Neurosurgery in the Treatment of Alcohol Use Disorder: A Systematic Literature Review

Alcohol abuse has impacts on public health worldwide. Conservative treatment to achieve abstinence consists of detoxification combined with psychotherapy and the use of drugs, but it is estimated that only half of the individuals achieve long-term abstinence with the available treatments. In this sense, neurosurgery appears as a therapeutic proposal. The present study aimed to gather information about the circuitry related to alcohol use disorder (AUD), to describe possible surgical targets, and to establish whether a surgical approach could be a safe and effective treatment option. A systematic review of the literature was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The 14 selected articles analyze ablative operations, deep brain stimulation (DBS), and a new procedure in which the patient is first submitted to repetitive transcranial magnetic stimulation to evaluate their response, and later an implant is surgically positioned on the evaluated target to obtain more lasting results. The most relevant outcomes were found when the anterior cingulate cortex (ACC) and the nucleus accumbens (NAcc) were used as targets, demonstrating a large reduction in alcohol intake and even its cessation. However, important side effects were observed, such as psychotic symptoms, right frontal venous infarction, seizures after implantation in the ACC and a hypomanic period after DBS in the NAcc, which could be reversed. Due to the lack of studies involving the surgical treatment of AUD, more clinical trials are needed to compare targets, to assess surgical techniques, and to estimate the safety of these techniques.

Safety and Feasibility of Nucleus Accumbens Surgery for Drug Addiction: A Systematic Review.

BACKGROUND: Substance addiction encompasses the incapacity to discontinue urgent drug use; many severely disabled patients might be considered appropriate candidates for surgery due to the high rates of relapse despite conservative treatment. A crucial finding in the brain of these patients is increased extracellular concentrations of dopamine in the nucleus accumbens (NAcc). OBJECTIVES: To determine the efficacy and safety of NAcc surgery for the treatment of substance dependence. MATERIALS AND METHODS: Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies in which NAcc surgery was performed to treat relapsing drug addiction with a minimum follow-up of six months. From database inception to April 10, 2020, we searched PubMed, Scopus, and LILACS. Two reviewers independently selected studies and extracted data. The main outcome was the relapse rate. The GRADE methods were applied to evaluate the quality of evidence. This study was registered with PROSPERO CRD42020177054. RESULTS: Fifteen studies involving 359 participants met inclusion criteria; eight (56%) included NAcc deep brain stimulation (DBS) in 13 patients with addiction for alcohol (N = 6, 46.1%), opioid (N = 4, 30.7%), and nicotine (N = 3, 15.3%); seven studies (N = 346, 44%) performed NAcc radiofrequency (RF) ablation for opioid (N = 334) and alcohol (N = 12) dependence. Relapse rates were 38.4% for DBS and 39% for RF ablation. CONCLUSIONS: Despite available studies reporting a benefit in the treatment of drug addictions with NAcc surgery, this systematic review stresses the need for carefully planned prospective studies in order to further address the efficacy and indications.

Effectiveness of Deep Brain Stimulation in Reducing Body Mass Index and Weight: A Systematic Review.

BACKGROUND: Obesity has become a major public health concern worldwide, with current behavioral, pharmacological, and surgical treatments offering varying rates of success and adverse effects. Neurosurgical approaches to treatment of refractory obesity include deep brain stimulation (DBS) on either specific hypothalamic or reward circuitry nuclei, which might contribute to weight reduction through different mechanisms. We aimed to determine the safety and clinical effect of DBS in medical refractory obesity. SUMMARY: Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies - observational and experimental - in which DBS was performed to treat refractory obesity. From database inception to April 2021, we conducted our search in PubMed, Scopus, and LILACS databases using the following MeSH terms: "Obesity" OR "Prader-Willi Syndrome" AND "Deep Brain Stimulation." The main outcomes were safety and weight loss measured with the body mass index (BMI). The Grading of Recommendations Assessment, Development, and Evaluation methods were applied to evaluate the quality of evidence. This study protocol was registered with PROSPERO ID: CRD42019132929. Seven studies involving 12 patients met the inclusion criteria; the DBS target was the nucleus accumbens in four (57.1%), the lateral hypothalamic area in two (29.6%), and the ventral hypothalamus in one (14.3%). Further, 33% of participants had obesity secondary to Prader-Willi syndrome (PWS) and 66.6% had primary obesity. The global BMI average at baseline was 46.7 (SD: 9.6, range: 32.2-59.1), and after DBS, 42.8 (SD: 8.8, range: 25-53.9), with a mean difference of 3.9; however, the delta in PWS patients was -2.3 and 10 in those with primary obesity. The incidence of moderate side effects was 33% and included manic symptoms (N = 2), electrode fracture (N = 1), and seizure (N = 1); mild complications (41.6%) included skin infection (N = 2), difficulties falling asleep (N = 1), nausea (N = 1), and anxiety (N = 1). KEY MESSAGES: Despite available small case series and case reports reporting a benefit in the treatment of refractory obesity with DBS, this study emphasizes the need for prospective studies with longer follow-ups in order to further address the efficacy and indications.

