treatments remain inadequate for most patients; only 30% make a complete recovery in their lifetime with different types of behavioral therapies. Several classes of psychotropic medications are used, but none are clearly effective. Roughly 10% of all patients diagnosed with AN die from starvation-related complications or suicide the highest mortality rate seen for anymental illness.
Two recent studies report the potential utility of DBS in treating severe cases of AN. In DBS, electrodes are implanted —typically bilaterally— within a targeted region of the brain; patients have power supplies implanted in their chests, which drive continuous, high-frequency stimulation of the targeted brain area. In one study, four female patients with anorexia received DBS targeted to the nucleus accumbens ( NAc ) , a region of ventral striatum that controls reward and motivation.
In the second study, six female patients received DBS targeted to Brodmann area 25 , the subgenual region of the anterior cingulate cortex (part of the prefrontal cortex) thought to be important for mood and decision making. After several months of continuous DBS, all four patients in the first study, and four of six in the second one, showed significant improvement in weight along with improvements in several other behavioral domains. Although the studies were exploratory phase 1 trials and were not adequately powered to determine efficacy, the provocative findings are cause for cautious optimism and provide a possible path toward an improved understanding of this syndrome.
What causes someone to starve herself (or himself) to the point of death?
Psychological explanations, such as having a distorted body image (thinking one is fat despite being cachectic) or being overly controlling or perfectionistic, seem like obvious descriptions of the core symptoms of the syndrome as opposed to mechanistic causes. Functional and structural brain imaging studies have implicated several regions of forebrain that are known to be crucial in reward, mood, motivation and decision making in AN. These include several regions of the prefrontal cortex, nucleus accumbens and dorsal striatum, amygdala (important for learned associations for both rewarding and aversive stimuli) and insula (a cortical region suggested to serve as a neural substrate of disgust). Previous evidence has shown that patients with AN have abnormal brain responses for example, in the prefrontal cortex and nucleus accumbens to food stimuli that are rewarding in normal individuals, leading to the suggestion of "abnormal reward processing" in AN. But these findings also seem derivative of the behavioral symptoms of the illness —where self-starvation is rewarding, in contrast to the extreme aversion felt by people without the disorder— and are therefore of limited utility.
A further limitation in understanding the neurobiological basis of AN is the lack of bona fide animal models. Most models involve forced calorie restriction of rodents and the resulting hyperactivity; other models disrupt gonadal steroids, based on the female preponderance of the syndrome in humans. However, in the absence of known anorexia-causing genes of strong effect and high penetrance in humans, all current animal models are of limited etiological and face validity. It is in this context that experimental trials of DBS in anorexia nervosa might break new ground. DBS enables the direct modification of the electrical activity within a given region of brain, and various brain imaging modalities allow for the elaboration of the circuit consequences downstream of such chronic DBS, approaches possible in both humans and animals.
It is thus possible that use of DBS, targeting distinct regions of brain with different frequencies and time of stimulation, will provide fundamental insight into the brain circuits that underlie AN. Given that most individuals with AN show symptoms of other mental disorders, including obsessivecompulsive traits, anxiety and depression, such exploratory DBS studies could help parse the neural substrates of anorexia and its psychological concomitants from these other symptom domains.
Results from PET studies indicate differences between subjects recovered from AN and healthy subjects in serotonin and dopamine receptor activity, indicating dysregulation of these systems involved in mood, anxiety, appetite and impulse control.
Several studies showed alterations in the serotonergic (5-HT)-system in AN. For example, Kaye et al. (2009) reported elevated 5 -HT metabolite levels, as well as elevated binding potential for postsynaptic 5 -HT1a receptors and diminished binding potential for 5-HT2a receptors in recovered AN patients. In contrast, ill AN patients were shown to have reduced amounts of the major 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Finally, it has been found that a dietary-induced reduction of tryptophan, the precursor of serotonin, is associated with decreased anxiety in AN patients . Starvation may help AN patients to briefly reduce 5-HT activity and thus give symptom relief.
These alterations in 5-HT function may be related to AN symptoms regarding inhibition of appetite, generalized inhibition, anxiety and obsessions through stimulation of 5-HT1a receptors.
Other studies showed that ill and recovered AN patients also have altered striatal dopamine ( DA ) function. Kaye et al. (1999) found reduced levels of DA metabolites in the cerebrospinal fluid in ill and recovered AN patients. Frank et al. (2005) found that patients recovered from AN had increased D2/D3 receptor binding potential in the ventral striatum ( VS ), indicating either increased D2/D3 receptor density or decreased extracellular DA, or both. In addition, functional DA D2 receptor gene polymorphisms have been associated with AN and subjects with AN have impaired visual discrimination learning, indicating altered DA neurotransmission in AN.
