Increased apathy post-interstitial laser capsulotomy for refractory obsessive-compulsive disorder.

BACKGROUND: MRI guided laser interstitial thermal therapy (M-LITT) capsulotomy has proven to be efficacious in decreasing refractory obsessive-compulsive disorder (OCD) related symptomatology yet capsulotomy either via radiosurgery or radiofrequency ablation has in some patients led to increased apathy following surgery. The current case series aims to investigate objective patient-reported change in apathy, disinhibition, depression, and executive dysfunction following anterior capsulotomy via M-LITT for OCD. METHODS: Ten consecutive patients pre- and post-M-LITT completed measures of OCD, apathy, disinhibition, executive dysfunction, and depression (Mtime between = 1.3 years; 0.42-3.7 years). Reliable Change Index (RCI) was used to evaluate change in pre- and post-M-LITT. OCD symptom response was evaluated using percent change (Y-BOCS scores: 24-34 % reduction indicating partial response; ≥35% reduction indicating full response). RESULTS: Positive post-surgical change was noted in OCD symptomatology with >65% reporting a partial or full response. However, six patients endorsed increased apathy with half of the non-responders (e.g., less than <24% score reduction on Y-BOCS) reporting increases in apathy. Patients reported relatively stable disinhibition and executive dysfunction, while over half reported a decrease in depression symptoms. Two of the non-responders and one responder endorsed increased apathy despite stable or improved depression symptoms, disinhibition, and executive dysfunction. CONCLUSIONS: Most patients in the current cohort achieved full-or-partial OCD recovery. Yet, 60% of patients also reported significant increases in apathy, despite experiencing a decrease in depression symptoms, with stable disinhibition and executive dysfunction. Despite these promising improvements in OCD symptomatology following M-LITT, further investigations of the impact of surgery and lesion location on apathy levels is clearly warranted using objective, quantifiable methods.

Exploring arterial anatomy of the internal capsule: an analysis of the deep vascular structures and related white matter pathways.

BACKGROUND AND OBJECTIVES: The internal capsule is supplied by perforators originating from the internal carotid artery, middle cerebral artery, anterior choroidal artery and anterior cerebral artery. The aim of this study is to examine the vascular anatomy of the internal capsule, along with its related white matter anatomy, in order to prevent potential risks and complications during surgical interventions. METHODS: Twenty injected hemispheres prepared according to the Klingler method were dissected. Dissections were photographed at each stage. The findings obtained from the dissections were illustrated to make them more understandable. Additionally, the origins of the arteries involved in the vascularization of the internal capsule, their distances to bifurcations, and variations in supplying territories have been thoroughly examined. RESULTS: The insular cortex and the branches of the middle cerebral artery on the insula and operculum were observed. Following decortication of the insular cortex, the extreme capsule, claustrum, external capsule, putamen and globus pallidus structures were exposed. The internal capsule is shown together with the lenticulostriate arteries running on the anterior, genu and posterior limbs. Perforators supplying the internal capsule originated from the middle cerebral artery, anterior cerebral artery, internal carotid artery and anterior choroidal artery. The internal capsule's vascular supply varied, with the medial lenticulostriate arteries (MLA) and lateral lenticulostriate arteries (LLA) being the primary arteries. The anterior limb was most often supplied by the MLA, while the LLA and anterior choroidal artery dominated the genu and posterior limb. The recurrent artery of Heubner originated mostly from the A2 segment. The distance from the ICA bifurcation to the origin of the first LLA on M1 is 9.55 ± 2.32 mm, and to the first MLA on A1 is 5.35 ± 1.84 mm. MLA branching from A1 and proximal A2 ranged from 5 to 9, while LLA originating from the MCA ranged from 7 to 12. CONCLUSION: This study provides comprehensive understanding of the arterial supply to the internal capsule by combining white matter dissection. The insights gained from this study can help surgeons plan and execute procedures including oncological, psychosurgical, and vascular more accurately and safely. The illustrations derived from the dissections serve as valuable educational material for young neurosurgeons and other medical professionals.