Nucleus accumbens as a stereotactic target for the treatment of addictions in humans: a literature review.

INTRODUCTION: Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson's Disease (PD), essential tremor (ET), and dystonia. More recently, a limited number of basic and clinical studies have indicated that DBS of the nucleus accumbens (NAc) and other neighbouring structures of the reward circuit may be an effective intervention for patients with treatment-refractory addiction. MATERIAL AND METHODS: We performed a structured literature review of human studies of DBS for addiction outlining the clinical efficacy and adverse events. We found 14 human studies targeting mostly the NAc with neighbouring structures such as anterior limb of the internal capsule (ALIC). Five studies including 12 patients reported the outcomes for alcohol dependence. Nine studies including 18 patients reported the outcomes for addictions to various psychoactive substances. The most common indication was addiction to heroin, found in 13 patients, followed by methamphetamine, 3 patients, cocaine, one patient, and polysubstance drug abuse in one patient. CONCLUSIONS: The limited clinical data available indicates that DBS may be a promising therapeutic modality for the treatment of intractable addiction. In general, the safety profile of DBS in patients with addiction is good. Based on the data published in the literature, the NAc is the most often targeted, and is probably the most effective, structure of the reward circuit in the treatment of addiction in humans. Given the ever-expanding understanding of the psychosurgery of addiction, DBS could in the future be a treatment option for patients suffering from intractable addictive disorders.

Rescue Anterior Capsulotomy after Failure of Nucleus Accumbens Deep Brain Stimulation in Anorexia Nervosa: A Case Report.

Anorexia nervosa (AN) is a highly disabling mental disorder with high rates of morbidity and mortality. Few psychological treatments and pharmacotherapy are proven to be effective for adult AN. Two invasive stereotactic neurosurgical interventions, deep brain stimulation (DBS) and anterior capsulotomy, are now commonly used as investigational approaches for the treatment of AN. Here, we report the long-term safety and efficacy of rescue bilateral anterior capsulotomy after the failure of bilateral nucleus accumbens (NAcc)-DBS in an 18-year-old female patient with life-threatening and treatment-resistant restricting subtype AN. Improvements in the neuropsychiatric assessment were not documented 6 months after the NAcc-DBS. Rescue bilateral anterior capsulotomy was proposed and performed, resulting in a long-lasting restoration of body weight and a significant and sustained remission in AN core symptoms. The DBS pulse generator was exhausted 2 years after capsulotomy and removed 3 years postoperatively. No relapse was reported at the last follow-up (7 years after the first intervention). From this case, we suggest that capsulotomy could be a rescue treatment for patients with treatment-resistant AN after NAcc-DBS failure. Further well-controlled studies are warranted to validate our findings.

Outcomes of deep brain stimulation surgery for substance use disorder: a systematic review.

