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.

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.

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.

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.

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.

Response properties of local field potentials and multiunit activity in the mouse visual cortex.

Extracellular local field potentials (LFPs) and multiunit activity (MUA) reflect the spatially integrated activity of multiple neurons in a given cortical structure. In the cat and primate visual cortices, these signals exhibit selectivity for visual stimulus features, such as orientation, direction of motion or spatial frequency. In the mouse visual cortex, a model which has been increasingly used in visual neuroscience, the visual stimulus selectivity of population signals has not been examined in detail. We recorded LFPs and MUA using multielectrode arrays and two derived measures, the high-pass filtered continuous MUA and the bipolar first spatial derivative of the LFP, in the visual cortex of isoflurane-anesthetized C57Bl/6 mice. We analyzed the onset latency and characterized the receptive fields in addition to the direction, orientation, and spatial and temporal frequency preferences of these signals. Population signals exhibited onset latencies as short as ∼30ms and possessed receptive fields as large as ∼38° with MUA receptive fields smaller than those of LFPs. All four population signals exhibited similar spatial frequency preferences (∼0.1 cycles per degree) and temporal frequency preferences (∼1 cycle per second). However, for all population signals, spatial and frequency tunings were broad and orientation and direction of motion preferences were absent. The characterization of the visual stimulus selectivity of LFPs and MUA in the mouse visual cortex should provide information regarding their usability in characterizing stimulus properties and disclose possible limitations.

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.

Absence of cross-modal reorganization in the primary auditory cortex of congenitally deaf cats.

To investigate possible cross-modal reorganization of the primary auditory cortex (field A1) in congenitally deaf cats, after years of auditory deprivation, multiunit activity and local field potentials were recorded in lightly anesthetized animals and compared with responses obtained in hearing cats. Local field potentials were also used for current source-density analyses. For visual stimulation, phase-reversal gratings of three to five different spatial frequencies and three to five different orientations were presented at the point of central vision. Peripheral visual field was tested using hand-held stimuli (light bar-shaped stimulus of different orientations, moved in different directions and flashed) typically used for neurophysiological characterization of visual fields. From 200 multiunit recordings, no response to visual stimuli could be found in A1 of any of the investigated animals. Using the current source-density analysis of local field potentials, no local generators of field potentials could be found within A1, despite of the presence of small local field potentials. No multiunit responses to somatosensory stimulation (whiskers, face, pinna, head, neck, all paws, back, tail) could be obtained. In conclusion, there were no indications for a cross-modal reorganization (visual, somatosensory) of area A1 in congenitally deaf cats.

Auditory novelty oddball allows reliable distinction of top-down and bottom-up processes of attention.

An auditory novelty-oddball task, which is known to evoke a P3 event-related potential (ERP) in a target condition and a novelty-P3 ERP in response to task-irrelevant unique environmental sounds, was repeatedly applied to healthy participants (n = 14) on two separate recording sessions, 7 days apart. Both target-P3 and novelty-P3 were internally consistent and test-retest reliable. Interestingly, novelty-P3 amplitude declined from the first to the second half of each recording session, whereas no systematic alteration between both sessions occurred. The target-P3 showed the opposite pattern, i.e. a reduced amplitude from the first to the second session, but no systematic change within each session. These findings suggest that novelty-P3 amplitude changes reflect habituation, whereas target-P3 session effects may indicate the adjusted amount of processing resources invested into the task. In general, the results support the interpretation of the novelty-P3 as indicating automatic, bottom-up related aspects of attention, whereas the target-P3, in the present paradigm, seems to reflect voluntary, top-down related aspects of attention.

Dynamic predictions: oscillations and synchrony in top-down processing.

Classical theories of sensory processing view the brain as a passive, stimulus-driven device. By contrast, more recent approaches emphasize the constructive nature of perception, viewing it as an active and highly selective process. Indeed, there is ample evidence that the processing of stimuli is controlled by top-down influences that strongly shape the intrinsic dynamics of thalamocortical networks and constantly create predictions about forthcoming sensory events. We discuss recent experiments indicating that such predictions might be embodied in the temporal structure of both stimulus-evoked and ongoing activity, and that synchronous oscillations are particularly important in this process. Coherence among subthreshold membrane potential fluctuations could be exploited to express selective functional relationships during states of expectancy or attention, and these dynamic patterns could allow the grouping and selection of distributed neuronal responses for further processing.

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.

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.

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.

Temporal binding and the neural correlates of sensory awareness.

Theories of binding have recently come into the focus of the consciousness debate. In this review, we discuss the potential relevance of temporal binding mechanisms for sensory awareness. Specifically, we suggest that neural synchrony with a precision in the millisecond range may be crucial for conscious processing, and may be involved in arousal, perceptual integration, attentional selection and working memory. Recent evidence from both animal and human studies demonstrates that specific changes in neuronal synchrony occur during all of these processes and that they are distinguished by the emergence of fast oscillations with frequencies in the gamma-range.

Temporal binding, binocular rivalry, and consciousness.

