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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.
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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.
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Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Audição , FenótipoRESUMO
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.
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Estimulação Encefálica Profunda , Doença de Parkinson , Córtex Sensório-Motor , Núcleo Subtalâmico , Ratos , Masculino , Animais , Núcleo Subtalâmico/fisiologia , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/terapia , Ratos Sprague-DawleyRESUMO
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.
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Doença de Parkinson , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Oxidopamina/efeitos adversos , Peso Corporal , Modelos Animais de DoençasRESUMO
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.
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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.
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Córtex Motor , Doença de Parkinson , Transtornos Parkinsonianos , Animais , Gânglios da Base , Redes Neurais de Computação , Transtornos Parkinsonianos/tratamento farmacológico , RatosRESUMO
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.
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Estimulação Encefálica Profunda , Transtorno Obsessivo-Compulsivo , Núcleos Septais , Lobo Frontal , Humanos , Cápsula Interna , Transtorno Obsessivo-Compulsivo/terapia , Resultado do TratamentoRESUMO
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.
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Estimulação Encefálica Profunda , Transtorno Obsessivo-Compulsivo , Feminino , Seguimentos , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/terapia , Qualidade de Vida , Resultado do TratamentoRESUMO
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.
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Núcleos Cerebelares , Cerebelo , Animais , Masculino , Córtex Pré-Frontal , Ratos , Ratos Sprague-Dawley , Comportamento SocialRESUMO
Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats. Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150⯵A and 130â¯Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0â¯mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS. CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS. Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.
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Estimulação Encefálica Profunda , Núcleos Intralaminares do Tálamo/fisiopatologia , Neostriado/fisiologia , Núcleo Accumbens/fisiologia , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologia , Córtex Sensório-Motor/fisiologia , Ritmo Teta/fisiologia , Síndrome de Tourette/fisiopatologia , Animais , Apomorfina/farmacologia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Eletrocorticografia , Masculino , Neostriado/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+]o), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+]o, α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.
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Depressão Alastrante da Atividade Elétrica Cortical , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Enxaqueca com Aura/enzimologia , Enxaqueca com Aura/genética , ATPase Trocadora de Sódio-Potássio/deficiência , Animais , Modelos Animais de Doenças , Doenças Genéticas Inatas/patologia , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Mutação , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
INTRODUCTION: The neurobiological mechanisms underlying the clinical effects of psychotherapy are scarcely understood. In particular, the modifying effects of psychotherapy on neuronal activity are largely unknown. We here present data from an innovative experimental paradigm using the example of a patient with treatment resistant obsessive-compulsive disorder (trOCD) who underwent implantation of bilateral electrodes for deep brain stimulation (DBS). The aim of the paradigm was to examine the short term effect of metacognitive therapy (MCT) on neuronal local field potentials (LFP) before and after 5 MCT sessions. METHODS: DBS electrodes were implanted bilaterally with stereotactic guidance in the bed nucleus of the stria terminalis/ internal capsule (BNST/IC). The period between implantation of the electrodes and the pacemaker was used for the experimental paradigm. DBS electrodes were externalized via extension cables, yielding the opportunity to record LFP directly from the BNST/IC. The experimental paradigm was designed as follows: (a) baseline recording of LFP from the BNST/IC, (b) application of 5 MCT sessions over 3 days, (c) post-MCT recording from the BNST/IC. The Obsessive-Compulsive Disorder- scale (OCD-S) was used to evaluate OCD symptoms. RESULTS: OCD symptoms decreased after MCT. These reductions were accompanied by a decrease of the relative power of theta band activity, while alpha, beta, and gamma band activity was significantly increased after MCT. Further, analysis of BNST/IC LFP and frontal cortex EEG coherence showed that MCT decreased theta frequency band synchronization. DISCUSSION: Implantation of DBS electrodes for treating psychiatric disorders offers the opportunity to gather data from neuronal circuits, and to compare effects of therapeutic interventions. Here, we demonstrate direct effects of MCT on neuronal oscillatory behavior, which may give possible cues for the neurobiological changes associated with psychotherapy.
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BACKGROUND: Deep brain stimulation (DBS) has been introduced as a treatment option for treatment-resistant obsessive-compulsive disorder (OCD). However, the optimal stimulation target and the corresponding stimulation settings remain unclear. Furthermore, there is limited knowledge about the acute effects of DBS. METHODS: In 3 patients with treatment-resistant OCD, DBS electrodes were implanted in the bed nucleus of the stria terminalis (BNST)/internal capsule (IC). On the next day, different electrode pairs (BNST only, IC only, and BNST/IC) were stimulated at different voltages (1, 2, and 3.5 V) for 5 minutes each. Afterwards, patients rated their perceived OCD symptoms and various emotional states on corresponding visual analog scales. RESULTS: Across locations, low voltage stimulation (1 and 2 V) was associated with reduction of OCD symptoms (i.e., anxiety and tension), in particular when the IC was stimulated. High voltage stimulation (3.5 V), in particular when BNST was involved, led to less reduction of OCD symptoms. Moreover, 3.5-V stimulation of the BNST (BNST only and BNST/IC) induced higher levels of anxiety, tension, and discomfort. Subjects also reported an increase in vegetative sensations. CONCLUSIONS: In summary, we demonstrate that both stimulation site and voltage settings show sweet spots (2 V at IC or BNST/IC) at which OCD symptom severity decreased while negative effects were minimal. Stimulation of IC fibers might be relevant both for acute and chronic effects. Whether acute effects are useful for outcome prediction remains to be shown in future studies.