The relationship between the extent of posterior limb of the internal capsule damage measured by non-contrast computed tomography and clinical outcomes after basal ganglia hemorrhage.

Assessing the extent of damage to the posterior limb of the internal capsule (PLIC) is important for early prediction of clinical outcomes in intracerebral hemorrhage (ICH) patients. Currently, using MRI to reconstruct the extent of damage to PLIC is not suitable for quick assessment of prognosis in emergency settings. We aimed to investigate whether the PLIC damage quantified by non-contrast computed tomography (NCCT) is associated with clinical outcomes after basal ganglia intracerebral hemorrhage (BG-ICH). This study retrospectively included 146 BG-ICH patients from the Department of Neurosurgery at the Second Affiliated Hospital of Chongqing Medical University. The damage to the PLIC was quantified using Tangency X measured by NCCT. The importance of features is determined using the Boruta algorithm and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Multivariate logistic regression models were established to examine the impact of PLIC damage on outcomes. Restricted Cubic Splines (RCS) were used to explore potential nonlinear relationships, and Receiver Operating Characteristic (ROC) curves were used to compare the predictive performance of Tangency X with other scoring systems for 6-month neurological outcomes (poor outcomes [mRS: 3-6]). In the multivariate logistic regression adjusting for all covariates, Tangency X was independently associated with an increased risk of poor outcomes (OR = 1.32, 95% CI: 1.17-1.52) in BG-ICH patients. There is a nonlinear relationship between Tangency X and poor outcomes. Specifically, the risk of poor outcomes increases by 1.29 times (OR = 1.29, 95% CI: 1.09-1.67) for each additional 1 mm increase in Tangency X beyond 4 mm. We next observed that the AUC for Tangency X in predicting poor outcomes is 0.8511. The extent of PLIC damage measured by NCCT may represent a promising predictor of poor outcomes after BG-ICH.

Formation of the Mouse Internal Capsule and Cerebral Peduncle: A Pioneering Role for Striatonigral Axons as Revealed in Isl1 Conditional Mutants.

The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of the following two major pathways: the striatopallidal (indirect) pathway or the striatonigral (direct) pathway. Striatonigral axons project long distances and encounter ascending tracts (thalamocortical) while coursing alongside descending tracts (corticofugal) as they extend through the internal capsule and cerebral peduncle. These observations suggest that striatal circuitry may help to guide their trajectories. To investigate the developmental contributions of striatonigral axons to internal capsule formation, we have made use of Sox8-EGFP (striatal direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporter mice in combination with immunohistochemical markers to trace these axonal pathways throughout development. We show that striatonigral axons pioneer the internal capsule and cerebral peduncle and are temporally and spatially well positioned to provide guidance for corticofugal and thalamocortical axons. Using Isl1 conditional knock-out (cKO) mice, which exhibit disrupted striatonigral axon outgrowth, we observe both corticofugal and thalamocortical axon defects with either ventral forebrain- or telencephalon-specific Isl1 inactivation, despite Isl1 not being expressed in either cortical or thalamic projection neurons. Striatonigral axon defects can thus disrupt internal capsule formation. Our genome-wide transcriptomic analysis in Isl1 cKOs reveals changes in gene expression relevant to cell adhesion, growth cone dynamics, and extracellular matrix composition, suggesting potential mechanisms by which the striatonigral pathway exerts this guidance role. Together, our data support a novel pioneering role for the striatal direct pathway in the correct assembly of the ascending and descending axon tracts within the internal capsule and cerebral peduncle.SIGNIFICANCE STATEMENT The basal ganglia are a group of subcortical nuclei with established roles in the coordination of voluntary motor programs, aspects of cognition, and the selection of appropriate social behaviors. Hence, disruptions in basal ganglia connectivity have been implicated in the motor, cognitive, and social dysfunction characterizing common neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, and tic disorder. Here, we identified a novel role for the striatonigral (direct) pathway in pioneering the internal capsule and cerebral peduncle, and in guiding axons extending to and from the cortex. Our findings suggest that the abnormal development of basal ganglia circuits can drive secondary internal capsule defects and thereby may contribute to the pathology of these disorders.

