Long-term comparative effectiveness of deep brain stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Twenty years after the first use of Deep Brain Stimulation (DBS) in obsessive-compulsive disorder (OCD), our knowledge of the long-term effects of this therapeutic option remains very limited. OBJECTIVE: Our study aims to assess the long-term effectiveness and tolerability of DBS in OCD patients and to look for possible predictors of long-term response to this treatment. METHODS: We studied the course of 25 patients with severe refractory OCD treated with DBS over an average follow-up period of 6.4 years (±3.2) and compared them with a control group of 25 patients with severe OCD who refused DBS and maintained their usual treatment. DBS was implanted at the ventral anterior limb of the internal capsule and nucleus accumbens (vALIC-Nacc) in the first six patients and later at the bed nucleus of stria terminalis (BNST) in the rest of patients. Main outcome was change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score between the two groups assessed using mixed models. Secondary effectiveness outcomes included Hamilton Depression Rating Scale (HDRS) and Global Assessment of Functioning (GAF) scores. RESULTS: Obsessive symptoms fell by 42.5% (Y-BOCS score) in patients treated with DBS and by 4.8% in the control group. Fifty-six per cent of DBS-treated patients could be considered responders at the end of follow-up and 28% partial responders. Two patients among those who rejected DBS were partial responders (8%), but none of the non-DBS group achieved criteria for complete response. HDRS and GAF scores improved significantly in 39.2% and 43.6% among DBS-treated patients, while did not significantly change in those who rejected DBS (improvement limited to 6.2% in HDRS and 4.2% in GAF scores). No statistically significant predictors of response were found. Mixed models presented very large comparative effect sizes for DBS (4.29 for Y-BOCS, 1.15 for HDRS and 2.54 for GAF). Few patients experienced adverse effects and most of these effects were mild and transitory. CONCLUSIONS: The long-term comparative effectiveness and safety of DBS confirm it as a valid option for the treatment of severe refractory OCD.

Differential loss of position sense and kinesthesia in sub-acute stroke.

Position sense and kinesthesia are thought to be independent sub-modalities of proprioception, based on neuromuscular recordings in the periphery. However, little evidence has demonstrated separation in the central nervous system (CNS). Stroke provides an interesting model to examine this dissociation in the CNS due to the heterogeneity of lesion locations and high incidence of proprioceptive impairment. Here, we aimed to determine if position sense and kinesthesia are behaviorally dissociable in a stroke patient model, and if behavioral dissociations in proprioception corresponded to different stroke lesion damage. Position sense and kinesthesia were assessed in subjects with unilateral stroke (N = 285) using two robotic tasks: Position Matching (PM) and Kinesthetic Matching (KIN). Without vision, the robot moved the subjects' stroke-affected arm and they mirror-matched perceived location (PM) or movement (KIN) with their opposite arm. Fifty-two percent of subjects had deficits in both PM and KIN, 22% had impairments in only one sub-modality (7% PM only, 15% KIN only). These subjects tended to have smaller lesions (internal capsule, basal ganglia, insula) compared to those with larger lesions affecting both sub-modalities. Overall, we observed separation of proprioceptive sub-modalities in a large number of stroke subjects, and that lesion load impacted the pattern of proprioceptive impairment.

A Driving-Force Predictor for Estimating Pathway Activation in Patient-Specific Models of Deep Brain Stimulation.

