Consequences of vestibular hypofunction in children with ADHD/DCD.

BACKGROUND: Children with Attention Deficit Hyperactivity Disorder (ADHD) demonstrate a heterogeneous sensorimotor, emotional, and cognitive profile. Comorbid sensorimotor imbalance, anxiety, and spatial disorientation are particularly prevalent among their non-core symptoms. Studies in other populations presented these three comorbid dysfunctions in the context of vestibular hypofunction. OBJECTIVE: To test whether there is a subgroup of children with ADHD who have vestibular hypofunction presenting with concomitant imbalance, anxiety, and spatial disorientation. METHODS: Children with ADHD-only (n = 28), ADHD + Developmental Coordination Disorder (ADHD + DCD; n = 38), and Typical Development (TD; n = 19) were evaluated for vestibular function by the Dynamic Visual Acuity test (DVA-t), balance by the Bruininks-Oseretsky Test of motor proficiency (BOT-2), panic anxiety by the Screen for Child Anxiety Related Emotional Disorders questionnaire-Child version (SCARED-C), and spatial navigation by the Triangular Completion test (TC-t). RESULTS: Children with ADHD vs. TD presented with a high rate of vestibular hypofunction (65 vs. 0 %), imbalance (42 vs. 0 %), panic anxiety (27 vs. 11 %), and spatial disorientation (30 vs. 5 %). Children with ADHD + DCD contributed more frequent and severe vestibular hypofunction and imbalance than children with ADHD-only (74 vs. 54 %; 58 vs. 21 %, respectively). A concomitant presence of imbalance, anxiety, and spatial disorientation was observed in 33 % of children with ADHD, all sharing vestibular hypofunction. CONCLUSIONS: Vestibular hypofunction may be the common pathophysiology of imbalance, anxiety, and spatial disorientation in children. These comorbidities are preferentially present in children with ADHD + DCD rather than ADHD-only, thus likely related to DCD rather than to ADHD disorder. Children with this profile may benefit from a vestibular rehabilitation intervention.

Functional impact of bilateral vestibular loss and the unexplained complaint of oscillopsia.

Introduction: The vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia. Methods: Participants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado-Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center. Results: Among the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test. Discussion: Even though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it.

The vestibular symptomatology of Machado-Joseph Disease.

BACKGROUND: Machado Joseph Disease (MJD) is an autosomal dominant neurodegenerative disease. In previous studies, we described significant bilateral horizontal Vestibulo-Ocular Reflex (VOR) deficit within this population without any reference to the presence of vestibular symptomatology. OBJECTIVE: To evaluate whether, beyond cerebellar ataxia complaints, MJD patients have typical vestibular symptomatology corresponding to the accepted diagnostic criteria of Bilateral Vestibulopathy (BVP) according to the definition of the International Barany Society of Neuro-Otology. METHODS: Twenty-one MJD, 12 clinically stable chronic Unilateral Vestibulopathy (UVP), 15 clinically stable chronic BVP, and 22 healthy Controls underwent the video Head Impulse Test (vHIT) evaluating VOR gain and filled out the following questionnaires related to vestibular symptomatology: The Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS) and the Beck Anxiety Inventory (BAI). RESULTS: The MJD group demonstrated significant bilateral vestibular impairment with horizontal gain less than 0.6 in 71% of patients (0.54±0.17). Similar to UVP and BVP, MJD patients reported a significantly higher level of symptoms than Controls in the DHI, ABC, VVS, and BAI questionnaires. CONCLUSIONS: MJD demonstrated significant VOR impairment and clinical symptoms typical of BVP. We suggest that in a future version of the International Classification of Vestibular Disorders (ICVD), MJD should be categorized under a separate section of central vestibulopathy with the heading of bilateral vestibulopathy. The present findings are of importance regarding the clinical diagnosis process and possible treatment based on vestibular rehabilitation.

