Effect of Deep Brain Stimulation in Rats Selectively Bred for Reduced Prepulse Inhibition

BackgroundSensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle reaction (ASR), is disturbed in certain neuropsychiatric disorders, such as schizophrenia, obsessive compulsive disorder, and Tourette's syndrome (TS). Deep brain stimulation (DBS) of the centromedian–parafascicular complex (CM-Pf), globus pallidus internus (in rats the entopeduncular nucleus – EPN), and the ventral striatum (in rats the nucleus accumbens – NAC) has been used for treatment in TS.ObjectiveWe tested whether DBS of these regions would alleviate breeding-induced low PPI in rats.MethodsRats with breeding-induced low and high PPI were bilaterally implanted with electrodes in the CM-Pf, the EPN, or the NAC. After two weeks, they were stimulated or sham stimulated for epochs of 6 days (in the EPN with a current of 20% below the individual threshold for stimulation-induced side effects, in the NAC or CM-Pf with 100 μA and 150 μA). On the 6th day the rats were tested for PPI of ASR.ResultsStimulation in the CM-Pf with 150 μA significantly alleviated PPI, while NAC stimulation was less effective. In PPI low rats electrode implantation in the EPN already improved PPI, while subsequent stimulation had no additional effect. Startle reaction of PPI low rats was not affected by stimulation of either region.ConclusionThe CM-Pf and the EPN are important for the modulation of sensorimotor gating in rats with breeding-induced low PPI. These rats may therefore be useful to further investigate the pathophysiological mechanisms of deficient sensorimotor gating and also mechanisms of action of DBS in these circumstances.     

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease

ObjectiveThe deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5–4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial.Materials and MethodsAttempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures.ResultsTwelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson’s Disease Rating Scale [UPDRS]–IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; p_interaction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire–39 (PDQ-39), and levodopa equivalent daily dose (LEDD).ConclusionsEleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT00282152.     

Epidural Direct Current Stimulation Over the Left Medial Prefrontal Cortex Facilitates Spatial Working Memory Performance in Rats

BackgroundExtensive evidence supports the notion that modulation of PFC excitability using low-intensity electrical stimulation is a promising modality for treating neuropsychiatric diseases and improving cognitive function.ObjectiveThis study examined the effects of epidural direct current stimulation (eDCS), a method providing smaller shunting of current and more focal stimulation, on spatial working memory.MethodsMale Wistar rats that were well trained in an 8-arm radial maze and in which 5-mm round electrodes were implanted over the left medial prefrontal cortex (mPFC) received anodal eDCS (400 μA during 11 min) (n = 9) or sham procedure (n = 9) five minutes before delayed tests in the radial maze.ResultsAnimals that received eDCS over the left mPFC had significantly fewer errors in the post-delay performance on the 1-h (P < 0.01), 4-h (P < 0.001), and 10-h (P < 0.001) delayed tests compared with sham-treated animals. General locomotor activity was unaffected because time spent in each visited arm did not change significantly by eDCS. There was no evidence of neuronal lesions in the mPFC underneath the eDCS.ConclusionsOur results suggest that epidural direct current stimulation over the mPFC facilitates spatial working memory in rats, an effect that persisted over the long term.     

Deep Brain Stimulation Evoked Potentials May Relate to Clinical Benefit in Childhood Dystonia

BackgroundDeep brain stimulation (DBS) of the globus pallidus internus (GPi) is a treatment for severe childhood-onset dystonia. A common challenge for clinicians is determining which contacts of the DBS electrode to stimulate in order to provide maximum future benefit to the patient.ObjectiveTo characterize how the cortical responses to DBS relate to stimulation parameters (i.e. electrode contacts, voltage, and pulse width) and clinical outcomes.MethodsWe examined 11 patients with dystonia undergoing DBS therapy (9–21 years old when implanted). We varied the active contacts, voltage, and pulse width of the stimulating electrode and analyzed the deep-brain stimulator evoked potentials (DBSEPs) measured with electroencephalogram, and assessed symptoms with the Barry-Albright dystonia scale. Statistical tests included: Repeated measures ANOVA, Mann–Whitney U test and paired t-test.ResultsDBSEPs near sensorimotor areas were larger ipsilaterally than contralaterally (P = 0.007). The rate of DBSEP amplitude increase with respect to stimulator voltage (voltage gain) and pulse width (pulse width gain) varied across subjects and stimulating contacts. Voltage gains were significantly higher among patients who showed larger improvements with DBS (P = 0.038). Additionally, a within-subject comparison of all patients showed that voltage gains were higher for contacts chosen for chronic stimulation as compared to those that were not (P = 0.007).ConclusionsDBSEPs may be good predictors of therapeutic response to stimulation at different electrode contacts. Furthermore, effective DBS therapy appears to modulate sensorimotor cortex. These findings may help clinicians optimize stimulator programming and may eventually lead to improved targeting during implantation.     

Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain

BackgroundThe midbrain periaqueductal grey (PAG) area is important for both pain modulation and cardiovascular control via the autonomic nervous system (ANS). While changes in blood pressure dependent upon dorsal or ventral electrode positioning have been described with PAG deep brain stimulation (DBS), little is known mechanistically about the relationships between pain and cardiovascular regulation in humans. Heart rate variability (HRV) is an established measure of cardiovascular regulation, and an index of autonomic function.Methods and results16 patients undergoing DBS of the rostral PAG for chronic neuropathic pain were investigated post-operatively to determine whether PAG stimulation would alter HRV, and the subjects' perception of pain. Mean heart rate together with HRV, time and frequency domain measures, low frequency (LF) and high frequency (HF) power components of heart rate and the ratio of LF to HF were calculated before and during DBS. Ventral but not dorsal PAG DBS significantly decreased the ratio of LF to HF power (p < 0.05, n = 8) with HF power significantly increased. Changes in LF/HF ratio correlated significantly with subjective reporting of analgesic efficacy using a visual analogue score (VAS; γ² = 0.36, p = 0.01, n = 16). Diffusion tensor imaging and probabilistic tractography of 17 normal controls' seeding voxels from the mean ventral and dorsal PAG stimulation sites of the 16 patient cohort revealed significant differences between rostral tract projections and separate, adjacent projections to ipsilateral dorsolateral medulla.ConclusionsVentral PAG DBS may increase parasympathetic activity to reduce pain via anatomical connections distinct from dorsal PAG DBS, which may act by sympathetic mechanisms.     

The actual use of directional steering and shorter pulse width in selected patients undergoing deep brain stimulation

IntroductionDirectional deep brain stimulation (DBS) and pulse with <60μs increase side-effects threshold, enlarging the therapeutic window. However, new systems allowing these advanced features are more expensive and often available only for a limited number of patients in some centers. It is unknown how many and which DBS patients actually need the advanced features because of an insufficient improvement with standard parameters.MethodsWe included in the analysis all patients with Parkinson's disease, dystonia and tremor who were selected to receive implantation of advanced DBS systems based on specific preoperative or intraoperative clinical features.ResultsAfter a median follow-up of 15 months, 54.9% of the 51 patients implanted with directional leads were using the advanced features in one or both leads (n = 42 leads, 42%), meaning these leads were programmed either with directional stimulation (n = 9, 9%), a shorter pw (n = 20, 20%) or both (n = 13, 13%). This included 92% of patients implanted in the Vim, 44% of those implanted in the STN, and 40% of those implanted in the GPi.ConclusionsDBS systems with advanced features may be particularly indicated for selected patients based on some clinical characteristics and the chosen target. This data may help clinicians allocate resources in a more informed way.     

Latency of subthalamic nucleus deep brain stimulation-evoked cortical activity as a potential biomarker for postoperative motor side effects

ObjectiveHere, we investigate whether cortical activation predicts motor side effects of deep brain stimulation (DBS) and whether these potential biomarkers have utility under general anesthesia.MethodsWe recorded scalp potentials elicited by DBS during surgery (n = 11), both awake and under general anesthesia, and in an independent ambulatory cohort (n = 8). Across a range of stimulus configurations, we measured the amplitude and timing of short- and long-latency response components and linked them to motor side effects.ResultsRegardless of anesthesia state, in both cohorts, DBS settings with capsular side effects elicited early responses with peak latencies clustering at <1 ms. This early response was preserved under anesthesia in all participants (11/11). In contrast, the long-latency components were suppressed completely in 6/11 participants. Finally, the latency of the earliest response could predict the presence of postoperative motor side effects both awake and under general anesthesia (84.8% and 75.8% accuracy, awake and under anesthesia, respectively).ConclusionDBS elicits short-latency cortical activation, both awake and under general anesthesia, which appears to reveal interactions between the stimulus and the corticospinal tract.SignificanceShort-latency evoked cortical activity can potentially be used to aid both DBS lead placement and post-operative programming.     