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Estimulação Encefálica Profunda/métodos , Cápsula Interna , Transtorno Obsessivo-Compulsivo/terapia , Adulto , Feminino , Humanos , Cápsula Interna/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although intercostal nerve injury is one of the major causes for post-thoracotomy pain, the exact mechanisms are still unclear. We sought to evaluate the electro-physiological changes of intercostal nerve injury after thoracotomy in a sheep model. METHODS: Adult sheep underwent thoracotomy in the sixth intercostal space by employing diathermy to superior border of the seventh rib. In two sheep, ribs were then spread using retractor spreading for a distance of 7 cm for 30 minutes. In the third sheep, thoracotomy was followed by harvesting intercostal muscles including the neurovascular bundle adjacent to inferior edge of the sixth rib. Thereafter, ribs were spread in the same way, but with the muscle flap dangled between the blades for intercostal nerve protection (dangling muscle flap technique). The nerve conduction velocity of the intercostal nerve was recorded before and after incision of intercostal muscles, immediately and 30 minutes after retractor placement and 30 minutes after removal of the retractor. RESULTS: In the sheep undergoing conventional thoracotomy, the physiological conductivity of intercostal nerve was completely blocked immediately after retractor placement using the same stimulation intensity or even the supra-threshold intensity. The conduction block persisted for 30 minutes during the retractor placement and further 30 minutes after removal of the retractor. In contrast, intercostal nerve conduction was not impaired throughout the experiment with the dangling muscle flap technique. CONCLUSIONS: Our experiment provides electro-physiological evidence for intercostal nerve injury after thoracotomy. The injury is primarily attributed to mechanical compression caused by the rib retractor.
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The loss of nigral dopaminergic neurons and the resulting dopamine (DA) depletion in the striatum (STR) lead to altered neuronal activity and enhanced beta activity in various regions of the basal ganglia (BG) motor loop in patients with Parkinson's disease and in rodents in the 6-hydroxydopamine (6-OHDA)-lesioned rat model. Intrastriatal DA graft implantation has been shown to re-innervate the host brain and restore DA input. Here, DA cell grafts were implanted into the STR of 6-OHDA-lesioned rats and the effect on neuronal activity under urethane anesthesia (1.4g/kg, injected intraperitoneally) was tested in the entopeduncular nucleus (EPN, the equivalent to the human globus pallidus internus), the output nucleus of the BG, and the globus pallidus (GP, the equivalent to the human globus pallidus externus), a key region in the indirect pathway. In animals, which were transplanted with cells derived from the ventral mesencephalon of embryonic day 12 rat embryos into the STR, the rotational behavior induced by DA agonists in 6-OHDA-lesioned rats was significantly improved. This was accompanied by alleviated EPN firing rate and reinstated patterns of neuronal activity in the GP and EPN. Analysis of oscillatory activity revealed enhanced beta activity in both regions, which was reduced after grafting. In summary these data indicate restoration of BG motor loop toward normal activity by DA graft integration.
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Potenciais de Ação , Gânglios da Base , Neurônios Dopaminérgicos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/fisiopatologia , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Several findings support the concept that sensorimotor integration is disturbed in Parkinson's disease (PD) and in levodopa-induced dyskinesias. In this study, we explored the neuronal firing activity of excitatory pyramidal cells and inhibitory interneurons in the forelimb region of the primary somatosensory cortex (S1FL-Ctx), along with its interaction with oscillatory activity of the primary motor cortex (MCtx) in 6-hydroxydopamine lesioned hemiparkinsonian (HP) and levodopa-primed dyskinetic (HP-LID) rats as compared to controls under urethane (1.4g/kg, i.p.) anesthesia. Further, gene expression patterns of distinct markers for inhibitory GABAergic neurons were analyzed in both cortical regions. While firing frequency and burst activity of S1FL-Ctx inhibitory interneurons were reduced in HP and HP-LID rats, measures of irregularity were enhanced in pyramidal cells. Further, enhanced coherence of distinct frequency bands of the theta/alpha, high-beta, and gamma frequency, together with enhanced synchronization of putative pyramidal cells and interneurons with MCtx oscillatory activity were observed. While GABA level was similar, gene expression levels of interneuron and GABAergic markers in S1FL-Ctx and MCtx of HP-LID rats differed to some extent. Our study shows that in a rat model of PD with dyskinesias, neuronal activity in putative interneurons was reduced, which was accompanied by high beta and gamma coherence between S1FL-Ctx and MCtx, together with changes in gene expression, indicating maladaptive neuroplasticity after long term levodopa treatment.