Tractography-based versus anatomical landmark-based targeting in vALIC deep brain stimulation for refractory obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD). Retrospective evaluation showed that stimulation closer to the supero-lateral branch of the medial forebrain bundle (slMFB), within the vALIC, was associated with better response to DBS. The present study is the first to compare outcomes of DBS targeted at the vALIC using anatomical landmarks and DBS with connectomic tractography-based targeting of the slMFB. We included 20 OCD-patients with anatomical landmark-based DBS of the vALIC that were propensity score matched to 20 patients with tractography-based targeting of electrodes in the slMFB. After one year, we compared severity of OCD, anxiety and depression symptoms, response rates, time to response, number of parameter adjustments, average current, medication usage and stimulation-related adverse effects. There was no difference in Y-BOCS decrease between patients with anatomical landmark-based and tractography-based DBS. Nine (45%) patients with anatomical landmark-based DBS and 13 (65%) patients with tractography-based DBS were responders (BF10 = 1.24). The course of depression and anxiety symptoms, time to response, number of stimulation adjustments or medication usage did not differ between groups. Patients with tractography-based DBS experienced fewer stimulation-related adverse effects than patients with anatomical landmark-based DBS (38 vs 58 transient and 1 vs. 17 lasting adverse effects; BF10 = 14.968). OCD symptoms in patients with anatomical landmark-based DBS of the vALIC and tractography-based DBS of the slMFB decrease equally, but patients with tractography-based DBS experience less adverse effects.

Common and differential connectivity profiles of deep brain stimulation and capsulotomy in refractory obsessive-compulsive disorder.

Neurosurgical interventions including deep brain stimulation (DBS) and capsulotomy have been demonstrated effective for refractory obsessive-compulsive disorder (OCD), although treatment-shared/-specific network mechanisms remain largely unclear. We retrospectively analyzed resting-state fMRI data from three cohorts: a cross-sectional dataset of 186 subjects (104 OCD and 82 healthy controls), and two longitudinal datasets of refractory patients receiving ventral capsule/ventral striatum DBS (14 OCD) and anterior capsulotomy (27 OCD). We developed a machine learning model predictive of OCD symptoms (indexed by the Yale-Brown Obsessive Compulsive Scale, Y-BOCS) based on functional connectivity profiles and used graphic measures of network communication to characterize treatment-induced profile changes. We applied a linear model on 2 levels treatments (DBS or capsulotomy) and outcome to identify whether pre-surgical network communication was associated with differential treatment outcomes. We identified 54 functional connectivities within fronto-subcortical networks significantly predictive of Y-BOCS score in patients across 3 independent cohorts, and observed a coexisting pattern of downregulated cortico-subcortical and upregulated cortico-cortical network communication commonly shared by DBS and capsulotomy. Furthermore, increased cortico-cortical communication at ventrolateral and centrolateral prefrontal cortices induced by DBS and capsulotomy contributed to improvement of mood and anxiety symptoms, respectively (p < 0.05). Importantly, pretreatment communication of ventrolateral and centrolateral prefrontal cortices were differentially predictive of mood and anxiety improvements by DBS and capsulotomy (effect sizes = 0.45 and 0.41, respectively). These findings unravel treatment-shared and treatment-specific network characteristics induced by DBS and capsulotomy, which may facilitate the search of potential evidence-based markers for optimally selecting among treatment options for a patient.

Anterior Capsulotomy for Refractory Obsessive-Compulsive Disorder: A Tractography and Lesion Geometry study.