Cyclic versus continuous deep brain stimulation in patients with obsessive compulsive disorder: A randomized controlled trial

BackgroundDeep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD), but patients typically require high stimulation voltages and DBS comes with a risk for adverse events (AE).ObjectiveThe aim of the present study was to advance DBS for OCD by optimizing energy efficiency and minimize adverse events using a cyclic form of stimulationMethodsThis double blind, randomized crossover trial compares 2 weeks of continuous versus cyclic DBS (0.1 s ON, 0.2 s OFF) in 16 patients with OCD. We compared OCD symptoms (Yale-Brown Obsessive-Compulsive Scale, Y-BOCS), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), AEs, battery life, cognitive performance and quality of life.ResultsAverage Y-BOCS scores at baseline increased significantly with 5.5 points (p = 0.006) in the cyclic condition. Average HAM-D and HAM-A scores increased with 2.2 (p = 0.088) and 2.8 points (p = 0.018). The overall health scale of quality of life worsened during cyclic DBS (p = 0.044). Patients reported on average 3.3 AEs during continuous stimulation and 4.4 AEs during cyclic stimulation (p = 0.175), though stimulation-related AEs such as headache and concentration problems reduced during cyclic DBS. Battery usage during continuous DBS was 0.021 V per hour compared to 0.008 V per hour during cyclic DBS.ConclusionThough specific stimulation-related AEs improved, cyclic stimulation (0.1 s ON, 0.2 s OFF) comes with a high relapse risk in patients with DBS for OCD. Cyclic DBS is no alternative for standard DBS treatment, but applicable in case of debilitating AEs.     

Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: A prefrontal interleaved TMS fMRI study

BackgroundPrefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia.Objective/Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity.MethodsWe enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10 Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition.ResultsOf the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p = 0.0157; max z-score = 4.7) and neighboring BA46 (p = 0.019; max z-score = 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p = 0.02; max z-score = 3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p = 0.004).ConclusionsSubjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia.     

ALDH2 polymorphism,associated with attenuating negative symptoms in patients with schizophrenia treated with add-on dextromethorphan

ObjectiveIncreasing the evidence of inflammation's contribution to schizophrenia; using anti-inflammatory or neurotrophic therapeutic agents to see whether they improve schizophrenia treatment. Dextromethorphan (DM), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, might protect monoamine neurons. Whether treating schizophrenia with risperidone plus add-on DM is more effective than risperidone (RISP) alone, and the association between the ALDH2 polymorphism and treatment response were investigated.MethodsA double-blind study in which patients with schizophrenia were randomly assigned to the RISP + DM (60 mg/day; n = 74) or the RISP + Placebo (n = 75) group. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) scores were used to evaluate clinical response during weeks 0, 1, 2, 4, 6, 8, and 11. The genotypes of the ALDH2 polymorphism were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A generalized estimating equation was used to analyze the effects of ALDH2 polymorphism on the clinical performance of DM.ResultsPANSS and SANS scores were significantly lower in both groups after 11 weeks of treatment. SANS total scores were significantly lower in the RISP + DM group in patients with the ALDH2*2*2 genotype.ConclusionsRISP plus add-on DM treatment reduced negative schizophrenia symptoms in patients with the ALDH2 polymorphism.     

Correspondence of optimal stimulation and beta power varies regionally in STN DBS for Parkinson disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) for Parkinson disease (PD) normalizes neuronal hypersynchrony in the beta frequency range (13–30 Hz). The spatial correspondence of maximal beta power to the site of optimal stimulation along the DBS lead trajectory has been debated.MethodsWe determined the trajectory locations of the active contact, maximal beta power, and the dorsal border of the STN (DB-STN) in DBS patients. Beta power profiles were measured during intraoperative microelectrode recording (MER). Active contact locations were assigned during blinded, postoperative DBS programming. The DB-STN was identified both electrophysiologically during MER and anatomically on MRI. After grouping DBS trajectories into quadrants relative to the anatomic STN midpoint, we examined regional variations in the relative trajectory locations of the three entities.ResultsSTN DBS significantly improved motor performance for all 13 DBS patients, with active contacts at the DB-STN. Along trajectories passing posterior-medial to the STN midpoint, maximal beta power co-localized with active contacts at the DB-STN (difference Δ = 0.4 ± 1.6 mm, p = 0.57). By contrast, in posterior-lateral trajectories, maximal beta arose within the STN, ventral to active contacts (Δ = 1.9 ± 1.3 mm, p = 0.002). For trajectories anterior to the STN midpoint, maximal beta power co-localized with the DB-STN, while active contacts were ventral to peak beta power (p = 0.05).ConclusionOur findings indicate that co-localization of optimal stimulation and beta power varies by anatomical region in STN DBS for Parkinson disease.     