Disturbances in the DA-system may contribute to an altered response to reward and alterations in decision-making and executive control found in patients with AN.
Similar alterations of 5-HT and DA function are also found in other reward-related disorders like OCD , although the exact mechanisms and the interactions between these and other neurotransmitter systems are not clarified yet.
Serotonin: imaging findings in eating disorders - 2011
Altered Brain Serotonin 5-HT1A Receptor Binding After Recovery From Anorexia Nervosa Measured by Positron Emission Tomography and [Carbonyl11C]WAY - 2005
Is DBS a treatment option for anorexia nervosa? - 2013
What, then, is the right DBS target site for anorexia nervosa?
Most studies to date that examine new applications of
DBS to neuropsychiatric disorders take the approach of using targets already established for other conditions. This makes sense, as the relative safety of these targets is known even after many years of continuous stimulation. Additionally,
DBS of a site used for an established condition (for example, motor abnormalities of Parkinson’s disease) can provide information as to whether other symptoms that accompany the syndrome, such as depression seen in Parkinson’s disease, are also alleviated. Thus,
DBS of the
nucleus accubens (and nearby regions involving the anterior limb of the internal capsule) has shown some early efficacy for the treatment of severe obsessive-compulsive disorder, whereas
DBS of
Brodmann area 25 is a leading target for the experimental treatment of severe depression. The ability of
DBS of these regions to induce some improvement in AN raises the question of whether such improvements occur primarily through the alleviation of obsessive-compulsive or depressive symptoms rather than the direct alleviation of abnormal feeding behavior.
“
The scheme illustrates two sites of DBS recently reported in humans1, 2 (solid lines) and possible additional sites (dashed line) and the ways in which coordinated studies in animals might explain the mechanism of action of DBS both at the site of stimulation and affected downstream circuitry. sg25, subgenual anterior cingulate cortex; NAc, nucleus accumbens; Hypo, hypothalamus; VTA, ventral tegmental area. ”
DBS of the subthalamic nucleus has been shown to cause weight gain in a subset of patients, raising the possibility that this region could be targeted for AN as well. However, based on our increasing knowledge of normal feeding pathways in animals, it would be interesting to carry out exploratory DBS studies of numerous other brain regions in individuals with AN, with an eye on treatment of selected domains of behavioral abnormalities. For example, it would be important to target more specific components of the reward circuitry, such as the ventral tegmental area and subregions of NAc, given that DBS of different NAc subregions has been shown to differentially modify food intake versus motivation for food in rats. It would also be interesting to target distinct hypothalamic nuclei that are known to have very different roles in the control of feeding behavior. As efficacy is established, it will be important to determine how long DBS must be continued to maintain a treatment response.
As well, determining the long-term safety of DBS of various sites will be crucial, although few longterm side effects have been reported to date in other conditions. Once DBS targets of robust and perhaps selective efficacy in AN are established, it would be possible to use this information to explore underlying mechanisms in animal models.
As one example, would the opposite type of manipulation of the homologous region in a rodent or nonhuman primate result in a syndrome of self-starvation, which has heretofore been very difficult to induce in animals? In parallel, it would be important to use animals to understand how DBS of a given region can be therapeutic in humans. Thus, it is not currently understood, for any clinical application of DBS, whether DBS works by affecting cell bodies or nerve terminals within, or axons that traverse, the area of stimulation. Effects on several types of glial cells are also possible. Moreover, DBS, as currently applied, involves very-high-frequency stimulation of a targeted brain region, which might just as readily inactivate these neural elements through depolarization blockade.
Given the similarities in symptomatology and associated neurocircuits between OCD and Anorexia Nervosa, the established efficacy of DBS in OCD, and the neurobiological correlates of AN as described above, DBS of the NAc and other areas associated with reward, e.g. the ACC (anterior cingulated cortex, associated with emotional processing, body image, self-monitoring, conflict resolution, and reward-based decision making), might be effective in patients with chronic, treatment refractory AN, providing not only weight restoration, but also significant and sustained improvement in AN core symptoms and associated comorbidities and complications. Possible targets for DBS in AN are the ACC, the ventral anterior limb of the capsula interna (vALIC) and the VS (consisting of the ventral caudate nucleus and the NAc).
Deep brain stimulation for obsessive-compulsive disorder:
past, present, and future - 2010
Treating the brain deep down: Brain surgery for anorexia nervosa? - 2013
Conclusions
This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective.
The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of Anorexia Nervosa, which still remains a mystery and poses a challenge for treatment.