[THE HIDDEN VESTIBULAR FEATURES OF MACHADO JOSEPH DISEASE (SPINOCEREBELLAR ATAXIA 3)].

INTRODUCTION: Machado-Joseph disease (MJD) is an inherited neurodegenerative disease with progressive cerebellar ataxia manifested through lack of coordination and balance. MJD patients also present significant Vestibulo-Ocular Reflex (VOR) deficit but their whole vestibular features have not been previously evaluated. We aimed to evaluate whether MJD patients have vestibular features fitting the diagnostic criteria of Bilateral Vestibulopathy established by the International Society for Neuro-otology. METHODS: Sixteen MJD patients and 21 healthy controls underwent a detailed clinical neuro-otological examination including a quantitative evaluation of the VOR gain using the video Head Impulse Test (vHIT). Vestibular-related symptoms were evaluated by the Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS). In addition, anxiety that is frequently present in vestibular disorders, was evaluated by the Beck Anxiety Inventory (BAI). RESULTS: MJD patients had significantly reduced horizontal VOR gain with significantly higher scores in all vestibular-related symptoms questionnaires. These symptoms scores were like those reported in studies evaluating patients with bilateral peripheral vestibular loss. CONCLUSIONS: Beyond the cerebellar deficits, MJD patients have vestibular signs and symptoms fitting the diagnostic criteria of Bilateral Vestibulopathy established by the International Society for Neuro-otology. These findings are of relevance not only for the diagnosis and evaluation of progressive cerebellar diseases but also for the possible beneficial effect of vestibular rehabilitation techniques on dizziness, balance and the emotional, physiological and functional aspects of MJD.

The overarching effects of vestibular deficit: Imbalance, anxiety, and spatial disorientation.

BACKGROUND: Comorbid Balance, Anxiety, and Spatial symptoms are observed in neurodevelopmental disorders and aging. Each of these symptoms was studied separately in association with vestibular hypofunction. We aimed to investigate whether such a diffuse range of symptoms has common vestibular pathophysiology. Specifically, we tested whether this Triad of dysfunctions is associated with central or peripheral vestibular hypofunction. We also assessed the possible contribution of semicircular canals (SCCs) vs. saccular function. METHODS: We tested patients with Peripheral bilateral and unilateral Vestibular Hypofunction (PVH), Machado Joseph Disease (MJD) with cerebellar and central bilateral vestibular hypofunction, and healthy controls. SCCs and sacculi functioning were evaluated by the video Head Impulse Test (vHIT) and cervical Vestibular Evoked Myogenic Potentials (cVEMP), respectively. Balance was assessed by the Activities-specific Balance Confidence scale (ABC), anxiety by the Hamilton Anxiety Rating Scale (HAM-A), and spatial orientation by the Object Perspective Taking test (OPT-t). RESULTS: PVH patients with vestibular SCCs and saccular hypofunction presented the Triad of symptoms, imbalance, anxiety, and spatial disorientation. MJD patients with SCCs-related vestibular hypofunction but preserved saccular-related vestibular function presented with a partial profile of imbalance and spatial disorientation. CONCLUSIONS: The present study provides evidence that peripheral vestibular hypofunction is associated with the Triad of dysfunctions, i.e., imbalance, anxiety, and spatial disorientation. The combination of SCCs and saccular hypofunction seems to contribute to the emergence of the Triad of symptoms.

Horizontal Vestibulo-Ocular Reflex Deficit as a Biomarker for Clinical Disease Onset, Severity, and Progression of Machado-Joseph Disease.