Identification of Deep Brain Stimulation Targets for Neuropathic Pain After Spinal Cord Injury Using Localized Increases in White Matter Fiber Cross Section

ObjectivesThe spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence-based approach to DBS target identification.Materials and MethodsTo classify localized neurostructural changes associated with NP in the SCI population, we compared white matter fiber density (FD) and cross section (FC) between SCI subjects with NP (n = 17) and SCI subjects without NP (n = 15) using diffusion-weighted magnetic resonance imaging (MRI). We then identified theoretical target locations for DBS using fiber bundles connected to significantly altered regions of white matter. Finally, we used computational models of DBS to determine if our theoretical target locations could be used to feasibly activate our fiber bundles of interest.ResultsWe identified significant increases in FC in the splenium of the corpus callosum in pain subjects when compared to controls. We then isolated five fiber bundles that were directly connected to the affected region of white matter. Our models were able to predict that our fiber bundles of interest can be feasibly activated with DBS at reasonable stimulation amplitudes and with clinically relevant implantation approaches.ConclusionsAltogether, we identified neuroarchitectural changes associated with NP in the SCI cohort and implemented a novel evidence-driven target selection approach for DBS to guide future research in neuromodulation treatment of NP after SCI.     

Longitudinal Impedance Variability in Patients with Chronically Implanted DBS Devices

BackgroundDeep brain stimulation (DBS) is an effective therapy for advanced movement disorders, but its optimal use is still controversial. One factor that could play a role in the proper delivery of therapeutic stimulation by current DBS devices is the variability of the impedance at the interface between the electrode surface and surrounding tissue.ObjectiveTo analyze variability and trends in the impedance of chronically-implanted DBS electrodes in subjects with movement disorders.MethodsWe reviewed impedance values from medical records of DBS patients at an academic tertiary-care movement disorders center. The standard deviation of data recorded within individual subjects and single contacts were used as measures of longitudinal impedance variability. A generalized linear mixed model (GLMM) determined if a number of effects had significant influences on impedance.ResultsWe analyzed 2863 impedance measurements from 94 subjects. Median variability, for subjects with follow-up from 6 months to 5 years (n = 77), was 194 Ω for individual subjects and 141 Ω for individual contacts, with a range spanning from 18 to over 600 Ω. The GLMM, incorporating all subjects (n = 94), identified time, electrical activity, implanted target, contact position on the electrode and side of implantation as significant predictors of impedance. Age and disease duration at surgery, gender or ethnicity were not significant predictors.ConclusionsOur analysis suggests that a significant amount of impedance variability can be expected in chronically implanted DBS electrodes and indicates a number of factors with possible predictive value. Further studies are needed to link impedance characteristics to clinical outcomes.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Use of a Pericranial Flap Technique for Deep Brain Stimulation Hardware Protection and Improved Cosmesis

ObjectivesDeep brain stimulation (DBS) has become an established neuromodulation therapy; however, surgical site complications such as hardware skin erosion remain an important risk and can predispose to infection, requiring explantation of the system. Nuances of surgical technique can affect wound healing, cosmetic outcome, comfort, and risk of infection. In this study, we describe our experience with a layered closure technique using a vascularized pericranial flap for improving cosmesis and protection of the implanted hardware against skin erosion and infection.Materials and MethodsWe retrospectively reviewed 636 individuals (746 lead implantations) who underwent DBS surgery by a single academic neurosurgeon between 2001 and 2020. A layered pericranial flap closure technique for the burr-hole and connector sites was instituted in 2015. We assessed the effects of a multimodal infection prevention approach that included the pericranial flap on hardware complication rates compared with the premultimodality cohort, and we report the nuances of the technique.ResultsIn our institutional experience, we found that implementation of a pericranial flap closure technique can enhance the subjective cosmetic result at the burr-hole cover site and increase patient comfort and satisfaction. In addition, we found a decrease in hardware infection rates in the current cohort with a multimodal infection prevention regimen that includes the pericranial-flap technique (n = 256, 2015–2020 period) to 1.2% (p = 0.006), from 6.9% in the earlier cohort (n = 490, 2001–2015 period).ConclusionsThe report highlights the potential of a pericranial-flap closure technique as a surgical adjunct to improve DBS surgical site healing and cosmesis and may, as part of a multimodal strategy, contribute to decreased risk of skin breakdown and hardware infection.     