OBJECTIVE: Detailed biophysical modeling of deep brain stimulation (DBS) provides a theoretical approach to quantify the cellular response to the applied electric field. However, the most accurate models for performing such analyses, patient-specific field-cable (FC) pathway-activation models (PAMs), are so technically demanding to implement that their use in clinical research is greatly limited. Predictive algorithms can simplify PAM calculations, but they generally fail to reproduce the output of FC models when evaluated over a wide range of clinically relevant stimulation parameters. Therefore, we set out to develop a novel driving-force (DF) predictive algorithm (DF-Howell), customized to the study of DBS, which can better match FC results. METHODS: We developed the DF-Howell algorithm and compared its predictions to FC PAM results, as well as to the DF-Peterson algorithm, which is currently the most accurate and generalizable DF-based method. Comparison of the various methods was quantified within the context of subthalamic DBS using activation thresholds of axons representing the internal capsule, hyperdirect pathway, and cerebellothalamic tract for various combinations of fiber diameters, stimulus pulse widths, and electrode configurations. RESULTS: The DF-Howell predictor estimated activation of the three axonal pathways with less than a 6.2% mean error with respect to the FC PAM for all 21 cases tested. In 15 of the 21 cases, DF-Howell outperformed DF-Peterson in estimating pathway activation, reducing mean-errors up to 22.5%. CONCLUSIONS: DF-Howell represents an accurate predictor for estimating axonal pathway activation in patient-specific DBS models, but errors still exist relative to FC PAM calculations. Nonetheless, the tractability of DF algorithms helps to reduce the technical barriers for performing accurate biophysical modeling in clinical DBS research studies.

Monitoring deep brain stimulation by measuring regional brain oxygen responses in freely moving mice.

BACKGROUND: Translational studies investigating the effects of deep brain stimulation (DBS) on brain function up to now mainly relied on BOLD responses measured with fMRI. However, fMRI studies in rodents face technical and practical limitations (e.g., immobilization, sedation or anesthesia, spatial and temporal resolution of data). Direct measurement of oxygen concentration in the brain using electrochemical sensors is a promising alternative to the use of fMRI. Here, we tested for the first time if such measurements can be combined with DBS. NEW METHOD: We combined bilateral DBS in the internal capsule (IC-DBS) with simultaneous amperometric measurements of oxygen in the medial prefrontal cortex (prelimbic area) and striatum of freely moving mice. Using a two-day within-animal experimental design, we tested the effects of DBS on baseline oxygen concentrations, and on novelty- and restraint-induced increases in oxygen concentration. RESULTS: Basal oxygen levels were stable across the daily sampling periods. Exposure to novelty and immobilization reproducibly increased oxygen concentrations in both areas. IC-DBS did not significantly alter basal oxygen, but reduced the novelty-induced increase in the striatum. COMPARISON WITH EXISTING METHOD(S): Amperometric detection of brain oxygen concentration with high temporal and spatial resolution can be performed in a number of key brain areas to study the effects of DBS in animal models of disease. The method is easily implemented and does not require expensive equipment or complicated data analysis processes. CONCLUSIONS: Direct and simultaneous measurement of brain oxygen concentration in multiple brain areas can be used to study the effects of bilateral DBS neuromodulation on brain activity in freely moving mice.

Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study.

BACKGROUND: Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction. METHODS: Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded. RESULTS: With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible. CONCLUSIONS: Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov, NCT01274988).

Constrained-induced movement therapy promotes motor function recovery by enhancing the remodeling of ipsilesional corticospinal tract in rats after stroke.

Constraint-induced movement therapy (CIMT), which forces the use of the impaired limb by restraining the unaffected limb, has been used extensively for the recovery of limb motor function after stroke. However, the underlying mechanism of CIMT remains unclear. Diffusion tensor imaging (DTI) is a well-known neuroimaging technique that reflects the microstructure of white matter tracts and potential changes associated with different treatments. The aim of this study is to use DTI imaging to determine how corticospinal tract (CST) fibers remodel in ischemic rats with CIMT. In the present study, rats were randomly divided into three groups: a middle cerebral artery occlusion group (MCAO), a therapeutic group (MCAO + CIMT), and a sham-operated group (sham). A plaster cast was used to restrict the unaffected limb of the rats in the MCAO + CIMT group for 14 days. The Catwalk system was used to assess the limb motor function of rats. Fractional anisotropy (FA) and the average diffusion coefficient (ADC) of the CST were quantified through DTI. The expression of the c-Jun-N-terminal kinase signaling pathway (JNK) was examined after 14 days of CIMT. We found that CIMT could accelerate and enhance motor function recovery, and the MCAO + CIMT group showed significantly increased FA values in the ipsilesional posterior limb of internal capsule (PLIC) compared with the MCAO group. In addition, we found no significant difference in the ratio of phosphorylated-JNK/total-JNK among the three groups, whereas the expression of P-JNK decreased significantly in the chronic phase of stroke. In conclusion, CIMT-induced functional recovery following ischemic stroke through facilitation of the remodeling of ipsilesional CST, and restoration after ischemic stroke may be associated with the declining value of the ratio of P-JNK/JNK.

Early assessment of lateralization and sex influences on the microstructure of the white matter corticospinal tract in healthy term neonates.

We assessed the sex and the lateralization differences in the corticospinal tract (CST) during the early postnatal period. Twenty-five healthy term neonates (13 girls, aged 39.2 ± 1.2 weeks, and 12 boys aged 38.6 ± 3.0 weeks) underwent Diffusion Tensor Imaging (DTI). Fiber tracking was performed to extract bilaterally the CST pathways and to quantify the parallel (E1 ) and perpendicular (E23 ) diffusions, the apparent diffusion coefficient (ADC), and fractional anisotropy (FA). The measurements were performed on the entire CST fibers and on four segments: base of the pons (CST-Po), cerebral peduncles (CST-CP), posterior limb of the internal capsule (CST-PLIC), and corona-radiata (CST-CR). Significantly higher E1 , lower E23, and higher FA in the right compared to the left were noted in the CST-PLIC of the girls. Significantly lower E23 and lower ADC with higher FA in the right compared to left were observed in the CST-CP of the boys. Moreover, the CST-PLIC of the boys had significantly higher E1 in the right compared to the left. There was a significant increase in left CST E1 of boys when compared with girls. Girls had a significantly lower E1 , lower E23 and, lower ADC in the left CST-CP compared with boys. In addition, girls had a significantly lower E23 and higher FA in the right CST-PLIC compared with boys. Sex differences and lateralization in structure-based segments of the CST were found in healthy term infants during early postnatal period. These findings are vital to understanding motor development of healthy term born neonates to better interpret newborn infants with abnormal neurodevelopment.

Acute Effects of Electrical Stimulation of the Bed Nucleus of the Stria Terminalis/Internal Capsule in Obsessive-Compulsive Disorder.

BACKGROUND: Deep brain stimulation (DBS) has been introduced as a treatment option for treatment-resistant obsessive-compulsive disorder (OCD). However, the optimal stimulation target and the corresponding stimulation settings remain unclear. Furthermore, there is limited knowledge about the acute effects of DBS. METHODS: In 3 patients with treatment-resistant OCD, DBS electrodes were implanted in the bed nucleus of the stria terminalis (BNST)/internal capsule (IC). On the next day, different electrode pairs (BNST only, IC only, and BNST/IC) were stimulated at different voltages (1, 2, and 3.5 V) for 5 minutes each. Afterwards, patients rated their perceived OCD symptoms and various emotional states on corresponding visual analog scales. RESULTS: Across locations, low voltage stimulation (1 and 2 V) was associated with reduction of OCD symptoms (i.e., anxiety and tension), in particular when the IC was stimulated. High voltage stimulation (3.5 V), in particular when BNST was involved, led to less reduction of OCD symptoms. Moreover, 3.5-V stimulation of the BNST (BNST only and BNST/IC) induced higher levels of anxiety, tension, and discomfort. Subjects also reported an increase in vegetative sensations. CONCLUSIONS: In summary, we demonstrate that both stimulation site and voltage settings show sweet spots (2 V at IC or BNST/IC) at which OCD symptom severity decreased while negative effects were minimal. Stimulation of IC fibers might be relevant both for acute and chronic effects. Whether acute effects are useful for outcome prediction remains to be shown in future studies.

