Ventral targeted anterior capsulotomy for treatment-resistant depression and obsessive-compulsive disorder: A treatment method with cases.

BACKGROUND: Ablative surgery using bilateral anterior capsulotomy (BAC) is an option for treatment resistant depression (TRD) and obsessive-compulsive disorder (TROCD). The location and extent of the lesion within anterior limb of the internal capsule (ALIC) remains uncertain. Accumulating evidence has suggested that the lesion should be located ventrally while limiting the dorsal extent. Our center is now targeting specific fiber tracts within the lower half of the ALIC. METHOD: Presurgical diffusion tensor Magnetic Resonance Imaging (MRI) was used to identify individual fibre tracts within the ventral aspect of the ALIC in the last two patients who underwent BAC at our center. One patient had TRD and the other had both TROCD and TRD. Radiofrequency-induced thermal lesions were created in the identified targets with lesion volumes between 20 and 229 mm3 (average 95 mm3). FINDINGS: Both patients were responders with neither experiencing significant side effects including compromised executive functions. LIMITATIONS: The generalizability of our findings is limited because the outcome is based on two subjects. CONCLUSION: This work suggests that BAC can be individually tailored and more limited to the ventral aspect of the ALIC and is effective and safe for TRD and TROCD. Accumulating data also suggests that to be clinically effective the length of the capsulotomy should be about 10mm. BAC's use may increase with the growing utilization and mastery of magnetic resonance guided focused ultrasound.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Deep brain stimulation for Tourette syndrome: modulation of the limbic-motor interface network.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for medically refractory Tourette syndrome (TS). Several effective targets have been reported, but there is still controversy about the networks involved in the efficacy of DBS for TS. Here, the authors aimed to identify the basal ganglia-thalamo-cortical networks associated with tic and obsessive-compulsive behavior (OCB) improvement and the network link between the two main targets for TS. METHODS: A retrospective analysis of 21 patients treated with pallidal and thalamic DBS was performed. Tics and OCB scores were recorded before and after DBS. The authors localized the electrodes in standard MNI (Montreal Neurological Institute) space and calculated the volume of tissue activated with the settings at the last follow-up to obtain areas of maximal improvement ("sweet spots") among all patients for the pallidal and thalamic targets. Tractography was used to show the white matter pathways associated with maximal tic and OCB improvement. RESULTS: Ten patients treated with pallidal DBS and 11 patients treated with thalamic DBS were included. Responder rates were 80% in the pallidal and 64% in the thalamic target groups. Sweet spots for tics and OCB clustered in several areas across the basal ganglia and thalamus delineated two main networks. Tic reduction in the pallidal target mapped to a limbic pallidothalamic network and in the thalamic target to the premotor thalamocortical network. Putting these two networks together will form the main output of the so-called limbic-motor interface network. However, OCB reduction mapped a dorsomedial prefrontal cortex/dorsal anterior cingulate (dmPFC/dACC) network. CONCLUSIONS: The authors demonstrated the involvement of the limbic-motor interface network during effective DBS for tics in patients with TS. OCB redution was associated with the additional involvement of dmPFC/dACC connections passing dorsal to the head of the globus pallidus pars externa on its way to the thalamus and midbrain.

White matter connectivity of subthalamic nucleus and globus pallidus interna targets for deep brain stimulation.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection. METHODS: The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 µsec for STN; 3.3 V and 90 µsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared. RESULTS: VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex. CONCLUSIONS: On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Connectivity-based parcellation of the amygdala and identification of its main white matter connections.

The amygdala plays a role in emotion, learning, and memory and has been implicated in behavioral disorders. Better understanding of the amygdala circuitry is crucial to develop new therapies for these disorders. We used data from 200 healthy-subjects from the human connectome project. Using probabilistic tractography, we created population statistical maps of amygdala connectivity to brain regions involved in limbic, associative, memory, and reward circuits. Based on the amygdala connectivity with these regions, we applied k-means clustering to parcellate the amygdala into three clusters. The resultant clusters were averaged across all subjects and the main white-matter pathways of the amygdala from each averaged cluster were generated. Amygdala parcellation into three clusters showed a medial-to-lateral pattern. The medial cluster corresponded with the centromedial and cortical nuclei, the basal cluster with the basal nuclei and the lateral cluster with the lateral nuclei. The connectivity analysis revealed different white-matter pathways consistent with the anatomy of the amygdala circuit. This in vivo connectivity-based parcellation of the amygdala delineates three clusters of the amygdala in a mediolateral pattern based on its connectivity with brain areas involved in cognition, memory, emotion, and reward. The human amygdala circuit presented in this work provides the first step for personalized amygdala circuit mapping for patients with behavioral disorders.

Sweet spots of standard and directional leads in patients with refractory essential tremor: white matter pathways associated with maximal tremor improvement.