Flexible vs. standard subthalamic stimulation in Parkinson disease: A double-blind proof-of-concept cross-over trial

BackgroundDeep brain stimulation (DBS) of the subthalamus (STN) is effective for the treatment of cardinal motor signs of Parkinson disease (PD). Structures around the STN can suppress dyskinesia and tremor (zona incerta) and improve gait and balance (substantia nigra pars reticulata).ObjectiveIs the newer 8-contact linear lead connected to a ‘flexible’ DBS system superior to standard 4-contact stimulation in PD patients receiving STN DBS?MethodsAfter 3 months of open label programming, 10 patients were randomized to standard or flexible stimulation before crossing over to the other arm (3 months each period). Patients and assessors were blinded.ResultsA trend to improvement in Patient Global Impression of Change scores was seen with standard to flexible stimulation and worsening from flexible to standard stimulation (mean ± SD: 0.7 ± 1.2 and −0.4 ± 1.5 respectively, p = 0.152). There was a significant reduction in the number of troublesome symptoms reported prior to DBS (2.6 ± 3.3 per patient), more so with flexible stimulation (0.4 ± 0.6 vs. 1.5 ± 1.6 with standard stimulation, p = 0.001 and p = 0.034). There was no significant difference between the flexible and standard stimulation groups.ConclusionFurther studies confirming that flexible stimulation is superior to standard DBS are warranted.     

Brief intermittent access to sucrose differentially modulates prepulse inhibition and acoustic startle response in obese CCK-1 receptor deficient rats

Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack the CCK-1 receptor and are hyperphagic and obese. CCK-1 receptors play a role in prepulse inhibition (PPI) by modulating mesolimbic dopamine transmission, a modulator of sensorimotor gating. Therefore, the present study assessed the effects of brief, daily sucrose access on PPI and acoustic startle response (ASR) in OLETF rat and age-matched non-mutant Long-Evans Tokushima Otsuka (LETO) rats. The results revealed that OLETF rats with sucrose access showed an increased ASR [F(1,16) = 6.84; P < 0.01)], relative to sucrose receiving LETO rats. No significant sucrose effect (P = 0.283) on PPI was noted in OLETF rats, whereas sucrose receiving LETO rats had a significantly lower (P < 0.05) PPI percentage than non-sucrose controls. In contrast, sucrose-receiving OLETF rats expressed significantly higher PPI percentage than LETO rats with identical sucrose presentation (P < 0.01). Taken together, these results suggest that sucrose access alters PPI and ASR in general, and the CCK-1 receptors play a modulatory role in facilitating or inhibiting these responses, respectively. A similar effect may be contributory to the hyperphagic behavioral phenotype of obese animal models with altered central dopamine regulation.     

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Facial Affect Recognition in Schizophrenia

ObjectiveFacial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia.MethodInpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions.ResultsFacial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohen's d = 1.45). There was no correlation with clinical improvement.ConclusionOur results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.     

fMRI of Deep Brain Stimulation at the Rat Ventral Posteromedial Thalamus

BackgroundFunctional magnetic resonance imaging (fMRI) of deep brain stimulation (DBS) has potentials to reveal neuroanatomical connectivity of a specific brain region in vivo.ObjectiveThis study aimed to demonstrate frequency and amplitude tunings of the thalamocortical tract using DBS fMRI at the rat ventral posteromedial thalamus.MethodsBlood oxygenation level dependent (BOLD) fMRI data were acquired in a total of twelve rats at a high-field 11.7 T MRI scanner with modulation of nine stimulus frequencies (1–40 Hz) and seven stimulus amplitudes (0.2–3.6 mA).ResultsBOLD response in the barrel cortex peaked at 25 Hz. The response increased with stimulus amplitude and reached a plateau at 1 mA. Cortical spreading depolarization (CSD) was observed occasionally after DBS that carries >10% BOLD waves spanning the entire ipsilateral cortex.ConclusionfMRI is sensitive to the frequency effect of DBS and has potential to investigate the function of a particular neuroanatomical pathway.