A Novel Framework for Network-Targeted Neuropsychiatric Deep Brain Stimulation

Neurosurgery 89:E116–E121, 2021

Deep brain stimulation (DBS) has emerged as a promising therapy for neuropsychiatric illnesses, including depression and obsessive-compulsive disorder, but has shown inconsistent results in prior clinical trials. We propose a shift away from the empirical paradigm for developing new DBS applications, traditionally based on testing brain targets with conventional stimulation paradigms. Instead, we propose a multimodal approach centered on an individualized intracranial investigation adapted from the epilepsy monitoring experience, which integrates comprehensive behavioral assessment, such as the Research Domain Criteria proposed by the National Institutes of Mental Health. In this paradigm-shifting approach, we combine readouts obtained from neurophysiology, behavioral assessments, and self-report during broad exploration of stimulation parameters and behavioral tasks to inform the selection of ideal DBS parameters. Such an approach not only provides a foundational understanding of dysfunctional circuits underlying symptom domains in neuropsychiatric conditions but also aims to identify generalizable principles that can ultimately enable individualization and optimization of therapy without intracranial monitoring.

Falls and Fear of Falling in Shunted Idiopathic Normal Pressure Hydrocephalus

Neurosurgery 89:122–128, 2021

Gait and balance impairment are typical symptoms of idiopathic normal pressure hydrocephalus (INPH), implicating that falls may afflict these patients.

OBJECTIVE: To investigate falls, related injuries, and associated psychological features, before and after shunt surgery for INPH and compared to the general population.

METHODS: The study included 176 patients shunted for INPH and 368 age- and sexmatched controls. Falls, fear of falling (FOF), fall-related injuries (mild-severe), confidence in avoiding falls (Swedish Falls Efficacy Scale (FES(S)), quality of life (QoL; EuroQoL 5-dimension 5 level instrument), and symptoms of depression (Geriatric Depression Scale 15) were investigated. Pre- and postoperative observational times were 12 mo before surgery and 21 mo after (mean). Recurrent fallers fell ≥2 times.

RESULTS: More INPH patients than controls were recurrent fallers (67% vs 11%; P < .001). They feared falling more often (FOF, mean   standard deviation: 3.3   1.1 vs 1.6   0.9; P < .001) and had lower confidence in avoiding falls (FES(S) 78   40 vs 126   14; P < .001). After surgery, INPH patients improved in all parameters but they did not reach the levels of the controls. Among fallers there was no difference between patients and controls in the severity of injuries suffered. Low QoL and symptoms of depression were more common among recurrent fallers than one-time or nonfallers in both shunted patients and controls (P ≤ .001).

CONCLUSION: Falls, FOF, and low confidence in avoiding falls are considerable problems in INPH that may be reduced by shunt surgery. We suggest that remaining risk of falling and preventative measures are routinely considered in postoperative follow-ups and rehabilitation planning.

Cerebrospinal Fluid Shunting Improves Long-Term Quality of Life in Idiopathic Normal Pressure Hydrocephalus

Neurosurgery, Volume 86, Issue 4, April 2020: 574–582

The short- and long-term impact of cerebrospinal fluid shunting on quality of life (QoL) in idiopathic normal pressure hydrocephalus (INPH) is poorly understood.

OBJECTIVE: To investigate QoL in shunted INPH patients compared to the population and to investigate which factors influence QoL in INPH.

METHODS: INPH patients consecutively shunted in Sweden during 2008-2010 were scrutinized. Population-based controls were age- and sex-matched to the patients. Included participants were the following:176 INPH patients and 368controls.QoLwas assessed using the EuroQol 5-dimension 5-level (EQ5D5L) instrument, which measures overall QoL and health status in 5 dimensions. Independency (accommodation and/or need for in-home care) and comorbidities were assessed. Patients were followed up 6-45 mo after surgery (mean follow-up time: 21 mo).

RESULTS: Shunting improved QoL (P < .001) and health status in all dimensions (P < .005). Shunted INPH patients had lower QoL than controls (P < .001). The patients’health status in mobility, self-care, daily activities, and anxiety/depression was worse than the controls both before and after surgery (P < .001). The main predictors of low QoL in INPH were symptoms of depression (P < .001) and severity of gait disturbance (P = .001). Fewer INPH patients than controls lived independently (45% vs 85%, P < .001). Time after shunting had no influence on QoL.

CONCLUSION: QoL remains improved in shunted INPH patients at a mean follow-up time of 21 mo, but the patients do not reach the same QoL as the population. Symptoms of depression and severity of gait disturbance are the strongest predictors of low QoL in INPH.