Because of the crucial importance of finding a useful biomarker for further clinical trials in Machado-Joseph disease (MJD), and based on our previous studies, we aimed to evaluate whether the horizontal vestibulo-ocular reflex (VOR) gain could be a reliable neurophysiological biomarker for the clinical onset, severity, and progression of the disease. Thirty-five MJD patients, 11 pre-symptomatic genetically confirmed MJD subjects, and 20 healthy controls underwent a detailed epidemiological and clinical neurological examination including the Scale for the Assessment and Rating of Ataxia (SARA). Their VOR gain was measured using the video Head Impulse Test system. Twenty of the MJD patients were re-tested after a period of 1-3 years. Horizontal VOR gain was abnormal in 92% of MJD, 54% pre-symptomatic, and 0% healthy controls. Horizontal VOR gain in the MJD group was significantly negatively correlated with SARA score in the first (r=0.66, p<0.001) and second (r=0.61, p<0.001) examinations. There was also a significant negative correlation between the percentage of change in horizontal VOR gain and the percentage of change in SARA score across both examinations (r=-0.54, p < 0.05). A regression model of the SARA score with the horizontal VOR gain and disease duration as predictors demonstrated that both the horizontal VOR gain and the disease duration had an independent contribution to the prediction of the SARA score. The horizontal VOR gain seems to be a reliable biomarker for the clinical onset, severity, and progression of MJD and could be used in further clinical studies.

How vestibular dysfunction transforms into symptoms of depersonalization and derealization?

BACKGROUND: Psychiatric Depersonalization/Derealization (DPDR) symptoms were demonstrated in patients with peripheral vestibular disorders. However, only semicircular canals (SCCs) dysfunction was evaluated, therefore, otoliths' contribution to DPDR is unknown. Also, DPDR symptoms in patients with central vestibular dysfunction are presently unknown. DPDR was also studied in the context of spatial disorientation and anxiety, but the relation of these cognitive and emotional functions to vestibular dysfunction requires clarification. METHODS: We tested patients with peripheral Bilateral Vestibular Hypofunction (pBVH), Machado Joseph Disease (MJD) with cerebellar and central bilateral vestibular hypofunction, and healthy controls. Participants completed the video Head Impulse Test (vHIT) for SCCs function, cervical Vestibular Evoked Myogenic Potentials test (cVEMPt) for sacculi function, Body Sensation Questionnaire (BSQ) for panic anxiety, Object Perspective-Taking test (OPTt) for spatial orientation and Cox & Swinson DPDR inventory for DPDR symptoms. RESULTS: pBVH patients showed significant SCCs and sacculi dysfunction, spatial disorientation, elevated panic anxiety, and DPDR symptoms. MJD patients showed significant SCCs hypofunction but preserved sacculi function, spatial disorientation but normal levels of panic anxiety and DPDR symptoms. Only pBVH patients demonstrated a positive correlation between the severity of the DPDR and spatial disorientation and panic anxiety. CONCLUSIONS: DPDR develops in association with sacculi dysfunction, either with or without SSCs dysfunction. Spatial disorientation and anxiety seem to mediate the transformation of vestibular dysfunction into DPDR symptoms. DPDR does not develop in MJD with central vestibular hypofunction but a normal saccular response. We propose a three-step model that describes the development of DPDR symptoms in vestibular patients.

Responses to balance challenges in persons with panic disorder: A pilot study of computerized static and dynamic balance measurements.

