Subcallosal Cingulate Gyrus Research Articles

P.2.c.025 Preliminary findings of the rest-activity cycles in patients with major depression following agomelatine and sertraline treatment

Positron emission tomography (PET) studies have shown that the antidepressant effect of chronic deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may be consequence of modifications of brain metabolism at key structures involved in depression. Like clinical benefits, these metabolic changes may reverse when the stimulation is discontinued, even preceding clinical worsening. However no data on immediate effects of DBS discontinuation are available. The aim of this study was to determine immediate cerebral metabolism changes during a short switch-off of electrical stimulation in implanted patients with treatment-resistant depression (TRD) who had achieved clinical improvement after a period of chronic DBS.Seven patients with TRD who had been previously implanted for DBS in SCG were included. After a period of clinical stabilization two consecutive FDG-PET were acquired, the first with active stimulation and the second after 48 h of inactive stimulation. A HAMD-17 to assess depressive symptoms was performed before both scans. Analyses were performed with SnPM8.Inactive stimulation was characterized by metabolism decreases in dorsal anterior cingulate (Broadmann Area, BA24), premotor region (BA6) and putamen with respect to active stimulation. No clinical changes according to HAMD-17 were detected.The main limitation of this study is the small sample size.Our results point to immediate effects of DBS discontinuation on metabolism of brain depressive network which precede clinical changes, helping to disentangle the rationale behind DBS efficacy in TRD.

Structural deficits in the emotion circuit and cerebellum are associated with depression, anxiety and cognitive dysfunction in methadone maintenance patients: A voxel-based morphometric study

Heroin users on methadone maintenance treatment (MMT) have elevated rates of co-morbid depression and are associated with have higher relapse rates for substance abuse. Structural abnormalities in MMT patients have been reported, but their impact on clinical performance is unknown. We investigated differences in gray matter volume (GMV) between 27 MMT patients and 23 healthy controls with voxel-based morphometry, and we correlated findings in the patients with Beck Depression Inventory scores, Beck Anxiety Inventory scores, and diminished cognitive functioning. MMT patients exhibited higher emotional deficits than healthy subjects. There was significantly smaller GMV in multiple cortices, especially in the left inferior frontal gyrus and left cerebellar vermis in the MMT group. The smaller GMV in the pre-frontal cortices, left sub-callosal cingulate gyrus, left post-central gyrus, left insula, and right cerebellar declive correlated with higher depression scores. The smaller GMV in the pre-frontal cortices, left sub-callosal cingulate gyrus, and left postcentral gyrus also correlated with higher anxiety scores, while smaller GMV in the cerebellum and bilateral insula was associated with impaired performance on tests of executive function. These results reveal that MMT patients have low GMV in brain regions that are hypothesized to influence cognition and emotion, and the GMV findings might be involved comorbid disorders in the MMT group.

A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression

Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression. Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50). Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery. Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Sll-04 Neuromodulatory Therapeutic Mechanism of rTMS

Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.

P02-541 - DBS in Treatment-Resistant Depression

IntroductionOf patients with depression, up to 20–30% are treatment-resistant. DBS is being investigated as a novel therapeutic modality that could be effective in this group.Objective and aimsSummary of clinical experience with DBS for treatment-resistant depression.MethodsReview of published literature.ResultsDBS is undergoing trials for use in patients with major depression unresponsive to pharmacotherapy, cognitive therapy and electroconvulsion. Targets include the subcallosal cingulate gyrus, the nucleus accumbens, the anterior limb of capsula interna, the hibernula and the lower thalamus stem, areas shown by PET-scan studies to be crucial in development of depression, anxiety and anhedonia.In published studies, more than 50% of patients have responded or entered remission, as observed by score drops in the Hamilton and Montgomery-Asberg Depression Rating Scales, results that have been sustained over time. Post-op scans of responsive patients demonstarate reduction of both blood flow and metabolic hyperactivity in aforementioned areas- especially the cingulate gyrus- and other cortical and subcortical regions, and an increase in prefrontal blood flow, suggesting that DBS acts by disrupting pathological activity and normalizing function in near and adjacent circuits.DBS is reversible and adjustable with rare complications: wound skin infections, headaches and hemorrhage, while temporary mood changes, paresthesias, anxiety and autonomie disturbances are easily treated with stimulation adjustments.ConclusionsDBS has shown promise as new therapeutic means for unresponsive patients. With clinical trials multiplying and neuroimaging providing insight for possible targets, its applications are to become more common in resistant depression and other psychiatric disorders.

