Stress Impairs Intentional Memory Control through Altered Theta Oscillations in Lateral Parietal Cortex.

Accumulating evidence suggests that forgetting is not necessarily a passive process but that we can, to some extent, actively control what we remember and what we forget. Although this intentional control of memory has potentially far-reaching implications, the factors that influence our capacity to intentionally control our memory are largely unknown. Here, we tested whether acute stress may disrupt the intentional control of memory and, if so, through which neural mechanism. We exposed healthy men and women to a stress (n = 27) or control (n = 26) procedure before they aimed repeatedly to retrieve some previously learned cue-target pairs and to actively suppress others. While control participants showed reduced memory for suppressed compared with baseline pairs in a subsequent memory test, this suppression-induced forgetting was completely abolished after stress. Using magnetoencephalography (MEG), we show that the reduced ability to suppress memories after stress is associated with altered theta activity in the inferior temporal cortex when the control process (retrieval or suppression) is triggered and in the lateral parietal cortex when control is exerted, with the latter being directly correlated with the stress hormone cortisol. Moreover, the suppression-induced forgetting was linked to altered connectivity between the hippocampus and right dorsolateral prefrontal cortex (PFC), which in turn was negatively correlated to stress-induced cortisol increases. These findings provide novel insights into conditions under which our capacity to actively control our memory breaks down and may have considerable implications for stress-related psychopathologies, such as posttraumatic stress disorder (PTSD), that are characterized by unwanted memories of distressing events.SIGNIFICANCE STATEMENT It is typically assumed that forgetting is a passive process that can hardly be controlled. There is, however, evidence that we may actively control, to some extent, what we remember and what we forget. This intentional memory control has considerable implications for mental disorders in which patients suffer from unwanted (e.g., traumatic) memories. Here, we demonstrate that the capacity to intentionally control our memory breaks down after stress. Using magnetoencephalography (MEG), we show that this stress-induced memory control deficit is linked to altered activity in the lateral parietal cortex and the connectivity between the hippocampus and right prefrontal cortex (PFC). These findings provide novel insights into conditions under which memory control fails and are highly relevant in the context of stress-related psychopathologies.

Cortical representation of interaural time difference in congenital deafness.

Binaural cues are required for localization of sound sources. In the present paper, representation of binaural cues has been investigated in the adult auditory cortex. Hearing and congenitally deaf cats were stimulated through binaural cochlear implants and unit responses were collected in the subregion of field A1 showing the largest amplitudes of evoked local field potentials. Sensitivity to interaural time difference (ITD) in the range from -600 to 600 micros was tested at intensities of 0-10 dB above hearing threshold. Template ITD functions were fitted to the data and parameters of ITD functions were compared between deaf and hearing animals. In deaf animals, fewer units responded to binaural stimulation, and those that responded had smaller maximal evoked firing rate. The fit to the template ITD functions was significantly worse in deaf animals, and the modulation depth in ITD functions was smaller, demonstrating a decrease in ITD sensitivity. With increasing binaural levels, hearing controls demonstrated systematic changes in ITD functions not found in deaf animals. Bimodal responses, likely related to precedence effect, were rare in deaf animals. The data demonstrate that despite some rudimentary sensitivity to interaural timing, cortical representation of ITDs is substantially altered by congenital auditory deprivation.

Interhemispheric synchronization of oscillatory neuronal responses in cat visual cortex.

Neurons in area 17 of cat visual cortex display oscillatory responses that can synchronize across spatially separate columns in a stimulus-specific way. Response synchronization has now been shown to occur also between neurons in area 17 of the right and left cerebral hemispheres. This synchronization was abolished by section of the corpus callosum. Thus, the response synchronization is mediated by corticocortical connections. These data are compatible with the hypothesis that temporal synchrony of neuronal discharges serves to bind features within and between the visual hemifields.

Role of reticular activation in the modulation of intracortical synchronization.

During aroused states of the brain, electroencephalographic activity is characterized by fast, irregular fluctuations of low amplitude, which are thought to reflect desynchronization of neuronal activity. This phenomenon seems at odds with the proposal that synchronization of cortical responses may play an important role in the processing of sensory signals. Here, activation of the mesencephalic reticular formation (MRF), an effective way to "desynchronize the electroencephalogram," was shown to facilitate oscillatory activity in the gamma frequency range and to enhance the stimulus-specific synchronization of neuronal spike responses in the visual cortex of cats.

Modulation of specific components of sleep disturbances by simultaneous subthalamic and nigral stimulation in Parkinson's disease.

OBJECTIVE: To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients. METHODS: The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances. RESULTS: PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = -2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = -2.041, p = 0.041). CONCLUSION: This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night.

Rapid feature selective neuronal synchronization through correlated latency shifting.

Spontaneous brain activity could affect processing if it were structured. We show that neuron pairs in cat primary visual cortex exhibited correlated fluctuations in response latency, particularly when they had overlapping receptive fields or similar orientation preferences. Correlations occurred within and across hemispheres, but only when local field potentials (LFPs) oscillated in the gamma-frequency range (40-70 Hz). In this range, LFP fluctuations preceding response onset predicted response latencies; negative (positive) LFPs were associated with early (late) responses. Oscillations below 10 Hz caused covariations in response amplitude, but exhibited no columnar selectivity or coordinating effect on latencies. Thus, during high gamma activity, spontaneous activity exhibits distinct, column-specific correlation patterns. Consequently, cortical cells undergo coherent fluctuations in excitability that enhance temporal coherence of responses to contours that are spatially contiguous or have similar orientation. Because synchronized responses are more likely than dispersed responses to undergo rapid and joint processing, spontaneous activity may be important in early visual processes.

Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

Integrator or coincidence detector? The role of the cortical neuron revisited.

Neurons can operate in two distinct ways, depending on the duration of the interval over which they effectively summate incoming synaptic potentials. If this interval is of the order of the mean interspike interval or longer, neurons act effectively as temporal integrators and transmit temporal patterns with only low reliability. If, by contrast, the integration interval is short compared to the interspike interval, neurons act essentially as coincidence detectors, relay preferentially synchronized input, and the temporal structure of their output is a direct function of the input pattern. Recently, interest in this distinction has been revived because experimental and theoretical results suggest that synchronous firing of neurons might play an important role for information processing in the cortex. Here, we argue that coincidence detection, rather than temporal integration, might be a prevalent operation mode of cortical neurons. We base our arguments on established biophysical properties of cortical neurons and on particular features of cortical dynamics.

Temporal coding in the visual cortex: new vistas on integration in the nervous system.

Although our knowledge of the cellular components of the cortex is accumulating rapidly, we are still largely ignorant about how distributed neuronal activity can be integrated to contribute to unified perception and behaviour. In the visual system, it is still unresolved how responses of feature-detecting neurons can be bound into representations of perceptual objects. Recent crosscorrelation studies show that visual cortical neurons synchronize their responses depending on how coherent features are in the visual field. These results support the hypothesis that temporal correlation of neuronal discharges may serve to bind distributed neuronal activity into unique representations. Furthermore, these studies indicate that neuronal responses with an oscillatory temporal structure may be particularly advantageous as carrier signals for such a temporal coding mechanism. Based on these recent findings, it is suggested here that binding of neuronal activity by a temporal code may provide a solution to the problem of integration in distributed neuronal networks.

Correlated firing in sensory-motor systems.

Traditionally, synchronous firing of neurons has been considered to be an epiphenomenon of neuronal networks, reflecting particular properties of circuitry, but having no functional relevance. In the past few years, an alternative view has been advocated, which suggests that temporal correlations serve a role in information processing by expressing relations among the responses of distributed neurons. This hypothesis has received experimental support from recent in vivo studies performed on the sensory systems of a variety of species. These results support earlier proposals that correlated activity might have an important function in sensory-motor integration and memory.

Neuronal assemblies: necessity, signature and detectability.