OBJECTIVE: In patients with essential tremor (ET) treated with standard deep brain stimulation (sDBS) whose ET had progressed and who no longer received optimal benefit from sDBS, directional deep brain stimulation (dDBS) may provide better tremor control. Current steering may provide better coverage of subcortical structures related to tremor control in patients with ET and significant progression without optimal response to sDBS. METHODS: This study included 6 patients with ET initially treated with sDBS whose tremor later progressed and who then underwent reimplantation with dDBS to optimize their tremor control. To investigate the differences in the local effects of sDBS and dDBS, the authors generated the volume of tissue activation (VTA) to calculate the sweet spots associated with the best possible tremor control with no side effects. Then, to investigate the anatomical structures associated with maximal tremor control, the white matter pathways of the posterior subthalamic areas (PSAs) were generated and their involvement with the sDBS and dDBS sweet spots was calculated. RESULTS: Tremor improvement was significantly better with dDBS (68.4%) than with sDBS (48.7%) (p = 0.017). The sDBS sweet spot was located within the ventral intermediate nucleus, whereas the sweet spot of the dDBS was mainly located within the PSA. The sweet spots of both sDBS and dDBS involved a similar portion of the cerebellothalamic pathway. However, the dDBS had greater involvement of the pallidofugal pathways than the sDBS. CONCLUSIONS: In patients with ET treated with sDBS who later had ET progression, dDBS provided better tremor control, which was related to directionality and a more ventral position. The involvement of both the cerebellothalamic and pallidofugal pathways obtained with dDBS is associated with additional improvement over the sDBS.

A structural connectivity atlas of limbic brainstem nuclei.

Background: Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. Objective: To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. Methods: Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. Results: A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. Conclusion: Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation.

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

Constrained-Spherical Deconvolution Tractography in the Evaluation of the Corticospinal Tract in Glioma Surgery.

Introduction: Tractography has demonstrated utility for surgical resection in the setting of primary brain tumors involving eloquent white matter (WM) pathways. Methods: Twelve patients with glioma in or near eloquent motor areas were analyzed. The motor status was recorded before and after surgery. Two different tractography approaches were used to generate the motor corticospinal tract (CST): Constrained spherical deconvolution probabilistic tractography (CSD-Prob) and single tensor deterministic tractography (Tens-DET). To define the degree of disruption of the CST after surgical resection of the tumor, we calculated the percentage of the CST affected by surgical resection, which was then correlated with the postoperative motor status. Moreover, the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of the CST generated by the CSD-Prob and the Tens-DET was measured and compared between the ipsilesional and contralesional side. Results: The CST was identified in all patients and its trajectory was displaced by the tumor. Only the CSD-Prob approach showed the CST with the characteristic fan-like projections from the precentral gyrus to the brainstem. Disruption of the CST was identified in 6/6 with postoperative motor deficit by CSD-Prob approach and in 5/6 in the Tens-DET. The degree of disruption was significantly associated with the motor deficit with the CSD-Prob approach (rho = -0.88, p = 0.021). However, with the Tens-DET approach the CST disruption did not show significant association with the motor function (rho = -0.27, p = 0.6). There was a significant decrease in FA (p = 0.006) and a significant increase in MD (p = 0.0004) and RD (p = 0.005) on the ipsilesional CST compared with the contralesional CST only with the CSD-Prob approach. Conclusion: CSD-Prob accurately represented the known anatomy of the CST and provided a meaningful estimate of microstructural changes of the CST affected by the tumor and its macrostructural damage after surgery. Newer surgical planning stations should include advanced models and algorithms of tractography in order to obtain more meaningful reconstructions of the WM pathways during glioma surgery.

Directional Deep Brain Stimulation Can Target the Thalamic "Sweet Spot" for Improving Neuropathic Dental Pain.

BACKGROUND: Neuropathic dental pain (NDP) is a chronic pain condition that is notoriously difficult to treat. To date, there are no deep brain stimulation (DBS) studies on this specific pain condition and no optimal target or "sweet spot" has ever been defined. OBJECTIVE: To determine the optimal thalamic target for improving this condition by utilizing the steering abilities of a directional DBS electrode (Vercise CartesiaTM Model DB-2202-45, Boston Scientific). METHODS: A literature search and review of our database identified 3 potential thalamic targets. A directional lead was implanted in a patient with NDP and its current steering used to test the effects in each nucleus. The patient reported her pain after 2 wk of stimulation in a prospective randomized blinded trial of one. Quality of life measurements were performed before and after 3 mo on their best setting. RESULTS: We identified 3 potential nuclei: the centromedian (CM), ventral posterior medial (VPM), and anterior pulvinar. The best results were during VPM stimulation (>90% reduction in pain) and CM stimulation (50% reduction). Following 3 mo of VPM-DBS in combination of lateral CM stimulation, their pain disability index dropped (from 25 to 0) and short form 36 improved (from 67.5 to 90). CONCLUSION: VPM stimulation in combination with CM stimulation is a promising target for NDP. DBS electrode directionality can be used to test multiple targets and select a patient specific "sweet spot" for NDP treatment.