Long has the standard of care for substance use disorder (SUD) been pharmacotherapy, psychotherapy, or rehabilitation with varying success. Deep brain stimulation (DBS) may have a beneficial reduction in the addiction-reward pathway. Recent studies have found reduced relapse and improvements in quality of life following DBS stimulation of the nucleus accumbens. We aim to identify positive outcomes and adverse effects to assess the viability of DBS as a treatment of addiction. A PubMed search following PRISMA guidelines was conducted to identify the entirety of reports reporting DBS as a treatment for SUD. Outcomes were extracted from the literature to be summarized, and a review of the quality of publications was also performed. From 2305 publications, 14 studies were found to fit the inclusion criteria published between 2007 and 2019. All studies targeted the nucleus accumbens (NAc) and remission rates at 6 months, 1 year, 2 years, and more than 6 years were 61% (20/33), 53% (17/32), 43% (14/30), and 50% (3/6), respectively. Not all studies detailed the stimulation settings or coordinates. The most common adverse effect across studies was a weight change of at least 2 kg. DBS shows potential as a long-term treatment of SUD in refractory patients. Further studies with controlled double-blind paradigms are needed for evaluation of the efficacy and safety of this treatment. Future studies should also investigate other brain regions for stimulation and optimal device stimulation parameters.

Anatomic Review of the Ventral Capsule/Ventral Striatum and the Nucleus Accumbens to Guide Target Selection for Deep Brain Stimulation for Obsessive-Compulsive Disorder.

BACKGROUND: Disturbances in the reward network of the brain underlie addiction, depression, and obsessive-compulsive disorder. The ventral capsule/ventral striatum and nucleus accumbens (NAc) region is a clinically approved target for deep brain stimulation for obsessive-compulsive disorder. METHODS: We performed a comprehensive literature review to define clinically relevant anatomy and connectivity of the ventral capsule/ventral striatum and NAc region to guide target selection for deep brain stimulation. RESULTS: Architecturally and functionally, the NAc is divided into the core and the shell, with each area having different connections. The shell primarily receives limbic information, and the core typically receives information from the motor system. In general, afferents from the prefrontal cortex, hippocampus, and amygdala are excitatory. The dopaminergic projections to the NAc from the ventral tegmental area modulate the balance of these excitatory inputs. Several important inputs to the NAc converge at the junction of the internal capsule (IC) and the anterior commissure (AC): the ventral amygdalofugal pathways that run parallel to and underneath the AC, the precommissural fornical fibers that run anterior to the AC, axons from the ventral prefrontal cortex and medial orbitofrontal cortex that occupy the most ventral part of the IC and embedding within the NAc and AC, and the superolateral branch of the medial forebrain bundle located parallel to the anterior thalamic radiation in the IC. CONCLUSIONS: The caudal part of the NAc passing through the IC-AC junction may be an effective target for deep brain stimulation to improve behavioral symptoms associated with obsessive-compulsive disorder.

Extracellular adenosine and slow-wave sleep are increased after ablation of nucleus accumbens core astrocytes and neurons in mice.

Sleep and wakefulness are controlled by a wide range of neuronal populations in the mammalian brain. Activation of adenosine A2A receptor (A2AR)-expressing neurons in the nucleus accumbens (NAc) core promotes slow-wave sleep (SWS). The neuronal mechanism by which activation of NAc A2AR neurons induces SWS, however, is unknown. We hypothesized that the ability of NAc activation to induce sleep is mediated by the classic somnogen adenosine, which can be formed by various processes in all types of cells. Here, to investigate whether astrocytes are involved in the ability of the NAc to regulate SWS, we ablated glial fibrillary acidic protein (GFAP)-positive cells in the NAc core of mice by virus-mediated expression of diphtheria toxin (DT) receptors and intraperitoneal administration of DT. Analysis of electroencephalogram and electromyogram recordings of DT-treated wild-type mice revealed that SWS was remarkably increased at 1 week after DT treatment, whereas sleep-wake behavior was unchanged in DT-treated A2AR knockout mice. Cell ablation was associated with an increased number of GFAP-positive cells and activation of microglia in the NAc. In-vivo microdialysis revealed significantly increased levels of extracellular adenosine in the NAc at 1 week after DT treatment. Our findings suggest that elevated adenosine levels in the NAc core promote SWS by acting on A2ARs and provide the first evidence that adenosine is an endogenous candidate for activating NAc A2AR neurons that have the ability to induce SWS.

Deep Brain Stimulation of Nucleus Accumbens for Methamphetamine Addiction: Two Case Reports.