The ease with which highly developed brains can generate representations of a virtually unlimited diversity of perceptual objects indicates that they have developed very efficient mechanisms to analyse and represent relations among incoming signals. Here, we propose that two complementary strategies are applied to cope with these combinatorial problems. First, elementary relations are represented by the tuned responses of individual neurons that acquire their specific response properties (feature selectivity) through appropriate convergence of input connections in hierarchically structured feed-forward architectures. Second, complex relations that cannot be represented economically by the responses of individual neurons are represented by assemblies of cells that are generated by dynamic association of individual, featureselective cells. The signature identifying the responses of an assembly as components of a coherent code is thought to be the synchronicity of the respective discharges. The compatibility of this hypothesis is examined in the context of recent data on the dynamics of synchronization phenomena, the dependence of synchronization on central states and the relations between the synchronization behaviour of neurons and perception.

Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson's disease.

OBJECTIVE: While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. METHODS: Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. RESULTS: Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. CONCLUSIONS: This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. SIGNIFICANCE: STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus.

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.

Neuronal surface changes in the dorsal vagal motor nucleus of the guinea pig in response to axotomy.

Ultrastructural changes occurring in the dorsal motor nucleus of the vagus of the guinea pig after nerve transection were investigated. Two neuronal populations could be distinguished. Large neurons corresponding to the vagal motoneurons showed chromatolysis. They were found to develop complex changes in cell surface, which appeared either as a folding up and formation of flaplike processes or as invagination of adjacent neuronal or glial elements. Large processes often covered part of the plasmalemma and formed stacks of several neuronal lamellae. Smaller processes were mostly seen to extend into the neuropil, where they intermingled and adopted a budlike shape. These changes occurred in the cell somata within the first week after axotomy. The dendrites were affected after a short delay. The changes persisted for several months in most of the neurons, including the ones that showed signs of recovery from chromatolysis. The newly formed cellular extensions had a growth-cone-like internal structure, containing numerous smooth-surfaced vesicles or cisternae, a feltwork of filamentous material, dense-cored vesicles, and occasionally free polyribosomes. These surface changes did not occur in the second neuronal cell type of this nucleus, which had a smaller perikaryon characterized by a scanty cytoplasm. These cells did not show a retrograde degeneration and thus are probably interneurons. Acetylcholinesterase was used as a cytochemical marker of neuronal membranes. Surprisingly, the vagal motoneurons did not show a loss of enzymatic activity after nerve transection. Rather, a redistribution seemed to occur with intensified staining of the plasmalemma. The newly formed processes were consistently found to be acetylcholinesterase positive. It is suggested that the morphological changes observed correspond to an as-yet-unobserved growth process in the adult central nervous system, which involves perikarya and dendrites of regenerating guinea pig vagal motoneurons.

Changes of acetylcholinesterase molecular forms in regenerating motor neurons.

Axotomy-induced changes of the molecular forms of acetylcholinesterase in the facial nucleus of the rat and guinea pig were investigated. Evidence is presented that facial motoneurons of the guinea pig are capable of synthesizing considerable amounts of 16S acetylcholinesterase, and furthermore that acetylcholinesterase isoenzymes show species differences in their response to axon transection. Three isoenzymes could be separated by velocity sedimentation, which correspond to G1 (4S), G4 (10S) and A12 (16S) acetylcholinesterase. After axotomy, G4 activity was decreased in both species by 40% 2-3 weeks after nerve transection. In the rat, G1 was even further depressed, whereas in guinea pig facial nucleus G1 showed only a slight change. A12 displayed a clear species difference: in the rat, it was decreased to 60% of control 5 days after axotomy. In guinea pig, however, A12 increased dramatically to values of 400-500% of the unoperated control, and maintained elevated levels even 120 days after operation. This result does not agree with the decrease of transmitter metabolism in regenerating nerves and provides support to the hypothesis that acetylcholinesterase in regenerating nerves may have functions different from transmitter hydrolysis.

