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In 1998, we proposed deep brain stimulation as a last-resort treatment option for patients suffering from severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, 24 OCD patients were included in a long-term follow-up study to evaluate the effects of electrical stimulation in the anterior limbs of the internal capsule (ALIC) and bed nucleus of the stria terminalis (BST). We find that electrical stimulation in the ALIC/BST area is safe and significantly decreases obsessions, compulsions, and associated anxiety and depressive symptoms, and improves global functioning in a blinded crossover trial ( n =17), after 4 years ( n =18), and at last follow-up (up to 171 months, n =24). Moreover, our data indicate that BST may be a better stimulation target compared with ALIC to alleviate OCD symptoms. We conclude that electrical stimulation in BST is a promising therapeutic option for otherwise treatment-resistant OCD patients.

Background: Recently, anterior limb of the internal capsule and nucleus accumbens deep brain stimulation (DBS) has been used in the treatment of medication-refractory obsessive–compulsive disorder (OCD). This region has been previously explored with lesion therapy, but with the advent of DBS there exists the possibility of monitoring the acute and chronic effects of electrical stimulation. The stimulation-induced benefits and side effects can be reversibly and blindly applied to a variety of locations in this region. Objective: To explore the acute effects of DBS in the anterior limb of the internal capsule and nucleus accumbens region. Methods: Ten total DBS leads in five patients with chronic and severe treatment-refractory OCD were tested. Patients were examined 30 days after DBS placement and received either “sham” testing or actual testing of the acute effects of DBS (the alternative condition tested 30 days later). Results: Pooled responses were reviewed for comparability of distribution using standard descriptive methods, and relationships between the variables of interest were sought using χ2 analysis. A total of 845 stimulation trials across the five patients were recorded and pooled. Of these 16% were elicited from sham stimulation and 17% from placebo (0 V stimulation). A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Non-mood-related responses were found to be significantly associated with the ventral lead contacts (0 and 1) (p = 0.001). Responses such as taste, smell and smile were strongly associated with the most ventral lead positions. Similarly, physiological responses—for example, autonomic changes, increased breathing rate, sweating, nausea, cold sensation, heat sensation, fear, panic and panic episodes—were significantly associated with ventral stimulation (p = 0.001). Fear and panic responses appeared clustered around the most ventral electrode (0). Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule. Conclusion: The acute effects of DBS in the region of the anterior limb of the internal capsule and nucleus accumbens, particularly when obtained in a blinded fashion, provide a unique opportunity to localise brain regions and explore circuitry.

White matter microstructural changes during the first three years of healthy brain development are characterized using two different models developed for limited clinical diffusion data: White Matter Tract Integrity (WMTI) metrics from Diffusional Kurtosis Imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI). Both models reveal a non-linear increase in intra-axonal water fraction and in tortuosity of the extra-axonal space as a function of age, in the genu and splenium of the corpus callosum and the posterior limb of the internal capsule. The changes are consistent with expected behavior related to myelination and asynchrony of fiber development. The intra- and extracellular axial diffusivities as estimated with WMTI do not change appreciably in normal brain development. The quantitative differences in parameter estimates between models are examined and explained in the light of each model's assumptions and consequent biases, as highlighted in simulations. Finally, we discuss the feasibility of a model with fewer assumptions. •We analyze the microstructural changes in human white matter tracts from ages 0 to 3.•We compare two biophysical models: White Matter Tract Integrity metrics and NODDI.•Both models reveal a large increase in axonal water fraction and tortuosity.•The changes are consistent with myelination, fiber asynchrony and classification.•The quantitative mismatch between models is explained by differences in assumptions.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Evaluating the integrity of the corticospinal tract at the height of the posterior limb of the internal capsule with a lateralization index has been applied to predict upper limb motor recovery after stroke in numerous diffusion tensor imaging studies. When comparing patient groups with healthy controls in this context, matching for age and gender is generally recommended. Since a generalized lateralization of diffusion strength to the dominant left hemisphere has been reported, it can be argued that handedness should also be accounted for. To address this question, we used the Human Connectome Project data set containing 1,065 diffusion-weighted MRI sets as well as information on handedness as defined by the Edinburgh Handedness Inventory. We hypothesized that handedness might be related to diffusion strength of the corticospinal tract. As commonly employed, we extracted fractional anisotropy values at the level of the internal capsule to calculate a laterality index. Contrary to our hypothesis, we found no association between corticospinal tract diffusion strength and handedness. We conclude that for handedness, no balancing between patient and control groups is needed when comparing corticospinal tract diffusivity parameters.

Development of axonal tracts requires interactions between growth cones and the environment. Tracts such as the anterior commissure and internal capsule are defective in mice with null mutation of Celsr3. We generated a conditional Celsr3 allele, allowing regional inactivation. Inactivation in telencephalon, ventral forebrain, or cortex demonstrated essential roles for Celsr3 in neurons that project axons to the anterior commissure and subcerebral targets, as well as in cells that guide axons through the internal capsule. When Celsr3 was inactivated in cortex, subcerebral projections failed to grow, yet corticothalamic axons developed normally, indicating that besides guidepost cells, additional Celsr3-independent cues can assist their progression. These observations provide in vivo evidence that Celsr3-mediated interactions between axons and guidepost cells govern axonal tract formation in mammals.

Knowledge of the individual course of the optic radiations (ORs) is important to avoid postoperative visual deficits. Cadaveric studies of the visual pathways are limited because it has not been possible to separate the OR from neighboring tracts accurately and results may not apply to individual patients. Diffusion tensor imaging studies may be able to demonstrate the relationships between the OR and neighboring fibers in vivo in individual subjects. To use diffusion tensor imaging tractography to study the OR and the Meyer loop (ML) anatomy in vivo. Ten healthy subjects underwent magnetic resonance imaging with diffusion imaging at 3 T. With the use of a fiducial-based diffusion tensor imaging tractography tool (Slicer 3.3), seeds were placed near the lateral geniculate nucleus to reconstruct individual visual pathways and neighboring tracts. Projections of the ORs onto 3-dimensional brain models were shown individually to quantify relationships to key landmarks. Two patterns of visual pathways were found. The OR ran more commonly deep in the whole superior and middle temporal gyri and superior temporal sulcus. The OR was closely surrounded in all cases by an inferior longitudinal fascicle and a parieto/occipito/temporo-pontine fascicle. The mean left and right distances between the tip of the OR and temporal pole were 39.8 ± 3.8 and 40.6 ± 5.7 mm, respectively. Diffusion tensor imaging tractography provides a practical complementary method to study the OR and the Meyer loop anatomy in vivo with reference to individual 3-dimensional brain anatomy.

Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture.