Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex.

Background: In children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. Methods: Hearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). Results: In the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p < 0.05). Deafened rats showed significantly more play fighting during development (p < 0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p > 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p < 0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p < 0.05). Conclusions: Hearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near-normal hearing.

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation-inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism-like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high-spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation-inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high-spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.

Subthalamic Nucleus Deep Brain Stimulation Restores Motor and Sensorimotor Cortical Neuronal Oscillatory Activity in the Free-Moving 6-Hydroxydopamine Lesion Rat Parkinson Model.

OBJECTIVES: Enhanced beta oscillations in cortical-basal ganglia (BG) thalamic circuitries have been linked to clinical symptoms of Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces beta band activity in BG regions, whereas little is known about activity in cortical regions. In this study, we investigated the effect of STN DBS on the spectral power of oscillatory activity in the motor cortex (MCtx) and sensorimotor cortex (SMCtx) by recording via an electrocorticogram (ECoG) array in free-moving 6-hydroxydopamine (6-OHDA) lesioned rats and sham-lesioned controls. MATERIALS AND METHODS: Male Sprague-Dawley rats (250-350 g) were injected either with 6-OHDA or with saline in the right medial forebrain bundle, under general anesthesia. A stimulation electrode was then implanted in the ipsilateral STN, and an ECoG array was placed subdurally above the MCtx and SMCtx areas. Six days after the second surgery, the free-moving rats were individually recorded in three conditions: 1) basal activity, 2) during STN DBS, and 3) directly after STN DBS. RESULTS: In 6-OHDA-lesioned rats (N = 8), the relative power of theta band activity was reduced, whereas activity of broad-range beta band (12-30 Hz) along with two different subbeta bands, that is, low (12-30 Hz) and high (20-30 Hz) beta band and gamma band, was higher in MCtx and SMCtx than in sham-lesioned controls (N = 7). This was, to some extent, reverted toward control level by STN DBS during and after stimulation. No major differences were found between contacts of the electrode grid or between MCtx and SMCtx. CONCLUSION: Loss of nigrostriatal dopamine leads to abnormal oscillatory activity in both MCtx and SMCtx, which is compensated by STN stimulation, suggesting that parkinsonism-related oscillations in the cortex and BG are linked through their anatomic connections.

Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma.

PURPOSE: Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell-associated polySia on glioblastoma outcome. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16-positive or Siglec-16-negative macrophages, and by exposing Siglec-16-positive or Siglec-16-negative macrophages to glioblastoma cell-derived membrane fractions. RESULTS: Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16-expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell-derived membranes. CONCLUSIONS: Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.

Severity Assessment of Complex and Repeated Intracranial Surgery in Rats.

INTRODUCTION: Evidence-based grading of the impact of intracranial surgery on rat's well-being is important for ethical and legal reasons. We assessed the severity of complex and repeated intracranial surgery in a 6-hydroxydopamine (6-OHDA) Parkinson's rat model with subsequent intracranial electrode implantation and in an intracranial tumor model with subsequent resection. METHODS: Stereotactic surgery was performed in adult male rats with the same general anesthesia and perioperative pain management. In Parkinson's model, Sprague Dawley rats received unilateral injection of 6-OHDA (n = 11) or vehicle (n = 7) into the medial forebrain bundle as first operation (1st OP). After four weeks, neural electrodes were implanted in all rats as second operation (2nd OP). For tumor formation, BDIX/UlmHanZtm rats (n = 8) received frontocortical injection of BT4Ca cells as 1st OP, followed by tumor resection as 2nd OP after one week. Multiple measures severity assessment was done two days before and four days after surgery in all rats, comprising clinical scoring, body weight, and detailed behavioral screening. To include a condition with a known burden, rats with intracranial tumors were additionally assessed up to a predefined humane endpoint that has previously been classified as "moderate". RESULTS: After the 1st OP, only 6-OHDA injection resulted in transient elevated clinical scores, a mild long-lasting weight reduction, and motor disturbances. After the second surgery, body weight was transiently reduced in all groups. All other parameters showed variable results. Principal component analysis showed a separation from the preoperative state driven by motor-related parameters after 6-OHDA injection, while separation after electrode implantation and more clearly after tumor resection was driven by pain-related parameters, although not reaching the level of the humane endpoint of our tumor model. CONCLUSION: Overall, cranial surgery of different complexity only transiently and rather mildly affects rat's well-being. Multiple measures assessment allows the differentiation of model-related motor disturbances in Parkinson's model from potentially pain-related conditions after tumor resection and electrode implantation.

Processing of auditory information in forebrain regions after hearing loss in adulthood: Behavioral and electrophysiological studies in a rat model.

Background: Hearing loss was proposed as a factor affecting development of cognitive impairment in elderly. Deficits cannot be explained primarily by dysfunctional neuronal networks within the central auditory system. We here tested the impact of hearing loss in adult rats on motor, social, and cognitive function. Furthermore, potential changes in the neuronal activity in the medial prefrontal cortex (mPFC) and the inferior colliculus (IC) were evaluated. Materials and methods: In adult male Sprague Dawley rats hearing loss was induced under general anesthesia with intracochlear injection of neomycin. Sham-operated and naive rats served as controls. Postsurgical acoustically evoked auditory brainstem response (ABR)-measurements verified hearing loss after intracochlear neomycin-injection, respectively, intact hearing in sham-operated and naive controls. In intervals of 8 weeks and up to 12 months after surgery rats were tested for locomotor activity (open field) and coordination (Rotarod), for social interaction and preference, and for learning and memory (4-arms baited 8-arms radial maze test). In a final setting, electrophysiological recordings were performed in the mPFC and the IC. Results: Locomotor activity did not differ between deaf and control rats, whereas motor coordination on the Rotarod was disturbed in deaf rats (P < 0.05). Learning the concept of the radial maze test was initially disturbed in deaf rats (P < 0.05), whereas retesting every 8 weeks did not show long-term memory deficits. Social interaction and preference was also not affected by hearing loss. Final electrophysiological recordings in anesthetized rats revealed reduced firing rates, enhanced irregular firing, and reduced oscillatory theta band activity (4-8 Hz) in the mPFC of deaf rats as compared to controls (P < 0.05). In the IC, reduced oscillatory theta (4-8 Hz) and gamma (30-100 Hz) band activity was found in deaf rats (P < 0.05). Conclusion: Minor and transient behavioral deficits do not confirm direct impact of long-term hearing loss on cognitive function in rats. However, the altered neuronal activities in the mPFC and IC after hearing loss indicate effects on neuronal networks in and outside the central auditory system with potential consequences on cognitive function.

Mechanical Stability of Nano-Coatings on Clinically Applicable Electrodes, Generated by Electrophoretic Deposition.

The mechanical stability of implant coatings is crucial for medical approval and transfer to clinical applications. Here, electrophoretic deposition (EPD) is a versatile coating technique, previously shown to cause significant post-surgery impedance reduction of brain stimulation platinum electrodes. However, the mechanical stability of the resulting coating has been rarely systematically investigated. In this work, pulsed-DC EPD of laser-generated platinum nanoparticles (PtNPs) on Pt-based, 3D neural electrodes is performed and the in vitro mechanical stability is examined using agarose gel, adhesive tape, and ultrasonication-based stress tests. EPD-generated coatings are highly stable inside simulated brain environments represented by agarose gel tests as well as after in vivo stimulation experiments. Electrochemical stability of the NP-modified surfaces is tested via cyclic voltammetry and that multiple scans may improve coating stability could be verified, indicated by higher signal stability following highly invasive adhesive tape stress tests. The brain sections post neural stimulation in rats are analyzed via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Measurements reveal higher levels of Pt near the region stimulated with coated electrodes, in comparison to uncoated controls. Even though local concentrations in the vicinity of the implanted electrode are elevated, the total Pt mass found is below systemic toxicologically relevant concentrations.

Burrowing behaviour of rats: Strain differences and applicability as well-being parameter after intracranial surgery.

In mice, burrowing is considered a species-typical parameter for assessing well-being, while this is less clear in rats. This exploratory study evaluated burrowing behaviour in three rat strains during training and in the direct postoperative phase after complex intracranial surgery in different neuroscience rat models established at Hannover Medical School or Aachen University Hospital. Male Crl:CD (SD; n = 18), BDIX/UlmHanZtm (BDIX; n = 8) and RjHan:WI (Wistar; n = 35) rats were individually trained to burrow gravel out of a tube on four consecutive days. Thereafter, BDIX rats were subjected to intracranial injection of BT4Ca cells and tumour resection (rat glioma model), SD rats to injection of 6-hydroxydopamine (6-OHDA) or vehicle (rat Parkinson's disease model) and Wistar rats to endovascular perforation or sham surgery (rat subarachnoid haemorrhage (SAH) model). Burrowing was retested on the day after surgery. During training, BDIX rats burrowed large amounts (mean of 2370 g on the fourth day), while SD and Wistar rats burrowed less gravel (means of 846 and 520 g, respectively). Burrowing increased significantly during training only in Wistar rats. Complex surgery, that is, tumour resection (BDIX), 6-OHDA injection (SD) and endovascular perforation or sham surgery for SAH (Wistar) significantly reduced burrowing and body weight, while simple stereotactic injection of tumour cells or vehicle did not affect burrowing. Despite the training, burrowing differed between the strains. In the direct postoperative phase, burrowing was reduced after complex surgery, indicating reduced well-being. Reduced burrowing was accompanied with postoperative weight loss, a validated and recognised quantitative measure for severity assessment.

Compromised mammillary body connectivity and psychotic symptoms in mice with di- and mesencephalic ablation of ST8SIA2.

Altered long-range connectivity is a common finding across neurodevelopmental psychiatric disorders, but causes and consequences are not well understood. Genetic variation in ST8SIA2 has been associated with schizophrenia, autism, and bipolar disorder, and St8sia2-/- mice show a number of related neurodevelopmental and behavioral phenotypes. In the present study, we use conditional knockout (cKO) to dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency in cortical interneurons, their cortical environment, or in the di- and mesencephalon. Neither separate nor combined cortical and diencephalic ablation of St8sia2 caused the disturbed thalamus-cortex connectivity observed in St8sia2-/- mice. However, cortical ablation reproduced hypoplasia of corpus callosum and fornix and mice with di- and mesencephalic ablation displayed smaller mammillary bodies with a prominent loss of parvalbumin-positive projection neurons and size reductions of the mammillothalamic tract. In addition, the mammillotegmental tract and the mammillary peduncle, forming the reciprocal connections between mammillary bodies and Gudden's tegmental nuclei, as well as the size of Gudden's ventral tegmental nucleus were affected. Only mice with these mammillary deficits displayed enhanced MK-801-induced locomotor activity, exacerbated impairment of prepulse inhibition in response to apomorphine, and hypoanxiety in the elevated plus maze. We therefore propose that compromised mammillary body connectivity, independent from hippocampal input, leads to these psychotic-like responses of St8sia2-deficient mice.

Diagnostic options for blunt abdominal trauma.

PURPOSE: Physical examination, laboratory tests, ultrasound, conventional radiography, multislice computed tomography (MSCT), and diagnostic laparoscopy are used for diagnosing blunt abdominal trauma. In this article, we investigate and evaluate the usefulness and limitations of various diagnostic modalities on the basis of a comprehensive review of the literature. METHODS: We searched commonly used databases in order to obtain information about the aforementioned diagnostic modalities. Relevant articles were included in the literature review. On the basis of the results of our comprehensive analysis of the literature and a current case, we offer a diagnostic algorithm. RESULTS: A total of 86 studies were included in the review. Ecchymosis of the abdominal wall (seat belt sign) is a clinical sign that has a high predictive value. Laboratory values such as those for haematocrit, haemoglobin, base excess or deficit, and international normalised ratio (INR) are prognostic parameters that are useful in guiding therapy. Extended focused assessment with sonography for trauma (eFAST) has become a well established component of the trauma room algorithm but is of limited usefulness in the diagnosis of blunt abdominal trauma. Compared with all other diagnostic modalities, MSCT has the highest sensitivity and specificity. Diagnostic laparoscopy is an invasive technique that may also serve as a therapeutic tool and is particularly suited for haemodynamically stable patients with suspected hollow viscus injuries. CONCLUSIONS: MSCT is the gold standard diagnostic modality for blunt abdominal trauma because of its high sensitivity and specificity in detecting relevant intra-abdominal injuries. In many cases, however, clinical, laboratory and imaging findings must be interpreted jointly for an adequate evaluation of a patient's injuries and for treatment planning since these data supplement and complement one another. Patients with blunt abdominal trauma should be admitted for clinical observation over a minimum period of 24 h since there is no investigation that can reliably rule out intra-abdominal injuries.

Epidemiological and Therapeutic Developments in Pelvic Ring Fractures Type C from 2004 to 2014 - a Retrospective Data Analysis of 2,042 Patients in the German Pelvic Register (DGU). / Epidemiologische und therapeutische Entwicklungen bei Beckenringfrakturen Typ C der Jahre 2004 bis 2014 ­ eine retrospektive Datenauswertung über 2042 Patienten des Deutschen Beckenregisters (DGU).

BACKGROUND: Pelvic ring fractures type C present a special challenge due to their high instability, the possible accompanying injuries and the high mortality rate of up to 18.9%. The aim of this retrospective analysis was to use the data from the DGU pelvic register to identify changes in the epidemiology and therapy for type C pelvic ring fractures between 2004 and 2014. MATERIALS AND METHODS: 2,042 patients with type C pelvic ring injury were retrospectively included. Three time periods with roughly equal patient groups were specified and differences in epidemiology and the type of therapy were evaluated. For the surgical cases, the time of the operation, the duration of the operation, blood loss, the location of the fracture and the type of osteosynthesis were evaluated and the reduction result was recorded. RESULTS: For the period under review, there is an age shift in the incidence of a type C pelvic ring fracture towards older age. The isolated pelvic injury has increased, while the proportion of pelvic injuries in the context of polytrauma has steadily decreased. Complications and mortality decreased as a percentage. The tendency towards minimally invasive procedures could be shown in the surgical care. Navigated procedures in the area of the pelvic ring have so far not proven successful. CONCLUSIONS: We were able to show that the majority of the patients are increasingly old, that there is no relevant trauma in the history and that there is an increase in the isolated pelvic fracture type C and a decrease in the number of polytraumatised or multiply injured patients. In conjunction with mortality from pelvic ring injuries, the successes of standardised, pelvic-specific emergency management, an adapted time of operation outside the vulnerable phase and stable osteosynthesis care, which enable early functional follow-up treatment, are also evident.

Predictive accuracy of CNN for cortical oscillatory activity in an acute rat model of parkinsonism.

In neurological and neuropsychiatric disorders neuronal oscillatory activity between basal ganglia and cortical circuits are altered, which may be useful as biomarker for adaptive deep brain stimulation. We investigated whether changes in the spectral power of oscillatory activity in the motor cortex (MCtx) and the sensorimotor cortex (SMCtx) of rats after injection of the dopamine (DA) receptor antagonist haloperidol (HALO) would be similar to those observed in Parkinson disease. Thereafter, we tested whether a convolutional neural network (CNN) model would identify brain signal alterations in this acute model of parkinsonism. A sixteen channel surface micro-electrocorticogram (ECoG) recording array was placed under the dura above the MCtx and SMCtx areas of one hemisphere under general anaesthesia in rats. Seven days after surgery, micro ECoG was recorded in individual free moving rats in three conditions: (1) basal activity, (2) after injection of HALO (0.5 mg/kg), and (3) with additional injection of apomorphine (APO) (1 mg/kg). Furthermore, a CNN-based classification consisting of 23,530 parameters was applied on the raw data. HALO injection decreased oscillatory theta band activity (4-8 Hz) and enhanced beta (12-30 Hz) and gamma (30-100 Hz) in MCtx and SMCtx, which was compensated after APO injection (P ¡ 0.001). Evaluation of classification performance of the CNN model provided accuracy of 92%, sensitivity of 90% and specificity of 93% on one-dimensional signals. The CNN proposed model requires a minimum of sensory hardware and may be integrated into future research on therapeutic devices for Parkinson disease, such as adaptive closed loop stimulation, thus contributing to more efficient way of treatment.

Comparing Direct and Pulsed-Direct Current Electrophoretic Deposition on Neural Electrodes: Deposition Mechanism and Functional Influence.

Electrophoretic deposition (EPD) of platinum nanoparticles (PtNPs) on platinum-iridium (Pt-Ir) neural electrode surfaces is a promising strategy to tune the impedance of electrodes implanted for deep brain stimulation in various neurological disorders such as advanced Parkinson's disease and dystonia. However, previous results are contradicting as impedance reduction was observed on flat samples while in three-dimensional (3D) structures, an increase in impedance was observed. Hence, defined correlations between coating properties and impedance are to date not fully understood. In this work, the influence of direct current (DC) and pulsed-DC electric fields on NP deposition is systematically compared and clear correlations between surface coating homogeneity and in vitro impedance are established. The ligand-free NPs were synthesized via pulsed laser processing in liquid, yielding monomodal particle size distributions, verified by analytical disk centrifugation (ADC). Deposits formed were quantified by UV-vis supernatant analysis and further characterized by scanning electron microscopy (SEM) with semiautomated interparticle distance analyses. Our findings reveal that pulsed-DC electric fields yield more ordered surface coatings with a lower abundance of particle assemblates, while DC fields produce coatings with more pronounced aggregation. Impedance measurements further highlight that impedance of the corresponding electrodes is significantly reduced in the case of more ordered coatings realized by pulsed-DC depositions. We attribute this phenomenon to the higher active surface area of the adsorbed NPs in homogeneous coatings and the reduced particle-electrode electrical contact in NP assemblates. These results provide insight for the efficient EPD of bare metal NPs on micron-sized surfaces for biomedical applications in neuroscience and correlate coating homogeneity with in vitro functionality.