Deep brain stimulation for stroke: Current uses and future directions.

BACKGROUND: Survivors of stroke often experience significant disability and impaired quality of life related to ongoing maladaptive responses and persistent neurologic deficits. Novel therapeutic options are urgently needed to augment current approaches. One way to promote recovery and ameliorate symptoms may be to electrically stimulate the surviving brain. Various forms of brain stimulation have been investigated for use in stroke, including deep brain stimulation (DBS). OBJECTIVE/METHODS: We conducted a comprehensive literature review in order to 1) review the use of DBS to treat post-stroke maladaptive responses including pain, dystonia, dyskinesias, and tremor and 2) assess the use and potential utility of DBS for enhancing plasticity and recovery from post-stroke neurologic deficits. RESULTS/CONCLUSIONS: A large variety of brain structures have been targeted in post-stroke patients, including motor thalamus, sensory thalamus, basal ganglia nuclei, internal capsule, and periventricular/periaqueductal grey. Overall, the reviewed clinical literature suggests a role for DBS in the management of several post-stroke maladaptive responses. More limited evidence was identified regarding DBS for post-stroke motor deficits, although existing work tentatively suggests DBS-particularly DBS targeting the posterior limb of the internal capsule-may improve paresis in certain circumstances. Substantial future work is required both to establish optimal targets and parameters for treatment of maladapative responses and to further investigate the effectiveness of DBS for post-stroke paresis.

Avoiding Internal Capsule Stimulation With a New Eight-Channel Steering Deep Brain Stimulation Lead.

OBJECTIVE: Novel deep brain stimulation (DBS) lead designs are currently entering the market, which are hypothesized to provide a way to steer the stimulation field away from neural populations responsible for side effects and towards populations responsible for beneficial effects. The objective of this study is to assess the performances of a new eight channel steering-DBS lead and compare this with a conventional cylindrical contact (CC) lead. APPROACH: The two leads were evaluated in a finite element electric field model combined with multicompartment neuron and axon models, representing the internal capsule (IC) fibers and subthalamic nucleus (STN) cells. We defined the optimal stimulation setting as the configuration that activated the highest percentage of STN cells, without activating any IC fibers. With this criterion, we compared monopolar stimulation using a single contact of the steering-DBS lead and CC lead, on three locations and four orientations of the lead. In addition, we performed a current steering test case by dividing the current over two contacts with the steering-DBS lead in its worst-case orientation. MAIN RESULTS: In most cases, the steering-DBS lead is able to stimulate a significantly higher percentage of STN cells compared to the CC lead using single contact stimulation or using a two contact current steering protocol when there is approximately a 1 mm displacement of the CC lead. The results also show that correct placement and orientation of the lead in the target remains an important aspect in achieving the optimal stimulation outcome. SIGNIFICANCE: Currently, clinical trials are set up in Europe with a similar design as the steering-DBS lead. Our results illustrate the importance of the orientation of the new steering-DBS lead in avoiding side effects induced by stimulation of IC fibers. Therefore, in clinical trials sufficient attention should be paid to implanting the steering DBS-lead in the most effective orientation.

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala.

The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

Episodic memory following deep brain stimulation of the ventral anterior limb of the internal capsule and electroconvulsive therapy.