Deep Brain Stimulation for Treatment-Resistant Depression: Follow-Up After 3 to 6 Years

A prevalence of at least 30% for treatment-resistant depression has prompted the investigation of alternative treatment strategies. Deep brain stimulation (DBS) is a promising targeted approach involving the bilateral placement of electrodes at specific neuroanatomical sites. Given the invasive and experimental nature of DBS for treatment-resistant depression, it is important to obtain both short-term and long-term effectiveness and safety data. This report represents an extended follow-up of 20 patients with treatment-resistant depression who received DBS to the subcallosal cingulate gyrus (Brodmann's area 25). After an initial 12-month study of DBS, patients were seen annually and at a last follow-up visit to assess depression severity, functional outcomes, and adverse events. The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3-6 years), the average response rate was 64.3%. Functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit. No significant adverse events were reported during this follow-up, although two patients died by suicide during depressive relapses. These data suggest that in the long term, DBS remains a safe and effective treatment for treatment-resistant depression. Additional trials with larger samples are needed to confirm these findings.

Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting

Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting

Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression

Background:A preliminary report in six patients suggested that deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may provide benefit in treatment-resistant depression (TRD). We now report the results of these and an additional 14 patients with extended follow-up. Methods:Twenty patients with TRD underwent serial assessments before and after SCG DBS. We determined the percentage of patients who achieved a response (50% or greater reduction in the 17-item Hamilton Rating Scale for Depression [HRSD-17]) or remission (scores of 7 or less) after surgery. We also examined changes in brain metabolism associated with DBS, using positron emission tomography. Results:There were both early and progressive benefits to DBS. One month after surgery, 35% of patients met criteria for response with 10% of patients in remission. Six months after surgery, 60% of patients were responders and 35% met criteria for remission, benefits that were largely maintained at 12 months. Deep brain stimulation therapy ...

Morphological variability of the subcallosal area of man

Knowledge of morphology of human anterior cingulate and medial frontal cortex related to the knee of corpus callosum is important in the diagnostics and neurosurgical treatment. Neuroimaging studies did not provide a clear picture of this region, what is also caused by terminological inconsistencies. It is not always clear what is actually defined under the terms subcallosal area, subcallosal cingulate gyrus, subcallosal gyrus, subcallosal region, or subgenual prefrontal gyrus. Our study of subcallosal area provides morphological data useful for recent imaging studies. Digital photographs (42 formaline fixed brains: 26 males, 16 females) were used in morphometry (surfaces and lengths) of subcallosal area. We defined all its boundaries: superoanterior, anterior, posterior, and inferior one. If anterior subcallosal sulcus, as anterior delineation of subcallosal area was absent, we used intercommissural line system. Anterior subcallosal sulcus we found in 86.9% of cases. Its variations were classified into four types: Type 1-vertical or slightly oblique sulcus (most often type on right hemispheres-30.1%), Type 2-in form of letter C or inverted letter C (most often type on left hemispheres-42.9%), Type 3-sulcus in form of letter S or inverted letter S, and Type 4-sulcus not belonging to any previous type. Mean surface of subcallosal area was in males 2.65cm(2) (right hemispheres), and on left 2.70cm(2). In females on right it was 2.56cm(2), and on left 2.55cm(2). All measured values were not significantly different (left/right; males/females). Accurate neuroanatomical localization requires exact determination of boundaries of subcallosal area. Therefore, standardized criteria were proposed for definition of subcallosal area.

Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200 μA, followed by 100 μA, and 300 μA. In contrast, 400 μA produced no effect. Using 200 μA, a frequency of 130 Hz was more effective than 20 Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST.

FC01-03 - Deep brain stimulation of subcallosal cingulate gyrus for treatment resistant depression

BackgroundDeep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) has been suggested to improve depressive symptoms in treatment-resistant depression (TRD). We now report preliminary results of DBS and one-year follow up in six patients.MethodsSix patients with severe TRD (Thase Resistance Index>4) underwent DBS surgery and subsequent monthly assessments. DBS response was defined as ≥50% reduction in the 17-item Hamilton Depression Rating Scale (HDRS) or HDRS< 8 (remission). Electrodes location was assessed in each patient by means of pre/post-DBS MRIs co-registration.ResultsDBS led to early and late reductions of average HDRS (from 22.5 to 9.8 and 6.25 respectively, see Figure 1 for evolution of HDRS mean scores). One month after surgery 16.7% of patients met criteria for response and for remission. Three months after response rates increased to 66.7% while remission rates were maintained. At six months, 66.7% of patients were responders. After 9 months, response rates arose up to 83.4% and these rates were largely maintained at 12 months. Remission rates showed similar growth over follow-up. No substantial differences were observed in electrodes location, and they were not found to be related to response or remission rates. The number of serious adverse effects was small with no patient experiencing permanent deficits.ConclusionsThis study suggests that DBS is relatively safe and provides significant improvement in patients with TRD. Improvement on average seems to be linearly progressive and, once melioration is achieved, it is maintained for at least one year. The procedure is well tolerated.

Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting

Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG), including Brodmann area 25, is currently being investigated for the treatment of major depressive disorder (MDD). As a potential emerging therapy, optimal target selection within the SCG has still to be determined. The authors compared the location of the electrode contacts in responders and nonresponders to DBS of the SCG and correlated the results with clinical outcome to help in identifying the optimal target within the region. Based on the location of the active contacts used for long-term stimulation in responders, the authors suggest a standardized method of targeting the SCG in patients with MDD. Postoperative MR imaging studies of 20 patients with MDD treated with DBS of the SCG were analyzed. The authors assessed the location of the active contacts relative to the midcommissural point and in relation to anatomical landmarks within the medial aspect of the frontal lobe. For this, a grid with 2 main lines was designed, with 1 line in the anterior-posterior and 1 line in the dorsal-ventral axis. Each of these lines was divided into 100 units, and data were converted into percentages. The anterior-posterior line extended from the anterior commissure (AC) to the projection of the anterior aspect of the corpus callosum (CCa). The dorsal-ventral line extended from the inferior portion of the CC (CCi) to the most ventral aspect of the frontal lobe (abbreviated "Fr" for the formula). Because the surgical technique did not vary across patients, differences in stereotactic coordinates between responders and nonresponders did not exceed 1.5 mm in any axis (x, y, or z). In patients who responded to the procedure, contacts used for long-term stimulation were in close approximation within the SCG. In the anterior-posterior line, these contacts were located within a 73.2 +/- 7.7 percentile distance from the AC (with the AC center being 0% and the line crossing the CCa being 100%). In the dorsal-ventral line, active contacts in responders were located within a 26.2 +/- 13.8 percentile distance from the CCi (with the CCi edge being 0% and the Fr inferior limit being 100%). In the medial-lateral plane, most electrode tips were in the transition between the gray and white matter of SCG. Active contacts in patients who responded to DBS were relatively clustered within the SCG. Because of the anatomical variability in the size and shape of the SCG, the authors developed a method to standardize the targeting of this region.

Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

Brain correlates of aesthetic expertise: A parametric fMRI study

Several studies have demonstrated that acquired expertise influences aesthetic judgments. In this paradigm we used functional magnetic resonance imaging (fMRI) to study aesthetic judgments of visually presented architectural stimuli and control-stimuli (faces) for a group of architects and a group of non-architects. This design allowed us to test whether level of expertise modulates neural activity in brain areas associated with either perceptual processing, memory, or reward processing. We show that experts and non-experts recruit bilateral medial orbitofrontal cortex (OFC) and subcallosal cingulate gyrus differentially during aesthetic judgment, even in the absence of behavioural aesthetic rating differences between experts and non-experts. By contrast, activity in nucleus accumbens (NAcc) exhibits a differential response profile compared to OFC and subcallosal cingulate gyrus, suggesting a dissociable role between these regions in the reward processing of expertise. Finally, categorical responses (irrespective of aesthetic ratings) resulted in expertise effects in memory-related areas such as hippocampus and precuneus. These results highlight the fact that expertise not only modulates cognitive processing, but also modulates the response in reward related brain areas.

Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression

A preliminary report in six patients suggested that deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may provide benefit in treatment-resistant depression (TRD). We now report the results of these and an additional 14 patients with extended follow-up. Twenty patients with TRD underwent serial assessments before and after SCG DBS. We determined the percentage of patients who achieved a response (50% or greater reduction in the 17-item Hamilton Rating Scale for Depression [HRSD-17]) or remission (scores of 7 or less) after surgery. We also examined changes in brain metabolism associated with DBS, using positron emission tomography. There were both early and progressive benefits to DBS. One month after surgery, 35% of patients met criteria for response with 10% of patients in remission. Six months after surgery, 60% of patients were responders and 35% met criteria for remission, benefits that were largely maintained at 12 months. Deep brain stimulation therapy was associated with specific changes in the metabolic activity localized to cortical and limbic circuits implicated in the pathogenesis of depression. The number of serious adverse effects was small with no patient experiencing permanent deficits. This study suggests that DBS is relatively safe and provides significant improvement in patients with TRD. Subcallosal cingulate gyrus DBS likely acts by modulating brain networks whose dysfunction leads to depression. The procedure is well tolerated and benefits are sustained for at least 1 year. A careful double-blind appraisal is required before the procedure can be recommended for use on a wider scale.