BACKGROUND: Methamphetamine (MA) addiction is one of the most prevalent socioeconomic and health problems worldwide. In recent years, deep brain stimulation (DBS) has increasingly been used for the treatment of addiction. CASE DESCRIPTION: This study reports on 2 MA-dependent patients who received DBS of the nucleus accumbens (NAc). During the approximately 2-year follow-up period, one patient (A) remained abstinent and presented with positive emotional experiences, whereas the other (B) had no significant psychobehavioral changes during stimulation at low-to-moderate voltages and subsequently relapsed. Through coregistration of preoperative magnetic resonance imaging with postoperative computed tomography/magnetic resonance imaging, the DBS electrode of patient A was confirmed to be accurately implanted in the NAc, whereas one side of the electrode of patient B deviated from the target. CONCLUSIONS: These case reports demonstrate that NAc-DBS maybe a possible treatment option for MA addiction.

The nucleus accumbens and alcoholism: a target for deep brain stimulation.

Alcohol use disorder (AUD) is a difficult to treat condition with a significant global public health and cost burden. The nucleus accumbens (NAc) has been implicated in AUD and identified as an ideal target for deep brain stimulation (DBS). There are promising preclinical animal studies of DBS for alcohol consumption as well as some initial human clinical studies that have shown some promise at reducing alcohol-related cravings and, in some instances, achieving long-term abstinence. In this review, the authors discuss the evidence and concepts supporting the role of the NAc in AUD, summarize the findings from published NAc DBS studies in animal models and humans, and consider the challenges and propose future directions for neuromodulation of the NAc for the treatment of AUD.

Therapeutic potential of deep brain stimulation of the nucleus accumbens in morbid obesity.

OBJECTIVE Morbid obesity is a growing problem worldwide. The current treatment options have limitations regarding effectiveness and complication rates. New treatment modalities are therefore warranted. One of the options is deep brain stimulation (DBS) of the nucleus accumbens (NAC). This review aims to summarize the current knowledge on NAC-DBS for the treatment of morbid obesity. METHODS Studies were obtained from multiple electronic bibliographic databases, supplemented with searches of reference lists. All animal and human studies reporting on the effects of NAC-DBS on body weight in morbidly obese patients were included. Articles found during the search were screened by 2 reviewers, and when deemed applicable, the relevant data were extracted. RESULTS Five relevant animal experimental papers were identified, pointing toward a beneficial effect of high-frequency stimulation of the lateral shell of the NAC. Three human case reports show a beneficial effect of NAC-DBS on body weight in morbidly obese patients. CONCLUSIONS The available literature supports NAC-DBS to treat morbid obesity. The number of well-conducted animal studies, however, is very limited. Also, the optimal anatomical position of the DBS electrode within the NAC, as well as the optimal stimulation parameters, has not yet been established. These matters need to be addressed before this strategy can be considered for human clinical trials.

Demotivating outcome of asymmetrical Nucleus Accumbens disconnection for cocaine related disorder: a translational point of view. / Desmotivadora evolución de la desconexión asimétrica del Núcleo Accumbens en el trastorno por consumo de cocaína: un punto de vista traslacional.

Letter to the editor.

Carta al editor.

Morphometric Analysis of the Nucleus Accumbens Using the Mulligan Staining Method.

BACKGROUND: There is a need to further anatomically describe the nucleus accumbens (NA), as there is a growing neurosurgical interest in this locus but a limited understanding of its structure. In this study, we evaluated quantitative NA parameters and spatial relationships with adjacent structures found in the telencephalon. METHODS: A total of 155 NA specimens from coronal sections and 3 NA specimens from transverse sections were stained using the Mulligan technique as modified by Barnard et al. The distance from the NA to other structures was then measured. RESULTS: The mean radius of the 155 NAs in the coronal sections was 6.23 ± 0.964 mm, averaging 8.99 ± 2.02 mm from midline (coordinate x), 27.09 ± 3.15 mm from the insula, 12.95 ± 3.21 mm from the outer border of the putamen, 10.52 ± 2.66 mm from the upper border of the caudate, and 8.84 ± 2.93 mm from the midline of the lateral ventricle. The mean distance from the NA center of gravity to the middle of the intercommissural line parallel to the midline (coordinate y) was 17.08 ±3.61 mm, and the mean vertical distance from the intercommissural line to the NA was 8.12 ± 1.265 mm. CONCLUSIONS: We obtained the stereotactic coordinates of (x, y, z) = (8, 17, -8) for the NA. From this and other delineations of the described position of the NA, it is possible to contribute to stereotactic surgical atlases, improving neurosurgical interventions in this structure.