INTRODUCTION: Several studies have shown an association between panic disorder (PD) and reduced balance abilities, mainly based on functional balance scales. This pilot study aims to demonstrate the feasibility of studying balance abilities of persons with PD (PwPD) using computerized static and, for the first time, dynamic balance measurements in order to characterize balance control strategies employed by PwPD. METHODS: Twelve PwPD and 11 healthy controls were recruited. PD diagnosis was confirmed using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and the severity of symptoms was evaluated using the Hamilton Anxiety Scale (HAM-A), PD Severity Scales (PDSS), and Panic and Agoraphobia Scale (PAS). Balance was clinically assessed using the Activities-Specific Balance Confidence (ABC) scale and physically by the Mini-Balance Evaluation Systems Test (Mini-BESTest). Dizziness was evaluated using the Dizziness Handicap Inventory (DHI) scale. Postural control was evaluated statically by measuring body sway and dynamically by measuring body responses to rapid unexpected physical perturbations. RESULTS: PwPD had higher scores on the HAM-A (17.6 ± 10.3 vs. 3.0 ± 2.9; p < .001), PDSS (11.3 ± 5.1 vs. 0; p < .001), and PAS (20.3 ± 8.7 vs. 0; p < .001) questionnaires and lower scores on the balance scales compared to the controls (ABC scale: 156.2 ± 5.9 vs. 160 ± 0.0, p = .016; Mini-BESTest: 29.4 ± 2.1 vs. 31.4 ± 0.9, p = .014; DHI: 5.3 ± 4.4 vs. 0.09 ± 0.3, p < .001). In the static balance tests, PwPD showed a not-significantly smaller ellipse area of center of pressure trajectory (p = .36) and higher body sway velocity (p = .46), whereas in the dynamic balance tests, PwPD had shorter recovery time from physical perturbations in comparison to controls (2.1 ± 1.2s vs. 1.6 ± 0.9 s, p = .018). CONCLUSION: The computerized balance tests results point to an adoption of a ''postural rigidity'' strategy by the PwPD, that is, reduced dynamic adaptations in the face of postural challenges. This may reflect a nonsecure compensatory behavior. Further research is needed to delineate this strategy.

Angular vestibulo ocular reflex loss with preserved saccular function in Machado-Joseph disease.

OBJECTIVE: To provide a comprehensive evaluation of the vestibular function in Machado-Joseph Disease (MJD). METHODS: 21 MJD patients and 19 healthy Controls underwent a detailed clinical neuro-otological evaluation including VOR gain of all six semicircular canals by video Head Impulse Test (vHIT), remaining horizontal VOR function by Suppression Head Impulse test (SHIMP), and saccular function by cervical Vestibular Evoked Myogenic Potentials (cVEMP). RESULTS: All MJD had significantly lower VOR gain in all six semicircular canals (p < 0.001) with a mean ± SEM of horizontal gain of 0.52 ± 0.04 and vertical gain of 0.57 ± 0.03 versus Controls' gain of 0.95 ± 0.01 and 0.81 ± 0.02, respectively (p < 0.001). MJD showed also a significantly lower VOR gain on the SHIMP test with left gain of 0.51 ± 0.04 and right gain of 0.46 ± 0.03 versus Controls' gain of 0.79 ± 0.01 and 0.83 ± 0.03, respectively (p < 0.001). In contrast, MJD had normal saccular function reflected by the presence of cVEMP response in 18/20 patients and in 12/17 of Controls, with a non-significant difference between MJD and Controls of P13 and N23 peaks latency and normalized peak-to-peak amplitude. ROC analysis of horizontal VOR gain resulted in an area under the curve of 0.993 making the average lateral canals' VOR gain an excellent classifier of MJD vs Controls. CONCLUSIONS: Horizontal and vertical VOR impairment with preserved sacculo-collic function seems to be a distinctive feature of MJD and could be explained by selective, mostly medial and superior vestibular nuclei degeneration. This study further supports the idea that horizontal VOR gain measured by vHIT could be a potential neurophysiological biomarker of MJD.

Selective Procedural Memory Impairment but Preserved Declarative Memory in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder that affects mainly the cerebellum and less other brain areas. While the ataxic/motor features of the disease have been well described, the cognitive consequences of the degeneration require additional testing. The aim of this study was to evaluate learning abilities in SCA3. We tested 13 SCA3 patients and 14 age-matched healthy controls, all of Yemenite origin, on a neuropsychological battery of procedural and declarative memory tests. SCA3 patients demonstrated impaired sequence learning on the procedural Serial Reaction Time test (SRTt) but normal learning on the procedural Weather Prediction Probabilistic Classification test (WPPCt). SCA3 patients showed normal learning on the declarative Rey Auditory Verbal Learning test (Rey-AVLt). The correlations between the learning measures of the SRTt, WPPCt, and Rey-AVLt tests in SCA3 and controls separately were not significant. These results imply that the cerebellar degeneration in SCA3 causes selective impairment in procedural sequence learning while the procedural probabilistic learning and declarative memory were mostly preserved. These findings support the assumption that procedural learning is not a homogeneous function and could be dissociated in cerebellar neurodegenerative disease.