Machine learning—aided personalized DTI tractographic planning for deep brain stimulation of the superolateral medial forebrain bundle using HAMLET

Acta Neurochirurgica (2019) 161:1559–1569

Growing interest exists for superolateral medial forebrain bundle (slMFB) deep brain stimulation (DBS) in psychiatric disorders. The surgical approach warrants tractographic rendition. Commercial stereotactic planning systems use deterministic tractography which suffers from inherent limitations, is dependent on manual interaction (ROI definition), and has to be regarded as subjective. We aimed to develop an objective but patient-specific tracking of the slMFB which at the same time allows the use of a commercial surgical planning system in the context of deep brain stimulation.

Methods The HAMLET (Hierarchical Harmonic Filters for Learning Tracts from Diffusion MRI) machine learning approach was introduced into the standardized workflow of slMFB DBS tractographic planning on the basis of patientspecific dMRI. Rendition of the slMFB with HAMLET serves as an objective comparison for the refinement of the deterministic tracking procedure. Our application focuses on the tractographic planning of DBS (N = 8) for major depression and OCD.

Results Previous results have shown that only fibers belonging to the ventral tegmental area to prefrontal/orbitofrontal axis should be targeted. With the proposed technique, the deterministic tracking approach, that serves as the surgical planning data, can be refined, over-sprouting fibers are eliminated, bundle thickness is reduced in the target region, and thereby probably a more accurate targeting is facilitated. The HAMLET-driven method is meant to achieve a more objective surgical fiber display of the slMFB with deterministic tractography.

Conclusions The approach allows overlying the results of patient-specific planning from two different approaches (manual deterministic and machine learningHAMLET). HAMLET shows the slMFB as a volume and thus serves as an objective tracking corridor. It helps to refine results from deterministic tracking in the surgical workspace without interfering with any part of the standard software solution. We have now included this workflow in our daily clinical experimental work on slMFB DBS for psychiatric indications.

Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery

Thyroid_system

A low triiodothyronine (T3) state is highly prevalent and is associated with a poor prognosis in critically ill patients. The authors investigated, in patients undergoing brain tumor surgery, the direct association of a perioperative low T3 syndrome with clinical outcomes and also with symptoms of depression and anxiety.

Methods. Ninety consecutive patients (71% women, median age 55 years), on admission for brain tumor surgery, were evaluated for sociodemographic and clinical characteristics. Their thyroid function profile was assessed on the morning of brain tumor surgery and on the morning after brain tumor surgery. Patients with free T3 concentrations of 3.1 pmol/L or less were considered to have low T3 syndrome. The patients were evaluated for symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) before and after surgery and for clinical outcomes using the Glasgow Outcome Scale (GOS) at discharge.

Results. After brain tumor surgery, free T3 concentrations decreased (p < 0.001) and the proportion of patients with low T3 levels increased from 38% to 54% (p = 0.02). Lower preoperative (rho = 0.30, p = 0.004) and postoperative (rho = 0.33, p = 0.002) free T3 concentrations correlated with low GOS scores at discharge. Preoperative low T3 syndrome (OR 5.49, 95% CI 1.27–23.69, p = 0.02) and postoperative low T3 syndrome (OR 8.73, 95% CI 1.49–51.21, p = 0.02) both increased risk for unfavorable clinical outcomes (GOS scores < 5) at discharge, after adjusting for age, sex, histological diagnosis of brain tumor, preoperative functional impairment, previous treatment for brain tumor, and depressive symptoms. Preoperative low T3 syndrome increased the risk for preoperative (HADS-depression subscale score ≥ 11; OR 4.12, 95% CI 1.16–14.58, p = 0.03) but not postoperative depressive symptoms independently from sociodemographic and clinical factors.

Conclusions. Low T3 syndrome is a strong independent predictor of unfavorable clinical outcomes and depressive symptoms, and its diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors.

Limbic system surgery for treatment-refractory obsessive-compulsive disorder

Limbic system surgery for treatment-refractory obsessive-compulsive disorder

J Neurosurg 118:491–497, 2013

Obsessive-compulsive disorder (OCD) is a common and disabling psychiatric illness, and in a significant proportion of patients with OCD the disease is refractory to conventional pharmacotherapy and psychotherapy. For more than half a century, patients with severe, treatment-resistant OCD have been treated with stereotactic limbic system lesions, including dorsal anterior cingulotomy. The authors present their results describing the efficacy and durability of limbic system surgery for OCD, characterizing a large cohort of patients treated at a single institution with a mean follow-up of more than 5 years.

Methods. The authors identified 64 consecutive patients undergoing cingulotomy for refractory OCD at the Massachusetts General Hospital between 1989 and 2009. Changes in OCD and major depressive disorder symptom severity were assessed at both the initial and most recent postoperative follow-up by using the Yale-Brown Obsessive Compulsive Scale and the Beck Depression Inventory, respectively. Full and partial OCD symptom responses were defined as Yale-Brown Obsessive Compulsive Scale score reductions of ≥ 35% and 25%–34%, respectively.