INTRODUCTION: A bilateral anterior capsulotomy effectively treats refractory obsessive-compulsive disorder (OCD). We investigated the geometry of lesions and disruption of white matter pathways within the anterior limb of the internal capsule (ALIC) in patients with different outcomes. METHODS: In this retrospective study, we analyzed data from 18 patients with refractory OCD who underwent capsulotomies. Patients were grouped into "responders" and "nonresponders" based on the percentage of decrease in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) after surgery. We investigated neurobehavioral adverse effects and analyzed the overlap between lesions and the ventromedial prefrontal (vmPFC) and dorsolateral prefrontal (dlPFC) pathways. Probabilistic maps were constructed to investigate the relationship between lesion location and clinical outcomes. RESULTS: Of the 18 patients who underwent capsulotomies, 12 were responders (>35% improvement in YBOCS), and six were nonresponders. The vmPFC pathway was more involved than the dlPFC pathway in responders (p = 0.01), but no significant difference was observed in nonresponders (p = 0.10). The probabilistic voxel-wise efficacy map showed a relationship between ventral voxels within the ALIC with symptom improvement. Weight gains occurred in 11/18 (61%) patients and could be associated with medial voxels within the ALIC. CONCLUSION: The optimal outcome after capsulotomy in refractory OCD is linked to vmPFC disruption in the ALIC. Medial voxels within the ALIC could be associated with weight gains following capsulotomy.

Anatomic evaluation of the posterior temporal approach via the Heschl's gyrus to the thalamus, internal capsule, and atrium.

OBJECTIVE: Posterior temporal craniotomy allows for the exposure of the superior surface of the planum temporale. Heschl's gyrus is the most prominent structure of the planum temporale and can be an anatomical landmark to approach deep brain structures such as the internal capsule, lateral thalamus, and ventricular atrium. METHODS: Ten human cadavers' heads underwent a posterior bilateral temporal craniotomy and the microsurgical dissection of Heschl's gyrus was performed and variables were measured with a neuronavigation system and statistically analyzed. RESULTS: The mean distance between the keyhole and Heschl's gyrus was 61.7 ± 7.3 mm, the mean distance between the stephanion to Heschl's gyrus was 40.8 ± 6.0 mm, and the mean distance between the temporal lobe and Heschl's gyrus was 54.9 ± 6.9 mm. The length of Heschl's gyrus was 24 ± 7.5 mm, and the inclination angle in the axial plane was 20.0 ± 3.7° having the vertex as its deepest point as the base on the surface of the temporal plane. From Heschl's gyrus, the distance from the surface to the internal capsule was 29.1 ± 5.6 mm, the distance to the lateral thalamus was 34.8 ± 7.3 mm, and the distance to the ventricular atrium was 39.6 ± 7.2 mm. No statistical difference was found between the right and left sides. CONCLUSIONS: Through a posterior temporal craniotomy, the temporal planum is exposed by opening the Sylvian fissure, where Heschl's gyrus can be identified and used as a natural corridor to approach the internal capsule, the ventricular atrium, and the lateral thalamus.

Evidence of Motor Skill Learning in Acute Stroke Patients Without Lesions to the Thalamus and Internal Capsule.