Epigenetic Regulation of Neural Transmission after Cerebellar Fastigial Nucleus Lesions in Juvenile Rats.

Structural and functional abnormalities in the cerebellar midline region, including the fastigial nucleus, have been reported in neuropsychiatric disorders, also comprising the cerebellar cognitive affecting syndrome. In rats, early fastigial lesions reduce social interaction during development and lead to cognitive and emotional deficits in adults, accompanied by compromised neuronal network activity. Since epigenetic mechanisms are implicated in the etiology of neuropsychiatric disorders, we investigated whether fastigial nucleus lesions in juvenile rats would impact epigenetic regulation of neural transmission. The fastigial nucleus was lesioned bilaterally in 23-day-old male rats. Sham-lesion and naïve rats served as controls. DNA methylation was investigated for target genes of the GABAergic, dopaminergic, glutamatergic and oxytocinergic systems in brain regions with anatomic connections to the fastigial nucleus, i.e., medial prefrontal cortex, nucleus accumbens, striatum, thalamus, and sensorimotor cortex. Protein expression was examined for the respective target genes in case of altered DNA methylation between lesion and control groups. Lesioning of the fastigial nucleus led to significant differences in the epigenetic regulation of glutamate decarboxylase 1 and the oxytocin receptor in the nucleus accumbens and the prefrontal cortex. No differences were found for the other target genes and brain regions. Our findings indicate that epigenetic dysregulation after lesioning of the fastigial nucleus may influence long-term recovery and the emergence of behavioral changes. Together with previous behavioral and electrophysiological investigations of this rat model, these observations can play a role in the cerebellar cognitive affective syndrome and other neuropsychiatric disorders.

Oscillatory activity in the BNST/ALIC and the frontal cortex in OCD: acute effects of DBS.

Deep brain stimulation (DBS) of the bed nucleus of the stria terminalis/anterior limb of the internal capsule (BNST/ALIC) is successfully used for treatment of patients with obsessive-compulsive disorder (OCD). Clinical and experimental studies have suggested that enhanced network synchronization in the theta band is correlated with severity of symptoms. The mechanisms of action of DBS remain unclear in OCD. We here investigate the effect of acute stimulation of the BNCT/ALIC on oscillatory neuronal activity in patients with OCD implanted with DBS electrodes. We recorded the oscillatory activity of local field potentials (LFPs) from DBS electrodes (contact + 0/- 3; bipolar configuration; both hemispheres) from the BNST/ALIC parallel with frontal cortical electroencephalogram (EEG) one day after DBS surgery in four patients with OCD. BNST/ALIC and frontal EEG oscillatory activities were analysed before stimulation as baseline, and after three periods of stimulation with different voltage amplitudes (1 V, 2 V and 3.5 V) at 130 Hz. Overall, acute high frequency DBS reduced oscillatory theta band (4-8 Hz; p < 0.01) but increased other frequency bands in BNST/ALIC and the frontal cortex (p < 0.01). We show that stimulation of the BNST/ALIC in OCD modulates oscillatory activity in brain regions that are involved in the pathomechanisms of OCD. Our findings confirm and extend the findings that enhanced theta oscillatory activity in neuronal networks may be a biomarker for OCD.

Long-Term Deep Brain Stimulation in Treatment-Resistant Obsessive-Compulsive Disorder: Outcome and Quality of Life at Four to Eight Years Follow-Up.