Tractography-Guided Anterior Capsulotomy for Major Depression and Obsessive-Compulsive Disorder: Targeting the Emotion Network.

BACKGROUND: Bilateral anterior capsulotomy (BAC) is an effective surgical option for patients with treatment-resistant major depression (TRMD) and treatment-resistant obsessive-compulsive disorder (TROCD). The size of the lesion and its precise dorsal-ventral location within the anterior limb of the internal capsule (ALIC) remain undefined. OBJECTIVE: To present a method to identify the trajectories of the associative and limbic white matter pathways within the ALIC for targeting in BAC surgery. METHODS: Using high-definition tractography, we prospectively tested the feasibility of this method in 2 patients with TRMD and TROCD to tailor the capsulotomy lesion to their limbic pathway. RESULTS: The trajectories of the associative and limbic pathways were identified in the ALIC of both patients and we targeted the limbic pathways by defining the dorsal limit of the lesion in a way to minimize the damage to the associative pathways. The final lesions were smaller than those that have been previously published. This individualized procedure was associated with long-term benefit in both patients. CONCLUSION: Tractography-guided capsulotomy is feasible and was associated with long-term benefit in patients with TRMD and TROCD.

Tremor and Quality of Life in Patients With Advanced Essential Tremor Before and After Replacing Their Standard Deep Brain Stimulation With a Directional System.

OBJECTIVES: Patients with essential tremor treated with thalamic deep brain stimulation may experience increased tremor with the progression of their disease. Initially, this can be counteracted with increased stimulation. Eventually, this may cause unwanted side-effects as the circumferential stimulation from a standard ring contact spreads into adjacent regions. Directional leads may offer a solution to this clinical problem. We aimed to compare the ability of a standard and a directional system to reduce tremor without side-effects and to improve the quality of life for patients with advanced essential tremor. MATERIALS AND METHODS: Six advanced essential tremor patients with bilateral thalamic deep brain stimulation had their standard system replaced with a directional system. Tremor rating scale scores were prospectively evaluated before and after the replacement surgery. Secondary analyses of quality of life related to tremor, voice, and general health were assessed. RESULTS: There was a significantly greater reduction in tremor without side-effects (p = 0.017) when using the directional system. There were improvements in tremor (p = 0.031) and voice (p = 0.037) related quality of life but not in general health for patients using optimized stimulation settings with the directional system compared to the standard system. CONCLUSIONS: In this cohort of advanced essential tremor patients who no longer had ideal tremor reduction with a standard system, replacing their deep brain stimulation with a directional system significantly improved their tremor and quality of life. Up-front implantation of directional deep brain stimulation leads may provide better tremor control in those patients who progress at a later time point.

Laser thermal therapy in the management of high-grade gliomas.

Laser interstitial thermal therapy (LITT) is a minimally invasive therapy that have been used for brain tumors, epilepsy, chronic pain, and other spine pathologies. This therapy is performed under imaging and stereotactic guidance to precisely direct the probe and ablate the area of interest using real-time magnetic resonance (MR) thermography. LITT has gained popularity as a treatment for glioma because of its minimally invasive nature, small skin incision, repeatability, shorter hospital stay, and the possibility of receiving adjuvant therapy shortly after surgery instead of several weeks as required after open surgical resection. Several reports have demonstrated the usefulness of LITT in the treatment of newly-diagnosed and recurrent gliomas. In this review, we will summarize the recent evidence of this therapy in the field of glioma surgery and the future perspectives of the use of LITT combined with other treatment strategies for this devastating disease.

Modulation of Nigrofugal and Pallidofugal Pathways in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical therapy for patients with Parkinson disease (PD). OBJECTIVE: To define the role of adjacent white matter stimulation in the effectiveness of STN-DBS. METHODS: We retrospectively evaluated 43 patients with PD who received bilateral STN-DBS. The volumes of activated tissue were analyzed to obtain significant stimulation clusters predictive of 4 clinical outcomes: improvements in bradykinesia, rigidity, tremor, and reduction of dopaminergic medication. Tractography of the nigrofugal and pallidofugal pathways was performed. The significant clusters were used to calculate the involvement of the nigrofugal and pallidofugal pathways and the STN. RESULTS: The clusters predictive of rigidity and tremor improvement were dorsal to the STN with most of the clusters outside of the STN. These clusters preferentially involved the pallidofugal pathways. The cluster predictive of bradykinesia improvement was located in the central part of the STN with an extension outside of the STN. The cluster predictive of dopaminergic medication reduction was located ventrolateral and caudal to the STN. These clusters preferentially involved the nigrofugal pathways. CONCLUSION: Improvements in rigidity and tremor mainly involved the pallidofugal pathways dorsal to the STN. Improvement in bradykinesia mainly involved the central part of the STN and the nigrofugal pathways ventrolateral to the STN. Maximal reduction in dopaminergic medication following STN-DBS was associated with an exclusive involvement of the nigrofugal pathways.