A neuro-inspired model-based closed-loop neuroprosthesis for the substitution of a cerebellar learning function in anesthetized rats.

Neuroprostheses could potentially recover functions lost due to neural damage. Typical neuroprostheses connect an intact brain with the external environment, thus replacing damaged sensory or motor pathways. Recently, closed-loop neuroprostheses, bidirectionally interfaced with the brain, have begun to emerge, offering an opportunity to substitute malfunctioning brain structures. In this proof-of-concept study, we demonstrate a neuro-inspired model-based approach to neuroprostheses. A VLSI chip was designed to implement essential cerebellar synaptic plasticity rules, and was interfaced with cerebellar input and output nuclei in real time, thus reproducing cerebellum-dependent learning in anesthetized rats. Such a model-based approach does not require prior system identification, allowing for de novo experience-based learning in the brain-chip hybrid, with potential clinical advantages and limitations when compared to existing parametric "black box" models.

Balance deficit enhances anxiety and balance training decreases anxiety in vestibular mutant mice.

Treatment of anxiety disorders by either pharmacological or behavioral means is applied with the intention to directly target the limbic system or high brain centers that down-regulate limbic activity. In spite of intense and long treatment, remission is not achieved in many patients, suggesting that their pathophysiology is not addressed by either of the above treatments. An alternative pathophysiology may be a disordered vestibular system, which may be studied in the context of comorbidity of balance and anxiety disorders. Here we studied whether mutant vestibular Headbanger (Hdb) mice demonstrate elevated anxiety and whether physical treatment of balance alleviates the behavioral symptoms of anxiety. Hdb and wildtype (Wt) mice were raised in either balance training or standard cages and were subjected repeatedly at 1-3 months of age to balance and anxiety-related tests. Results demonstrated progressive deterioration of balance performance and parallel elevation of anxiety in untrained Hdb as compared to untrained Wt mice. Training significantly improved balance performance of Hdb mice and in parallel, decreased the level of anxiety compared to untrained Hdb mice. These findings confirm that vestibular pathophysiology may be causally related to development of anxiety and suggest that in some clinical cases of anxiety, the appropriate treatment is physical rehabilitation of balance.

Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy.

Cerebellar inhibitory output shapes the temporal dynamics of its somatosensory inferior olivary input.

The cerebellum is necessary and sufficient for the acquisition and execution of adaptively timed conditioned motor responses following repeated paired presentations of a conditioned stimulus and an unconditioned stimulus. The underlying plasticity depends on the convergence of conditioned and unconditioned stimuli signals relayed to the cerebellum by the pontine nucleus and the inferior olive (IO), respectively. Adaptive timing of conditioned responses relies on the correctly predicted onset of the unconditioned stimulus, usually a noxious somatosensory stimulus. We addressed two questions: First, does the IO relay information regarding the duration of somatosensory stimuli to the cerebellum? Multiple-unit recordings from the IO of anesthetized rats that received periorbital airpuffs of various durations revealed that sustained somatosensory stimuli are invariably transformed into phasic IO outputs. The phasic response was followed by a post-peak depression in IO activity as compared to baseline, providing the cerebellum with a highly synchronous signal, time-locked to the stimulus' onset. Second, we sought to examine the involvement of olivocerebellar interactions in this signal transformation. Cerebello-olivary inhibition was interrupted using temporary pharmacological inactivation of cerebellar output nuclei, resulting in more sustained (i.e., less synchronous) IO responses to sustained somatosensory stimuli, in which the post-peak depression was substituted with elevated activity as compared to baseline. We discuss the possible roles of olivocerebellar negative-feedback loops and baseline cerebello-olivary inhibition levels in shaping the temporal dynamics of the IO's response to somatosensory stimuli and the consequences of this shaping for cerebellar plasticity and its ability to adapt to varying contexts.