Cognitive functions like perception, memory, language, or consciousness are based on highly parallel and distributed information processing by the brain. One of the major unresolved questions is how information can be integrated and how coherent representational states can be established in the distributed neuronal systems subserving these functions. It has been suggested that this so-called "binding problem" may be solved in the temporal domain. The hypothesis is that synchronization of neuronal discharges can serve for the integration of distributed neurons into cell assemblies and that this process may underlie the selection of perceptually and behaviorally relevant information. As we intend to show here, this temporal binding hypothesis has implications for the search of the neural correlate of consciousness. We review experimental results, mainly obtained in the visual system, which support the notion of temporal binding. In particular, we discuss recent experiments on the neural mechanisms of binocular rivalry which suggest that appropriate synchronization among cortical neurons may be one of the necessary conditions for the buildup of perceptual states and awareness of sensory stimuli.

Patterns of synchronization in the superior colliculus of anesthetized cats.

Sensorimotor transformations in the mammalian superior colliculus (SC) are mediated by large sets of distributed neurons. For such distributed coding systems, stimulus superposition poses problems attributable to the merging of neural populations coding for different stimuli. Such superposition problems could be overcome by synchronization of neuronal discharges, because it allows the selection of a subset of distributed responses for further joint processing. To assess the putative role of such a temporal binding mechanism in the SC, we have applied correlation analysis to visually evoked collicular activity. We performed recordings of single-unit and multiunit activity in the SC of anesthetized and paralyzed cats with multiple electrodes. Autocorrelation analysis revealed that collicular neurons often discharged in broad (20-100 msec) bursts or with an oscillatory patterning in the alpha- and beta-frequency range. Significantly modulated cross-correlograms were observed in 50% (128 of 258) of the collicular multiunit recording pairs, and for these pairs significant correlations occurred in 44% of the stimulation epochs. For the single-unit pairs, significant interactions were observed in 14 of 48 cases studied (29%). Collicular cross-correlograms were often oscillatory, and these oscillations covered a broad frequency range of up to 100 Hz, with a predominance of oscillation frequencies in the alpha- and beta-range. In the majority of the significant correlograms (64%) the phase lag of the center peak was <5 msec. The probability of collicular synchronization increased with the overlap of the receptive fields and the proximity of the recording sites. Correlations were also observed between cells in the superficial and deep SC layers. Collicular synchronization required activation of the respective cells with a single coherent stimulus and broke down when the neurons were activated with two different stimuli. These data are consistent with the notion that collicular synchrony could define assemblies of functionally related cells.

Correlation analysis of corticotectal interactions in the cat visual system.

We have studied the temporal relationship between visual responses in various visual cortical areas [17, 18, postero medial lateral suprasylvian (PMLS), postero lateral lateral suprasylvian (PLLS), 21a]) and the superficial layers of the cat superior colliculus (SC). To this end, simultaneous recordings were performed in one or several visual cortical areas and the SC of anesthetized paralyzed cats, and visually evoked multiunit responses were subjected to correlation analysis. Significant correlations occurred in 117 (24%) of 489 cortex-SC pairs and were found for all cortical areas recorded. About half of the significant correlograms showed an oscillatory modulation. In these cases, oscillation frequencies covered a broad range, the majority being in the alpha- and beta-band. On average, significant center peaks in cross-correlograms had a modulation amplitude of 0.34. Our analysis revealed a considerable intertrial variability of correlation patterns with respect to both correlation strength and oscillation frequency. Furthermore, cortical areas differed in their corticotectal correlation patterns. The percentage of cells involved a corticotectal correlation, as well as the percentage of significantly modulated correlograms in such cases, was low for areas 17 and PMLS but high for areas 18 and PLLS. Analysis of the cortical layers involved in these interactions showed that consistent temporal relationships between cortical and collicular responses were not restricted to layer V. Our data demonstrate a close relationship between corticotectal interactions and intracortical or intracollicular synchronization. Trial-by-trial analysis from these sites revealed a clear covariance of corticotectal correlations with intracortical synchronization. The probability of observing corticotectal interactions increased with enhanced local cortical and collicular synchronization and, in particular, with interareal cortical correlations. Corticotectal correlation patterns resemble in many ways those described among areas of the visual cortex. However, the correlations observed are weaker than those between nearby cortical sites, exhibit usually broader peaks and for some cortical areas show consistent phase-shifts. Corticotectal correlations represent population phenomena that reflect both the local and global temporal organization of activity in the cortical and collicular network and do not arise from purely monosynaptic interactions. Our findings show that both striate and extrastriate inputs affect the superficial SC in a cooperative manner and, thus, do not support the view that responses in the superficial SC depend exclusively on input from the primary visual areas as implied by the concept of "two corticotectal systems." We conclude that the corticotectal projections convey temporal activation patterns with high reliability, thus allowing the SC evaluation of information encoded in the temporal relations between responses of spatially disseminated cortical neurons. As a consequence, information distributed across multiple cortical areas can affect the SC neurons in a coherent way.