Axonal transport of 16S acetylcholinesterase is increased in regenerating peripheral nerve in guinea-pig, but not in rat.

The axonal transport of the molecular forms of acetylcholinesterase was investigated in regenerating facial nerves of guinea-pig and rat. Four forms were separated by velocity sedimentation corresponding to 16S (A12), 10S (G4), 6S (G2) and 4S (G1) acetylcholinesterase. They displayed species-specific changes, which are in good accordance with those previously found in the neuronal perikarya. In the rat, axonal transport decreased for all forms. In the guinea-pig, however, the molecular forms showed differential changes. Whereas after transection, the nerve content of 10S acetylcholinesterase decreased, 16S activity was considerably increased. Anterograde transport of 16S acetylcholinesterase was found to be enhanced, whilst transport of the 10S from decreased. The two lighter forms showed only minor changes. Similar results were obtained for the guinea-pig sciatic nerve. Changes in the localization of acetylcholinesterase activity were investigated by electron microscopical cytochemistry. In the normal facial nerve of both species, activity was located intra-axonally in tubular membraneous structures and on the outer surface of the axonal membrane. In the regenerating facial nerve of the rat, intra-axonal as well as axolemmal activity decreased. Axonal sprouts at the end of the proximal nerve stump showed no activity. In the guinea-pig, however, activity of the axonal membrane increased. This was especially prominent on the surface of axonal sprouts. Strong activity was found also in the extracellular space between the sprouting axons and in the endoneurial space filled by collagen fibres. Biochemical analysis of this region revealed that the histochemical activity was mainly due to the A12 form. Thus it was concluded that, in the guinea-pig, axonal sprouts represent a target for axonally transported A12 acetylcholinesterase, which may also be secreted to extracellular sites.

Synchronization of visual responses in the superior colliculus of awake cats.

Multi-unit responses to moving stimuli were recorded simultaneously from several sites in the superior colliculus of awake cats. Correlation analysis revealed that response synchronization was a prominent feature of visually evoked neural activity in both superficial and deep collicular layers. Responses at about half of the recordings separated by < or = 1 mm showed significant correlations. The synchronized responses oscillated in the gamma frequency range (30-70 Hz) which contrasts to conditions in anaesthetized cats where oscillations predominantly occurred in the alpha and beta frequency range (10-20 Hz). Response synchronization was most pronounced with coherent motion stimuli and broke down with incoherent stimuli. These results agree with previous findings on corticotectal synchronization and support the hypothesis that synchronization in the millisecond range serves to group collicular neurons into functionally coherent assemblies.

Precise timing of neuronal discharges within and across cortical areas: implications for synaptic transmission.

Multielectrode recordings were performed in a variety of structures of structures of the mammalian brain in order to examine temporal relations among simultaneously measured neuronal responses. Data indicate close correlations between perceptual phenomena and zero-time lag synchronization of distributed neuronal discharges.

Conditions of perceptual selection and suppression during interocular rivalry in strabismic and normal cats.

Presenting the two eyes with incongruent stimuli leads to the phenomenon of interocular rivalry. At any given time, one of the stimuli is perceptually suppressed in order to avoid double vision. In squinting subjects, rivalry occurs permanently also for congruent stimuli because of developmental rearrangement of cortical circuitry. In this study, we have investigated the dynamics and stimulus dependence of rivalry in six esotropic, four exotropic and three non-strabismic cats. As an indicator for perception, we used optokinetic nystagmus that was induced by moving gratings. The esotropic cats were tested for their visual acuity by means of a jumping stand procedure. The results show that one eye can dominate perception even if both eyes have equal visual acuity and are presented with stimuli of equal contrast. Strong eye dominance asymmetry was found in all but one of the tested cats. Notably, all three of the normal cats showed a clear asymmetry in perceptual selection. Measurements with varying contrast and velocity of the stimuli revealed that the influence of these parameters on perceptual selection was independent of the presence of strabismus. In all cats, the time during which a given eye dominated perception increased with the contrast and decreases with the velocity of the stimulus presented to this eye.