BACKGROUND: Obsessive compulsive disorder (OCD) is a severe disabling disease, and around 10% of patients are considered to be treatment-resistant (tr) in spite of guideline-based therapy. Deep brain stimulation (DBS) has been proposed as a promising treatment for patients with trOCD. However, the optimal site for stimulation is still a matter of debate, and clinical long-term follow-up observations including data on quality of life are sparse. We here present six trOCD patients who underwent DBS with electrodes placed in the bed nucleus of the stria terminalis/anterior limb of the internal capsule (BNST/ALIC), followed for four to eight years after lead implantation. MATERIALS AND METHODS: In this prospective observational study, six patients (four men, two women) aged 32-51 years and suffering from severe to extreme trOCD underwent DBS of the BNST/ALIC. Symptom severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and quality of life using the World Health Organization Quality of Life assessment scale (WHO-QoL BREF). Follow-up was obtained at least for four years in all patients. RESULTS: With chronic DBS for four to eight years, four of the six patients had sustained improvement. Two patients remitted and two patients responded (defined as >35% symptom reduction), while the other two patients were considered nonresponders on long-term. Quality of life markedly improved in remitters and responders. We did not observe peri-interventional side effects or adverse effects of chronic stimulation. CONCLUSIONS: Chronic DBS of ALIC provides long-term benefit up to four to eight years in trOCD, although not all patients take profit. Targeting the BNST was not particularly relevant since no patient appeared to benefit from direct stimulation of the BNST. Quality of life improved in DBS responders, documented by improved QoL scores and, even more important, by regaining of autonomy and improving psychosocial functioning.

Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition.

Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital deafness or autism) or are dysfunctional (possibly after sudden, stressful auditory trauma or age-dependent hearing loss linked with cognitive decline). Fast auditory processing deficits can occur despite maintained basal hearing. In that case, tonic inhibitory strength is reduced in ascending auditory nuclei, and fast inhibitory parvalbumin positive interneuron (PV-IN) dendrites are diminished in auditory and frontal brain regions. This leads to deficits in central neural gain control linked to hippocampal LTP/LTD deficiencies, cognitive deficits, and unbalanced extra-hypothalamic stress control. Under these conditions, a diminished inhibitory strength may weaken local neuronal coupling to homeostatic vascular responses required for the metabolic support of auditory adjustment processes. We emphasize the need to distinguish these two states of excitatory/inhibitory imbalance in hearing disorders: (i) Under conditions of preserved fast auditory processing and sustained tonic inhibitory strength, an excitatory/inhibitory imbalance following auditory deprivation can maintain precise hearing through a memory linked, transient disinhibition that leads to enhanced spiking fidelity (central neural gain⇑) (ii) Under conditions of critically diminished fast auditory processing and reduced tonic inhibitory strength, hyperexcitability can be part of an increased synchronization over a broader frequency range, linked to reduced spiking reliability (central neural gain⇓). This latter stage mutually reinforces diminished metabolic support for auditory adjustment processes, increasing the risks for canonical dementia syndromes.

The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous γ oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

Lesion of the Fastigial Nucleus in Juvenile Rats Deteriorates Rat Behavior in Adulthood, Accompanied by Altered Neuronal Activity in the Medial Prefrontal Cortex.

The cerebellar cognitive affective syndrome may result from various cerebellar injuries. Although it is not exactly known which anatomical structures are involved, the fastigial nucleus has been thought to play a pivotal role according to recent studies. Here we investigate whether bilateral fastigial nucleus lesions in juvenile rats affect cognitive-associative and limbic related functions in adulthood. Furthermore, potential effects on the neuronal activity in the medial prefrontal cortex (mPFC) and local field coherence with the sensorimotor cortex (SMCtx) were evaluated. The fastigial nucleus was lesioned bilaterally by thermocoagulation via stereotaxically inserted electrodes in 23-day old male Sprague Dawley rats. Naïve and sham-lesioned rats (electrodes inserted above the nucleus and no electrical current applied) served as controls. As adults, all groups were tested for cognitive-associative function, social behavior, and anxiety. Thereafter, electrophysiological recordings were obtained under urethane anesthesia. Finally, lesions and recording sites were histologically verified. Spatial learning in a radial maze test and learning in an operant learning paradigm was disturbed in rats with fastigial lesions. Furthermore, in the elevated plus maze anxiety was enhanced, whereas social behavior was not affected. Electrophysiological recordings showed enhanced local field coherence between mPFC and SMCtx across all frequency bands. Impaired cognitive and affective functions together with enhanced coherence between mPFC and SMCtx after bilateral fastigial nucleus lesions indicate that the fastigial nucleus contribute to the development of the cerebellar cognitive affective syndrome and associated motor behavior.