BACKGROUND: Electroconvulsive Therapy (ECT) and Deep Brain Stimulation (DBS) are effective treatments for patients with treatment-resistant depression (TRD). However, a common side effect of ECT is autobiographical memory loss (e.g., personal experiences), whereas the impact of DBS on autobiographical memories has never been established. OBJECTIVE: Comparing autobiographical memories following DBS and ECT. METHODS: In two hospitals in The Netherlands, we interviewed 25 TRD patients treated with DBS of the ventral anterior limb of the internal capsule (vALIC), 14 TRD patients treated with ECT and 22 healthy controls (HC) with the Autobiographical Memory Inventory - Short Form (AMI-SF) in a prospective, longitudinal study between March 2010 and August 2016. Patients treated with DBS were interviewed before surgery, after surgery, and twice during treatment over 122.7 (SD: ±22.2) weeks. Patients treated with ECT were tested before ECT, after six right unilateral (RUL) ECT sessions and twice following ECT over 65.1 (±9.3) weeks. Controls were tested four times over 81.5 (±15.6) weeks. RESULTS: Compared to HC, the AMI-SF score decreased faster in both TRD groups (P < 0.001). More specifically, AMI-SF score decreased in a comparable rate as HC after DBS surgery, but decreased more during treatment. The AMI-SF decrease in the ECT group was larger than both the DBS and HC groups. CONCLUSIONS: Both ECT and vALIC DBS result in a faster autobiographical memory decline compared to HC. DBS might have a negative impact on autobiographical memories, although less so than ECT. Future work should dissect whether DBS or characteristics of TRD cause this decline.

Localization of orofacial representation in the corona radiata, internal capsule and cerebral peduncle in Macaca mulatta.

Subcortical white matter injury is often accompanied by orofacial motor dysfunction, but little is known about the structural substrates accounting for these common neurological deficits. We studied the trajectory of the corticobulbar projection from the orofacial region of the primary (M1), ventrolateral (LPMCv), supplementary (M2), rostral cingulate (M3) and caudal cingulate (M4) motor regions through the corona radiata (CR), internal capsule (IC) and crus cerebri of the cerebral peduncle (ccCP). In the CR each pathway was segregated. Medial motor area fibers (M2/M3/M4) arched over the caudate and lateral motor area fibers (M1/LPMCv) curved over the putamen. At superior IC levels, the pathways were widespread, involving the anterior limb, genu and posterior limb with the M3 projection located anteriorly, followed posteriorly by projections from M2, LPMCv, M4 and M1, respectively. Inferiorly, all pathways maintained this orientation but shifted posteriorly, with adjacent fiber bundles overlapping minimally. In the ccCP, M3 fibers were located medially and M1 fibers centromedially, with M2, LPMCv, and M4 pathways overlapping in between. Finally, at inferior ccCP levels, all pathways overlapped. Following CR and superior IC lesions, the dispersed pathway distribution may correlate with acute orofacial dysfunction with spared pathways contributing to orofacial motor recovery. In contrast, the gradually commixed nature of pathway representation inferiorly may enhance fiber vulnerability and correlate with severe, prolonged deficits following lower subcortical and midbrain injury. Additionally, in humans these findings may assist in interpreting orofacial movements evoked during deep brain stimulation, and neuroimaging tractography efforts to localize descending orofacial motor pathways.

Deep brain stimulation of the anterior limb of the internal capsule for treatment of therapy-refractory obsessive compulsive disorder (OCD): a case study highlighting neurocognitive and psychiatric changes.

Obsessive compulsive disorder (OCD) is an anxiety disorder characterized by repeated, unwanted thoughts and behaviors. Individuals with this condition often experience significant emotional distress secondary to their symptoms. Additionally, impairments in attention/concentration, processing speed, and executive functions are typically observed. The exact pathology of OCD remains unknown; consequently, it can be difficult to treat patients with severe symptomatology. Deep brain stimulation (DBS) may be a viable treatment option for individuals who do not respond to medication and/or cognitive behavioral therapy. The following case discusses DBS of the anterior limb of the internal capsule for a patient with severe, therapy-refractory OCD, including pre- to postoperative neurocognitive and psychiatric changes.

Minimally Invasive Surgery for Evacuating the Intracerebral Hematoma in Early Stages Decreased Secondary Damages to the Internal Capsule in Dog Model of ICH Observed by Diffusion Tensor Imaging.