BACKGROUND: It is currently unknown whether motor skill learning (MSkL) with the paretic upper limb is possible during the acute phase after stroke and whether lesion localization impacts MSkL. Here, we investigated MSkL in acute (1-7 days post) stroke patients compared with healthy individuals (HIs) and in relation to voxel-based lesion symptom mapping. METHODS: Twenty patients with acute stroke and 35 HIs were trained over 3 consecutive days on a neurorehabilitation robot measuring speed, accuracy, and movement smoothness variables. Patients used their paretic upper limb and HI used their nondominant upper limb on an MSkL task involving a speed/accuracy trade-off. Generalization was evaluated on day 3. All patients underwent a 3-dimensional magnetic resonance imaging used for VSLM. RESULTS: Most patients achieved MSkL demonstrated by day-to-day retention and generalization of the newly learned skill on day 3. When comparing raw speed/accuracy trade-off values, HI achieved larger MSkL than patients. However, relative speed/accuracy trade-off values showed no significant differences in MSkL between patients and HI on day 3. In patients, MSkL progression correlated with acute motor and cognitive impairments. The voxel-based lesion symptom mapping showed that acute vascular damage to the thalamus or the posterior limb of the internal capsule reduced MSkL. CONCLUSIONS: Despite worse motor performance for acute stroke patients compared with HI, most patients were able to achieve MSkL with their paretic upper limb. Damage to the thalamus and posterior limb of the internal capsule, however, reduced MSkL. These data show that MSkL could be implemented into neurorehabilitation during the acute phase of stroke, particularly for patients without lesions to the thalamus and posterior limb of the internal capsule. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01519843.

Interstitial laser anterior capsulotomy for obsessive-compulsive disorder: lesion size and tractography correlate with outcome.

BACKGROUND: Anterior capsulotomy is a well-established treatment for refractory obsessive-compulsive disorder (OCD). MRI-guided laser interstitial thermal therapy (LITT) allows creation of large, sharply demarcated lesions with the safeguard of real-time imaging. OBJECTIVE: To characterise the outcomes of laser anterior capsulotomy, including radiographical predictors of improvement. METHODS: Patients with severe OCD refractory to pharmacotherapy and cognitive-behavioural therapy underwent bilateral anterior capsulotomy via LITT. The primary outcome was per cent reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score over time. Lesion size was measured on postablation MRI. Disconnection of the anterior limb of the internal capsule (ALIC) was assessed via individual and normative tractography. RESULTS: Eighteen patients underwent laser anterior capsulotomy. Median follow-up was 6 months (range 3-51 months). Time occupied by obsessions improved immediately (median Y-BOCS item 1 score 4-1, p=0.002). Mean (±SD) decrease in Y-BOCS score at last follow-up was 46%±32% (16±11 points, p<0.0001). Sixty-one per cent of patients were responders. Seven patients (39%) exhibited transient postoperative apathy. One patient had an asymptomatic intracerebral haemorrhage. Reduction in Y-BOCS score was positively associated with ablation volume (p=0.006). Individual tractography demonstrated durable ALIC disconnection. Normative tractography revealed a dorsal-ventral gradient, with disconnection of orbitofrontal streamlines most strongly associated with a positive response (p<0.0001). CONCLUSIONS: Laser anterior capsulotomy resulted in immediate, marked improvement in OCD symptom severity. Larger lesions permit greater disconnection of prefrontal-subcortical pathways involved in OCD. The importance of greater disconnection is presumably related to variation in ALIC structure and the complex role of the PFC in OCD.

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Potential optimization of focused ultrasound capsulotomy for obsessive compulsive disorder.

Obsessive-compulsive disorder is a debilitating and often refractory psychiatric disorder. Magnetic resonance-guided focused ultrasound is a novel, minimally invasive neuromodulatory technique that has shown promise in treating this condition. We investigated the relationship between lesion location and long-term outcome in patients with obsessive-compulsive disorder treated with focused ultrasound to discern the optimal lesion location and elucidate the efficacious network underlying symptom alleviation. Postoperative images of 11 patients who underwent focused ultrasound capsulotomy were used to correlate lesion characteristics with symptom improvement at 1-year follow-up. Normative resting-state functional MRI and normative diffusion MRI-based tractography analyses were used to determine the networks associated with successful lesions. Patients with obsessive-compulsive disorder treated with inferior thalamic peduncle deep brain stimulation (n = 5) and lesions from the literature implicated in obsessive-compulsive disorder (n = 18) were used for external validation. Successful long-term relief of obsessive-compulsive disorder was associated with lesions that included a specific area in the dorsal anterior limb of the internal capsule. Normative resting-state functional MRI analysis showed that lesion engagement of areas 24 and 46 was significantly associated with clinical outcomes (R = 0.79, P = 0.004). The key role of areas 24 and 46 was confirmed by (i) normative diffusion MRI-based tractography analysis, showing that streamlines associated with better outcome projected to these areas; (ii) association of these areas with outcomes in patients receiving inferior thalamic peduncle deep brain stimulation (R = 0.83, P = 0.003); and (iii) the connectedness of these areas to obsessive-compulsive disorder-causing lesions, as identified using literature-based lesion network mapping. These results provide considerations for target improvement, outlining the specific area of the internal capsule critical for successful magnetic resonance-guided focused ultrasound outcome and demonstrating that discrete frontal areas are involved in symptom relief. This could help refine focused ultrasound treatment for obsessive-compulsive disorder and provide a network-based rationale for potential alternative targets.