A VLSI field-programmable mixed-signal array to perform neural signal processing and neural modeling in a prosthetic system.

A very-large-scale integration field-programmable mixed-signal array specialized for neural signal processing and neural modeling has been designed. This has been fabricated as a core on a chip prototype intended for use in an implantable closed-loop prosthetic system aimed at rehabilitation of the learning of a discrete motor response. The chosen experimental context is cerebellar classical conditioning of the eye-blink response. The programmable system is based on the intimate mixing of switched capacitor analog techniques with low speed digital computation; power saving innovations within this framework are presented. The utility of the system is demonstrated by the implementation of a motor classical conditioning model applied to eye-blink conditioning in real time with associated neural signal processing. Paired conditioned and unconditioned stimuli were repeatedly presented to an anesthetized rat and recordings were taken simultaneously from two precerebellar nuclei. These paired stimuli were detected in real time from this multichannel data. This resulted in the acquisition of a trigger for a well-timed conditioned eye-blink response, and repetition of unpaired trials constructed from the same data led to the extinction of the conditioned response trigger, compatible with natural cerebellar learning in awake animals.

Bioactive anti-inflammatory coating for chronic neural electrodes.

Chronic electrodes are widely used for brain degenerative and psychiatric diseases such as Parkinson's disease,major depression, and obsessive-compulsive disorder, and for neuronal prosthesis. Brain immune reaction to electrodes in the form of glial scar encapsulates the electrode and reduces the efficacy of deep brain stimulation and neuronal prosthesis.State-of-the-art strategies for improving brain­electrode interface use passive protein coating to "camouflage" the electrode from the immune system. In this study, we actively reduced the brain immune reaction to the chronic electrodes using immune suppressing protein, that is, interleukin (IL)-1 receptor antagonist. IL-1 receptor antagonist-coated electrodes and non coated electrodes were chronically implanted in rats. An additional group of rats was chronically implanted with IL-1 receptor antagonist- and laminin-coated electrodes (as passive protein). Examination of glial scaring 1 and 4 weeks after implantation indicated a significant reduction in the amount of glial scar in the vicinity of the IL-1 receptor antagonist-coated electrode in comparison to both non coated electrode and laminin-coated electrodes. The results strongly suggest that active immune suppressing protein reduces the level of immune reaction to chronic electrodes already after 1 week after implantation and generates less immune reaction than passive protein coating [corrected].

Amygdala conditioning modulates sensory input to the cerebellum.

Localization of emotional learning in the amygdala and discrete motor learning in the cerebellum provides empirical means to study the mechanisms mediating the interaction between fast emotional and slow motor learning. Behavioral studies have demonstrated that fear conditioning facilitates the motor conditioning. The present study tests the hypothesis that the amygdala output induces this facilitation by increasing the salience of the conditioned stimulus (CS) representation in the pontine nucleus (PN) input to the cerebellum. Paired trials of CS-US (unconditioned stimulus) were applied to anesthetized rats, a condition that allows for amygdala-based fear conditioning but not cerebellar-based motor conditioning. Multiple unit recordings in the PN served to assess the salience of the CS. Results showed that CS-US conditioning increased the PN-reactivity to the CS. Lidocaine-induced reversible inactivation of the amygdala prevented the facilitatory effect of conditioning on the PN-reactivity to the CS. These findings suggest that the amygdala-based conditioned responses reach the PN and increase the salience of the CS signal there, perhaps facilitating cerebellar conditioning. This facilitatory effect of the amygdala may be conceptualized under the 'two-stage theory of learning', which predicts that emotional learning in the first stage accelerates the motor learning in the second stage. We hereby demonstrate the physiological mechanism through which fast emotional learning in the first stage facilitates slow cerebellar learning in the second stage.