Deep brain stimulation for severe treatment-resistant obsessive-compulsive disorder: An open-label case series.

OBJECTIVE: Deep brain stimulation can be of benefit in carefully selected patients with severe intractable obsessive-compulsive disorder. The aim of this paper is to describe the outcomes of the first seven deep brain stimulation procedures for obsessive-compulsive disorder undertaken at the Neuropsychiatry Unit, Royal Melbourne Hospital. The primary objective was to assess the response to deep brain stimulation treatment utilising the Yale-Brown Obsessive Compulsive Scale as a measure of symptom severity. Secondary objectives include assessment of depression and anxiety, as well as socio-occupational functioning. METHODS: Patients with severe obsessive-compulsive disorder were referred by their treating psychiatrist for assessment of their suitability for deep brain stimulation. Following successful application to the Psychosurgery Review Board, patients proceeded to have deep brain stimulation electrodes implanted in either bilateral nucleus accumbens or bed nucleus of stria terminalis. Clinical assessment and symptom rating scales were undertaken pre- and post-operatively at 6- to 8-week intervals. Rating scales used included the Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Inventory, Depression Anxiety Stress Scale and Social and Occupational Functioning Assessment Scale. RESULTS: Seven patients referred from four states across Australia underwent deep brain stimulation surgery and were followed for a mean of 31 months (range, 8-54 months). The sample included four females and three males, with a mean age of 46 years (range, 37-59 years) and mean duration of obsessive-compulsive disorder of 25 years (range, 15-38 years) at the time of surgery. The time from first assessment to surgery was on average 18 months. All patients showed improvement on symptom severity rating scales. Three patients showed a full response, defined as greater than 35% improvement in Yale-Brown Obsessive Compulsive Scale score, with the remaining showing responses between 7% and 20%. CONCLUSION: Deep brain stimulation was an effective treatment for obsessive-compulsive disorder in these highly selected patients. The extent of the response to deep brain stimulation varied between patients, as well as during the course of treatment for each patient. The results of this series are comparable with the literature, as well as having similar efficacy to ablative psychosurgery techniques such as capsulotomy and cingulotomy. Deep brain stimulation provides advantages over lesional psychosurgery but is more expensive and requires significant multidisciplinary input at all stages, pre- and post-operatively, ideally within a specialised tertiary clinical and/or academic centre. Ongoing research is required to better understand the neurobiological basis for obsessive-compulsive disorder and how this can be manipulated with deep brain stimulation to further improve the efficacy of this emerging treatment.

Perimovement decrease of alpha/beta oscillations in the human nucleus accumbens.

The human nucleus accumbens is thought to play an important role in guiding future action selection via an evaluation of current action outcomes. Here we provide electrophysiological evidence for a more direct, i.e., online, role during action preparation. We recorded local field potentials from the nucleus accumbens in patients with epilepsy undergoing surgery for deep brain stimulation. We found a consistent decrease in the power of alpha/beta oscillations (10-30 Hz) before and around the time of movements. This perimovement alpha/beta desynchronization was observed in seven of eight patients and was present both before instructed movements in a serial reaction time task as well as before self-paced, deliberate choices in a decision making task. A similar beta decrease over sensorimotor cortex and in the subthalamic nucleus has been directly related to movement preparation and execution. Our results support the idea of a direct role of the human nucleus accumbens in action preparation and execution.

Removing and reimplanting deep brain stimulation therapy devices in resistant OCD (when the patient does not respond): case report.

BACKGROUND: Deep brain stimulation (DBS) is emerging as a promising tool in the treatment of refractory obsessive-compulsive disorder (OCD) but the search for the best target still continues. This issue is especially relevant when particularly resistant profiles are observed in some patients, which have been ascribed to individual responses to DBS according to differential patterns of connectivity. As patients have been implanted, new dilemmas have emerged, such as what to do when the patient does not respond to surgery. CASE PRESENTATION: Here we describe a 22-year-old male with extremely severe OCD who did not respond to treatment with DBS in the nucleus accumbens, but who did respond after explanting and reimplanting leads targeting the ventral capsule-ventral striatum region. Information regarding the position of the electrodes for both surgeries is provided and possible brain structures affected during stimulation are reviewed. To our knowledge this case is the first in the literature reporting the removal and reimplantation of DBS leads for therapeutical benefits in a patient affected by a mental disorder. CONCLUSION: The capability for explantation and reimplantation of leads should be considered as part of the DBS therapy reversibility profile in resistant mental disorders, as it allows application in cases of non-response to the first surgery.