Hypoglycemic hemiparesis as stroke mimic with transient splenial lesion and internal capsule involvement: A reversible clinico-radiological concurrence.

Hypoglycemia presents with a spectrum of neurological manifestations ranging from lightheadedness to confusion and coma. We report here the case of a 61-year-old woman with right hemiparesis presenting within the window period for stroke thrombolysis. MRI brain showed diffusion restriction in posterior limb of left internal capsule and splenium. Patient had documented hypoglycemia of 38 mg/dL. Patient's hemiparesis resolved after glucose correction, and radiological findings completely resolved after 10 days. We present this case to highlight the rare radiological finding of simultaneous internal capsule and splenium involvement in hypoglycemic hemiparesis and the importance to rule out stroke mimics to avoid unwanted thrombolysis.

Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis.

BACKGROUND: Deep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle, and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS. METHODS: In a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study combined individual patient's stimulation parameters at 12- and 24-month follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation. RESULTS: The individual electric stimulation fields by stimulation in the BNST were similar at both the 12- and 24-month follow-up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe), and the anterior commissure. A statistical significant correlation (p < 0.05) between clinical effect measured by the Yale-Brown Obsessive Compulsive Scale and stimulation was found at the 12-month follow-up in the ventral ALIC and anteromedial GPe. CONCLUSIONS: Many of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc, and BNST may perhaps be considered to be stimulation of the same target.

Deep Brain Stimulation Reduces Conflict-Related Theta and Error-Related Negativity in Patients With Obsessive-Compulsive Disorder.

OBJECTIVES: Obsessive-compulsive disorder (OCD) is a psychiatric disorder with alterations of cortico-striato-thalamo-cortical loops and impaired performance monitoring. Electrophysiological markers such as conflict-related medial frontal theta (MFT) and error-related negativity (ERN) may be altered by clinically effective deep brain stimulation (DBS) of the anterior limb of the internal capsule and nucleus accumbens (ALIC/NAc). We hypothesized that ALIC/NAc DBS modulates electrophysiological performance monitoring markers. MATERIALS AND METHODS: Fifteen patients (six male) with otherwise treatment-refractory OCD receiving ALIC/NAc DBS performed a flanker task with EEG recordings at three sessions: presurgery and at follow-up with DBS on and off. We examined MFT, ERN, and task performance. Furthermore, we investigated interrelations with clinical efficacy and then explored the influence of the location of individual stimulation volumes on EEG modulations. RESULTS: MFT and ERN were significantly attenuated by DBS with differences most pronounced between presurgery and DBS-on states. Also, we observed reaction time slowing for erroneous responses during DBS-off. Larger presurgery ERN amplitudes were associated with decreased clinical efficacy. Exploratory anatomical analyses suggested that stimulation volumes encompassing the NAc were associated with MFT modulation, whereas ALIC stimulation was associated with modulation of the ERN and clinical efficacy. CONCLUSION: ALIC/NAc DBS diminished MFT and ERN, demonstrating modulation of the medial frontal performance monitoring system in OCD. Furthermore, our findings encourage further studies to explore the ERN as a potential predictor for clinical efficacy.