BACKGROUND: Diffusion tensor imaging was used to observe the effects of performing early minimally invasive surgery (MIS) on internal capsule in dog model of intracerebral hemorrhage (ICH). METHODS: Twenty-five male dogs were selected to prepare an ICH model, and then they were randomly distributed into a model control (MC) group (5 dogs) or an MIS group (20 dogs). In the MIS group, the intracerebral hematoma was evacuated by stereotactic minimally invasive procedures over 6 hours (5 dogs), 12 hours (5 dogs), 18 hours (5 dogs), or 24 hours (5 dogs) after successful induction of ICH. The same procedure was performed in the MC group but without evacuating the hematoma. All the animals were sacrificed within 2 weeks after the hematoma was surgically evacuated. The neurologic deficit score and diffusion tensor imaging (DTI) were observed before and after the MIS. The perihematomal blood-brain barrier (BBB) permeability and the brain water content (BWC) were measured 2 weeks after the hematoma was surgically evacuated. RESULTS: The DTI demonstrated that integrity of the internal capsule restored largely after surgery and the fractional anisotropy (FA) values of the internal capsule on the hematoma side increased significantly as compared with those in the MC group or those before surgery in the same group. The postoperative ratios of FA values of each MIS subgroup increased compared with the MC group and those before surgery in the same subgroup before operation. The neurologic deficit score, the perihematomal BBB permeability, and the BWC of each MIS subgroup decreased significantly compared with those of the MC group. The 6-12-hour group displayed a more favorable result. CONCLUSIONS: Performing the MIS in the early stage (6-12 hours) after ICH could decrease the secondary damages to the internal capsule so as to promote the recovery of motor function. The optimal time window for MIS should be within 6-12 hours after onset of ICH.

An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients' response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder. METHODS: Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance. RESULTS: Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP. CONCLUSIONS: DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients' response to ERP therapy.

Electrical stimulation in the bed nucleus of the stria terminalis alleviates severe obsessive-compulsive disorder.

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.

Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome.

Deep brain stimulation (DBS) has been reported to have beneficial effects in severe, treatment-refractory cases of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). In this report, the authors present the first case in which DBS was used to treat the neuropsychiatric symptoms of Kleefstra syndrome, a rare genetic disorder characterized by childhood hypotonia, intellectual disability, distinctive facial features, and myriad psychiatric and behavioral disturbances. A 24-year-old female patient with childhood hypotonia, developmental delay, and diagnoses of autism spectrum disorder, OCD, and TS refractory to medical management underwent the placement of bilateral ventral capsule/ventral striatum (VC/VS) DBS leads, with clinical improvement. Medical providers and family observed gradual and progressive improvement in the patient's compulsive behaviors, coprolalia, speech, and social interaction. Symptoms recurred when both DBS electrodes failed because of lead fracture and dislodgement, although the clinical benefits were restored by lead replacement. The symptomatic and functional improvements observed in this case of VC/VS DBS for Kleefstra syndrome suggest a novel indication for DBS worthy of further investigation.

One diffusion acquisition and different white matter models: how does microstructure change in human early development based on WMTI and NODDI?

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.

Linx mediates interaxonal interactions and formation of the internal capsule.

During the development of forebrain connectivity, ascending thalamocortical and descending corticofugal axons first intermingle at the pallial-subpallial boundary to form the internal capsule (IC). However, the identity of molecular cues that guide these axons remains largely unknown. Here, we show that the transmembrane protein Linx is robustly expressed in the prethalamus and lateral ganglionic eminence-derived corridor and on corticofugal axons, but not on thalamocortical axons, and that mice with a null mutation of Linx exhibit a complete absence of the IC. Moreover, regional inactivation of Linx either in the prethalamus and LGE or in the neocortex leads to a failure of IC formation. Furthermore, Linx binds to thalamocortical projections, and it promotes outgrowth of thalamic axons. Thus, Linx guides the extension of thalamocortical axons in the ventral forebrain, and subsequently, it mediates reciprocal interactions between thalamocortical and corticofugal axons to form the IC.