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Potenciais de Ação/fisiologia , Discinesia Induzida por Medicamentos/patologia , Córtex Motor/patologia , Neurônios/fisiologia , Doença de Parkinson Secundária/patologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiparkinsonianos/efeitos adversos , Apomorfina/farmacologia , Modelos Animais de Doenças , Feminino , Glutamato Descarboxilase/metabolismo , Levodopa/efeitos adversos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA/genética , Receptores de GABA/metabolismo , Simpatolíticos/toxicidade , Espectrometria de Massas em TandemRESUMO
The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.
Assuntos
Estimulação Encefálica Profunda/métodos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/cirurgia , Núcleo Tegmental Pedunculopontino/diagnóstico por imagem , Núcleo Tegmental Pedunculopontino/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Estimulação Encefálica Profunda/efeitos adversos , Humanos , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/etiologiaRESUMO
Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.
Assuntos
Estimulação Encefálica Profunda/métodos , Doença de Parkinson/cirurgia , Núcleo Tegmental Pedunculopontino/anatomia & histologia , Núcleo Tegmental Pedunculopontino/cirurgia , Terminologia como Assunto , Humanos , Doença de Parkinson/diagnósticoRESUMO
Electrical stimulation of the primary visual cortex (V1) is an experimental approach for visual prostheses. We here compared the response to intracortical and epicortical stimulation of the primary visual cortex by using c-Fos immunoreactivity as a marker for neuronal activation. The primary visual cortex of male Sprague Dawley rats was unilaterally stimulated for four hours using bipolar electrodes placed either intracortically in layer IV (n=26) or epicortically (n=20). Four different current intensities with a constant pulse width of 200µs and a constant frequency of 10Hz were used, for intracortical stimulation with an intensity of 0µA (sham-stimulation), 10µA, 20µA and 40µA, and for epicortical stimulation 0µA, 400µA, 600µA and 800µA. Subsequently all animals underwent c-Fos immunostaining and c-Fos expression was assessed in layer I-VI of the primary visual cortex within 200µm and 400µm distance to the stimulation site. C-Fos expression was higher after intracortical stimulation compared to epicortical stimulation, even though ten times lower current intensities were applied. Furthermore intracortical stimulation resulted in more focal neuronal activation than epicortical stimulation. C-Fos expression was highest after intracortical stimulation with 20µA compared to all other intensities. Epicortical stimulation showed a linear increase of c-Fos expression with the highest expression at 800µA. Sham stimulation showed similar expression of c-Fos in both hemispheres. The contralateral hemisphere was not affected by intracortical or epicortical stimulation of either intensities. In summary, intracortical stimulation resulted in more focal neuronal activation with less current than epicortical stimulation. This model may be used as a simple but reliable model to evaluate electrodes for microstimulation of the primary visual cortex before testing in more complex settings.
Assuntos
Genes fos/fisiologia , Neurônios/metabolismo , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Animais , Estimulação Elétrica , Eletrodos Implantados , Lateralidade Funcional/fisiologia , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Ratos , Ratos Sprague-Dawley , Córtex Visual/citologia , Próteses VisuaisRESUMO
BACKGROUND: Electrodes for neural stimulation and recording are used for the treatment of neurological disorders. Their features critically depend on impedance and interaction with brain tissue. The effect of surface modification on electrode impedance was examined in vitro and in vivo after intracranial implantation in rats. Electrodes coated by electrophoretic deposition with platinum nanoparticles (NP; <10 and 50 nm) as well as uncoated references were implanted into the rat's subthalamic nucleus. After postoperative recovery, rats were electrostimulated for 3 weeks. Impedance was measured before implantation, after recovery and then weekly during stimulation. Finally, local field potential was recorded and tissue-to-implant reaction was immunohistochemically studied. RESULTS: Coating with NP significantly increased electrode's impedance in vitro. Postoperatively, the impedance of all electrodes was temporarily further increased. This effect was lowest for the electrodes coated with particles <10 nm, which also showed the most stable impedance dynamics during stimulation for 3 weeks and the lowest total power of local field potential during neuronal activity recording. Histological analysis revealed that NP-coating did not affect glial reactions or neural cell-count. CONCLUSIONS: Coating with NP <10 nm may improve electrode's impedance stability without affecting biocompatibility. Increased impedance after NP-coating may improve neural recording due to better signal-to-noise ratio.