Early Thrombectomy Protects the Internal Capsule in Patients With Proximal Middle Cerebral Artery Occlusion.

BACKGROUND AND PURPOSE: Proximal middle cerebral artery (MCA) occlusions impede blood flow to the noncollateralized lenticulostriate artery territory. Previous work has shown that this almost inevitably leads to infarction of the dependent gray matter territories in the striate even if perfusion is restored by mechanical thrombectomy. Purpose of this analysis was to evaluate potential sparing of neighboring fiber tracts, ie, the internal capsule. METHODS: An observational single-center study of patients with proximal MCA occlusions treated with mechanical thrombectomy and receiving postinterventional high-resolution diffusion-weighted imaging was conducted. Patients were classified according to internal capsule ischemia (IC+ versus IC-) at the postero-superior level of the MCA lenticulostriate artery territory (corticospinal tract correlate). Associations of IC+ versus IC- with baseline variables as well as its clinical impact were evaluated using multivariable logistic or linear regression analyses adjusting for potential confounders. RESULTS: Of 92 included patients with proximal MCA territory infarctions, 45 (48.9%) had an IC+ pattern. Longer time from symptom-onset to groin-puncture (adjusted odds ratio, 2.12 [95% CI, 1.19-3.76] per hour), female sex and more severe strokes were associated with IC+. Patients with IC+ had lower rates of substantial neurological improvement and functional independence (adjusted odds ratio, 0.26 [95% CI, 0.09-0.81] and adjusted odds ratio, 0.25 [95% CI, 0.07-0.86]) after adjustment for confounders. These associations remained unchanged when confining analyses to patients without ischemia in the corona radiata or the motor cortex and here, IC+ was associated with higher National Institutes of Health Stroke Scale motor item scores (ß, +2.8 [95% CI, 1.5 to 4.1]) without a significant increase in nonmotor items (ß, +0.8 [95% CI, -0.2 to 1.9). CONCLUSIONS: Rapid mechanical thrombectomy with successful reperfusion of the lenticulostriate arteries often protects the internal capsule from subsequent ischemia despite early basal ganglia damage. Salvage of this eloquent white matter tract within the MCA lenticulostriate artery territory seems strongly time-dependent, which has clinical and pathophysiological implications.

Deep brain stimulation for psychiatric disorders: From focal brain targets to cognitive networks.

Deep brain stimulation (DBS) is a promising intervention for treatment-resistant psychiatric disorders, particularly major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Up to 90% of patients who have not recovered with therapy or medication have reported benefit from DBS in open-label studies. Response rates in randomized controlled trials (RCTs), however, have been much lower. This has been argued to arise from surgical variability between sites, and recent psychiatric DBS research has focused on refining targeting through personalized imaging. Much less attention has been given to the fact that psychiatric disorders arise from dysfunction in distributed brain networks, and that DBS likely acts by altering communication within those networks. This is in part because psychiatric DBS research relies on subjective rating scales that make it difficult to identify network biomarkers. Here, we overview recent DBS RCT results in OCD and MDD, as well as the follow-on imaging studies. We present evidence for a new approach to studying DBS' mechanisms of action, focused on measuring objective cognitive/emotional deficits that underpin these and many other mental disorders. Further, we suggest that a focus on cognition could lead to reliable network biomarkers at an electrophysiologic level, especially those related to inter-regional synchrony of the local field potential (LFP). Developing the network neuroscience of DBS has the potential to finally unlock the potential of this highly specific therapy.