[The role of the nucleus accumbens in psychiatric disorders].

The nucleus accumbens is the most inferior part of the striatum and is mainly connected to the limbic system. It is neurochemically and immunohistochemically divided into a shell laterally and a core medially. As a functionally central structure between amygdala, basal ganglia, mesolimbic dopaminergic regions, mediodorsal thalamus and prefrontal cortex, the nucleus accumbens appears to play a modulative role in the flow of the information from the amygdaloid complex to these regions. Dopamine is a major neurotransmitter of the nucleus accumbens and this nucleus has a modulative function to the amygdala-basal ganglia-prefrontal cortex circuit. Together with the prefrontal cortex and amygdala, nucleus accumbens consists a part of the cerebral circuit which regulates functions associated with effort. It is anatomically located in a unique way to serve emotional and behavioral components of feelings. It is considered as a neural interface between motivation and action, having a key-role in food intake, sexual behavior, reward-motivated behavior, stress-related behavior and substance-dependence. It is involved in several cognitive, emotional and psychomotor functions, altered in some psychopathology. Moreover it is involved in some of the commonest and most severe psychiatric disorders, such as depression, schizophrenia, obsessive-compulsive disorder and other anxiety disorders, as well as in addiction, including drugs abuse, alcoholism and smoking. Nucleus accumbens has also a role in other psychiatric disorders such as bipolar disorder, attention deficit/ hyperactivity disorder and post-traumatic stress disorder. Because of its rich dopaminergic projections, this nucleus has been subject of many studies in animals as well as in humans, connecting its malfunction with the disturbed reward process observed in depression. Neuromodulation interventions targeting the nucleus accumbens are nowadays applied in strictly selected patients suffering from treatment-resistant depression, obsessive-compulsive disorder, Tourette syndrome and addiction to drugs or alcohol. Specifically, bilateral and unilateral (right) deep brain stimulation of the nucleus accumbens has been applied in obsessive-compulsive patients resulting into significant improvement of their symptoms and their quality of life. Nucleus accumbens deep brain stimulation has been also associated with antidepressant and anxiolytic effect, as well as quality of life improvement in patients suffering from severe resistant depression. Finally, this minimally invasive stereotactic procedure has been proved beneficial for all phenotypic components of the Tourette syndrome, with remarkable reduction of the syndrome's motor manifestations, including tics.

Electrical high frequency stimulation modulates GABAergic activity in the nucleus accumbens of freely moving rats.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective treatment option for those affected by obsessive compulsive disorder, who do not respond to pharmacological treatment strategies. Yet, little is known about the mechanism by which DBS achieve its therapeutic effects. Previous studies have shown an increase in GABA levels due to high frequency stimulation (HFS) in the rat caudate putamen. Here, the effect of high frequency stimulation in the nucleus accumbens of conscious and freely moving rats was characterized using unilateral but simultaneous microdialysis and HFS with a frequency of 124 Hz and 0.5 mA current. Extracellular levels of neurotransmitters - GABA, glutamate, dopamine, serotonin and their metabolites were quantified by means of HPLC with electrochemical detection. Basal levels of GABA were significantly increased in animals of the stimulation group compared to the control group without HFS. The levels of other neurotransmitters were unaffected. The influence of NMDA receptor antagonist, memantine (5 mg/kg) on the effect of HFS was investigated by subcutaneous administration of memantine on the day of the experiment. Memantine (without stimulation) enhanced basal GABA and dopamine levels. However, under the influence of both memantine and HFS, GABA levels were not affected by HFS whereas dopamine levels decreased during the stimulation period. The results of our study demonstrate that HFS in the nucleus accumbens of freely moving rats induces selective increase in GABA outflow and show a possible involvement of NMDA receptors in the mechanistic action of HFS.