Progressive vestibular mutation leads to elevated anxiety.

Anxiety disorders are among the most common mental disorders, and are comorbid with balance disorders in a significant proportion of these individuals. Presently, it is unclear whether anxiety and balance disorders are causally related, and what direction this causality may take. We argue that balance disorders may predispose an individual to anxiety and that demonstration of such causality may be informative to the development of preferred treatment for such individuals. To demonstrate that balance disorders may predispose to anxiety, we studied headbanger (Hdb) mutant mice in which the balance disorder is due to progressive vestibular impairment and wildtype (Wt) mice. Balance was assessed by swim and tail-hang tests that demonstrated clear behavioral balance deficits in the Hdb mice. Anxiety was assessed by open-field and elevated plus-maze tests, which confirmed elevated anxiety in the Hdb mice. These findings demonstrate that congenital vestibular genotype predisposes the animal to elevated levels of anxiety in space-related tests. Similar causality in clinics may redirect treatment strategies in afflicted patients.

In the eye of the beholder: internally driven uncertainty of danger recruits the amygdala and dorsomedial prefrontal cortex.

Interpretation of emotional context is a pivotal aspect of understanding social situations. A critical component of this process is assessment of danger levels in the surrounding, which may have a direct effect on the organism's survival. The limbic system has been implicated in mediating this assessment. In situations of uncertainty, the evaluation process may also call for greater involvement of prefrontal cortex for decision-making and planning of an appropriate behavioral response. In the following study, morphed face images depicting emotional expressions were used to examine brain correlates of subjective uncertainty and perceptual ambiguity regarding danger. Fear and neutral expressions of 20 faces were morphed, and each of the face videos was divided into three sequences of equal length representing three levels of objective certainty regarding the expressions neutral, fear, and ambiguous. Sixteen subjects were scanned in a 1.5-T scanner while viewing 60 x 6-sec video sequences and were asked to report their subjective certainty regarding the level of danger surrounding the face on a four-level scale combining definite/maybe and danger/no-danger values. The individual responses were recorded and used as the basis for a "subjective protocol" versus an "objective protocol." Significant activations of the amygdala, dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex were observed under the subjective protocol of internally driven uncertainty, but not under objective stimuli-based ambiguity. We suggest that this brain network is involved in generating subjective assessment of social affective cues. This study provides further support to the "relevance detector" theory of the amygdala and implicates its importance to behavior relying heavily on subjective assessment of danger, such as in the security domain context.

Mice with vestibular deficiency display hyperactivity, disorientation, and signs of anxiety.

Previous studies revealed that vestibular cues are crucial for exploration in the absence of visual cues. The working hypothesis of this study was, accordingly, that mice with vestibular dysfunction would become disoriented or unable to globally explore an unfamiliar environment. In 2- and 3-month-old mutant headbanger (Hdb) mice, stereocilia of hair cells are abnormally elongated, yet maintain partial staircase arrangement, suggesting some spared vestibular function at these ages. Here we tested a group of 3-month-old mutant Hdb and a group of non-mutant mice obtained from the same litters (Wt mice). Each individual mouse was introduced into a dark 120 cm x 120 cm arena and its behavior was followed for 10 min. Hdb mice were hyperactive and appeared to engage in local exploration, traveling in a restricted zone for a while and then shifting to travel in another zone. In contrast, Wt mice traveled across zones incessantly with fewer visits to recently entered zones. Thus, Hdb seemed to display local compared with the global exploration of Wt mice, indicating that they were less oriented in the global environment. In addition, Hdb exhibited numerous stretch-attends, which is suggested as a sign of elevated anxiety. Altogether, the three comorbidities of hyperactivity, anxiety, and disorientation can be presented as a syndrome associated with vestibular deficiency in this animal model, and serve in studying vestibular deficiency in humans.