Results. Regarding OCD symptom improvement, at the first postoperative follow-up (mean 10.7 months), 35% of patients demonstrated a full response and 7% were partial responders. Thirty patients had a subsequent procedure (repeat cingulotomy or subcaudate tractotomy). By the most recent follow-up (mean 63.8 months), rates climbed to 47% and 22% for full and partial responses, respectively. Of the 24 patients with at least a partial response at initial follow-up, 20 (83%) retained at least a partial response at final follow-up. Comorbid major depressive disorder severity decreased by 17% at the most recent follow-up.

Conclusions. Limbic system surgery based on initial cingulotomy offers a durable and effective treatment option for appropriately selected patients with severe OCD who have not responded to conventional pharmacotherapy or psychotherapy.

Limbic system surgery for treatment-refractory obsessive-compulsive disorder

Limbic system surgery for treatment-refractory obsessive-compulsive disorder- a prospective long-term follow-up of 64 patients

DOI: 10.3171/2012.11.JNS12389

Obsessive-compulsive disorder (OCD) is a common and disabling psychiatric illness, and in a significant proportion of patients with OCD the disease is refractory to conventional pharmacotherapy and psychotherapy. For more than half a century, patients with severe, treatment-resistant OCD have been treated with stereotactic limbic system lesions, including dorsal anterior cingulotomy.

The authors present their results describing the efficacy and durability of limbic system surgery for OCD, characterizing a large cohort of patients treated at a single institution with a mean follow-up of more than 5 years.

Methods. The authors identified 64 consecutive patients undergoing cingulotomy for refractory OCD at the Massachusetts General Hospital between 1989 and 2009. Changes in OCD and major depressive disorder symptom severity were assessed at both the initial and most recent postoperative follow-up by using the Yale-Brown Obsessive Compulsive Scale and the Beck Depression Inventory, respectively. Full and partial OCD symptom responses were defined as Yale-Brown Obsessive Compulsive Scale score reductions of ≥ 35% and 25%–34%, respectively.

Results. Regarding OCD symptom improvement, at the first postoperative follow-up (mean 10.7 months), 35% of patients demonstrated a full response and 7% were partial responders. Thirty patients had a subsequent procedure (repeat cingulotomy or subcaudate tractotomy). By the most recent follow-up (mean 63.8 months), rates climbed to 47% and 22% for full and partial responses, respectively. Of the 24 patients with at least a partial response at initial follow-up, 20 (83%) retained at least a partial response at final follow-up. Comorbid major depressive disorder severity decreased by 17% at the most recent follow-up.

Conclusions. Limbic system surgery based on initial cingulotomy offers a durable and effective treatment option for appropriately selected patients with severe OCD who have not responded to conventional pharmacotherapy or psychotherapy.

Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living?

J Neurosurg 117:749–754, 2012

Although decompressive hemicraniectomy has been shown to reduce death and improve functional outcome following malignant middle cerebral artery territory infarction, there is ongoing debate as to whether surgery should be routinely performed, considering the very high rates of disability and functional dependence in survivors. Through a systematic review of the literature, the authors sought to determine the outcome from a patient’s perspective.

Methods. In September 2010, a MEDLINE search of the English-language literature was performed using various combinations of 12 key words. A total of 16 papers were reviewed and individual study data were extracted.

Results. There was significant variability in study design, patient eligibility criteria, timing of surgery, and methods of outcome assessment. There were 382 patients (59% male, 41% female) with a mean age of 50 years, 25% with dominant-hemisphere infarction. The mortality rate was 24% and the mean follow-up in survivors was 19 months (range 3–114 months). Of 156 survivors with available modified Rankin Scale (mRS) scores, 41% had favorable functional outcome (mRS Score ≤ 3), whereas 47% had moderately severe disability (mRS Score 4). Among 157 survivors with quality of life assessment, the mean overall reduction was 45%: 67% for physical aspect and 37% for psychosocial aspect. Of 114 screened survivors, depression affected 56% and was moderate or severe in 25%. Most patients and/or caregivers (77% of the 209 interviewed) were satisfied and would give consent again for the procedure.

Conclusions. Despite high rates of physical disability and depression, the vast majority of patients are satisfied with life and do not regret having undergone surgery.

 

Multicenter study on subcallosal cingulate DBS for depression

J Neurosurg 116:315–322, 2012. DOI: 10.3171/2011.10.JNS102122

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.

Methods. 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).

Results. 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.

Conclusions. 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 for depression

J Neurosurg 111:1209–1215, 2009.(DOI: 10.3171/2008.10.JNS08763)

Object. 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.

Methods. Postoperative MR imaging studies of 20 patients with MDD treated with DBS of the SCG were ana- lyzed. 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).

Results. 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.

Conclusions. Active contacts in patients who responded to DBS were relatively clustered within the SCG. Be- cause of the anatomical variability in the size and shape of the SCG, the authors developed a method to standardize the targeting of this region.