Acute motor deficit and subsequent remyelination-associated recovery following internal capsule demyelination in mice.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by accumulated motor disability. However, whether remyelination promotes motor recovery following demyelinating injury remains unclear. Damage to the internal capsule (IC) is known to result in motor impairment in multiple sclerosis and stroke. Here, we induced focal IC demyelination in mice by lysophosphatidylcholine (LPC) injection, and examined its effect on motor behavior. We also compared the effect of LPC-induced IC damage to that produced by endothelin-1 (ET1), a potent vasoconstrictor used in experimental stroke lesions. We found that LPC or ET1 injections induced asymmetric motor deficit at 7 days post-lesion (dpl), and that both lesion types displayed increased microglia/macrophage density, myelin loss, and axonal dystrophy. The motor deficit and lesion pathology remained in ET1-injected mice at 28 dpl. In contrast, LPC-injected mice regained motor function by 28 dpl, with corresponding reduction in activated microglia/macrophage density, and recovery of myelin staining and axonal integrity in lesions. These results suggest that LPC-induced IC demyelination results in acute motor deficit and subsequent recovery through remyelination, and may be used to complement future drug screens to identify drugs for promoting remyelination.

Genetic ablation of the Rho GTPase Rnd3 triggers developmental defects in internal capsule and the globus pallidus formation.

The forebrain includes the cerebral cortex, the thalamus, and the striatum and globus pallidus (GP) in the subpallium. The formation of these structures and their interconnections by specific axonal tracts take place in a precise and orchestrated time and spatial-dependent manner during development. However, the knowledge of the molecular and cellular mechanisms that are involved is rather limited. Moreover, while many extracellular cues and specific receptors have been shown to play a role in different aspects of nervous system development, including neuron migration and axon guidance, examples of intracellular signaling effectors involved in these processes are sparse. In the present work, we have shown that the atypical RhoGTPase, Rnd3, is expressed very early during brain development and keeps a dynamic expression in several brain regions including the cortex, the thalamus, and the subpallium. By using a gene-trap allele (Rnd3gt ) and immunological techniques, we have shown that Rnd3gt/gt embryos display severe defects in striatal and thalamocortical axonal projections (SAs and TCAs, respectively) and defects in GP formation already at early stages. Surprisingly, the corridor, an important intermediate target for TCAs is still present in these mutants. Mechanistically, a conditional genetic deletion approach revealed that Rnd3 is primarily required for the normal development of Medial Ganglionic Eminence-derived structures, such as the GP, and therefore acts non-cell autonomously in SAs and TCAs. In conclusion, we have demonstrated the important role of Rnd3 as an early regulator of subpallium development in vivo and revealed new insights about SAs and TCAs development.

Mapping the corticoreticular pathway from cortex-wide anterograde axonal tracing in the mouse.

The corticoreticular pathway (CRP) has been implicated as an important mediator of motor recovery and rehabilitation after central nervous system damage. However, its origins, trajectory and laterality are not well understood. This study mapped the mouse CRP in comparison with the corticospinal tract (CST). We systematically searched the Allen Mouse Brain Connectivity Atlas (© 2011 Allen Institute for Brain Science) for experiments that used anterograde tracer injections into the right isocortex in mice. For each eligible experiment (N = 607), CRP and CST projection strength were quantified by the tracer volume reaching the reticular formation motor nuclei (RFmotor ) and pyramids, respectively. Tracer density in each brain voxel was also correlated with RFmotor versus pyramids projection strength to explore the relative trajectories of the CRP and CST. We found significant CRP projections originating from the primary and secondary motor cortices, anterior cingulate, primary somatosensory cortex, and medial prefrontal cortex. Compared with the CST, the CRP had stronger projections from each region except the primary somatosensory cortex. Ipsilateral projections were stronger than contralateral for both tracts (above the pyramidal decussation), but the CRP projected more bilaterally than the CST. The estimated CRP trajectory was anteromedial to the CST in the internal capsule and dorsal to the CST in the brainstem. Our findings reveal a widespread distribution of CRP origins and confirm strong bilateral CRP projections, theoretically increasing the potential for partial sparing after brain lesions and contralesional compensation after unilateral injury.