Comparing brain activity patterns during spontaneous exploratory and cue-instructed learning using single photon-emission computed tomography (SPECT) imaging of regional cerebral blood flow in freely behaving rats.

Learning can be categorized into cue-instructed and spontaneous learning types; however, so far, there is no detailed comparative analysis of specific brain pathways involved in these learning types. The aim of this study was to compare brain activity patterns during these learning tasks using the in vivo imaging technique of single photon-emission computed tomography (SPECT) of regional cerebral blood flow (rCBF). During spontaneous exploratory learning, higher levels of rCBF compared to cue-instructed learning were observed in motor control regions, including specific subregions of the motor cortex and the striatum, as well as in regions of sensory pathways including olfactory, somatosensory, and visual modalities. In addition, elevated activity was found in limbic areas, including specific subregions of the hippocampal formation, the amygdala, and the insula. The main difference between the two learning paradigms analyzed in this study was the higher rCBF observed in prefrontal cortical regions during cue-instructed learning when compared to spontaneous learning. Higher rCBF during cue-instructed learning was also observed in the anterior insular cortex and in limbic areas, including the ectorhinal and entorhinal cortexes, subregions of the hippocampus, subnuclei of the amygdala, and the septum. Many of the rCBF changes showed hemispheric lateralization. Taken together, our study is the first to compare partly lateralized brain activity patterns during two different types of learning.

Disrupted cross-laminar cortical processing in ß amyloid pathology precedes cell death.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aß are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.

Estimation of the spatiotemporal structure of event-related desynchronization and synchronization in magnetoencephalography.

We present a comprehensive methodology for identifying cerebral areas involved in event-related changes of electromagnetic activity of the human brain, and also for tracing the temporal evolution of this activity. Information from pre- and peristimulus time intervals--in terms of event-related synchronization (ERS) and desynchronization (ERD) of the magnetoencephalographic (MEG) signal--was directly incorporated in the relevant test statistics. For the individual steps of the analysis, we used particular estimations of the time-frequency distribution of the energy along with particular error control methods, that is, short-time Fourier transform and false-discovery rate at the sensor level and multitapers and familywise error rate at the source level. This procedure was applied to two types of group-level tests, a within-condition test and a between-conditions test. The performance of the proposed methodology is assessed by (1) analyzing the event-related brain activity from two experimental conditions of an auditory MEG experiment--passive listening to a sequence of frequency-modulated sweeps and their active categorization with respect to the direction of frequency modulation, and (2) comparing the findings with those obtained with a widely used cluster-based analysis.

Single-trial reconstruction of auditory evoked magnetic fields by means of Template Matching Pursuit.

We present a new paradigm for the adaptive estimation of evoked brain responses in single trials, based upon the combination of the matching pursuit (MP) algorithm and template matching, and referred to as Template Matching Pursuit (TMP). In contrast to the classical template matching with invariant single-trial morphology and to previous approaches using MP with strong similarity constraint on functions in sequential trials, this adaptive approach allows for a wide variety of waveforms, and its universality is retained by parametrizing all relevant waveforms in terms of Gabor functions. A survey of single-trial estimates obtained for 10 subjects (∼4000 individual trials in total) confirms the validity of the assumption of a good approximation of single-trial waveforms. Owing to the fully parametric approach, we can easily perform also any quantitative analysis of such a huge dataset. As an example we take the trial-to-trial variability of the peak amplitude and latency of the auditory M100 component. This methodology provides estimates of diversified morphologies, which makes it free from the limitations inherent to any restrictive model. This seems advantageous in the context of the ongoing debate as to the neural mechanisms of average evoked brain responses.

The combination of appetitive and aversive reinforcers and the nature of their interaction during auditory learning.

Learned changes in behavior can be elicited by either appetitive or aversive reinforcers. It is, however, not clear whether the two types of motivation, (approaching appetitive stimuli and avoiding aversive stimuli) drive learning in the same or different ways, nor is their interaction understood in situations where the two types are combined in a single experiment. To investigate this question we have developed a novel learning paradigm for Mongolian gerbils, which not only allows rewards and punishments to be presented in isolation or in combination with each other, but also can use these opposite reinforcers to drive the same learned behavior. Specifically, we studied learning of tone-conditioned hurdle crossing in a shuttle box driven by either an appetitive reinforcer (brain stimulation reward) or an aversive reinforcer (electrical footshock), or by a combination of both. Combination of the two reinforcers potentiated speed of acquisition, led to maximum possible performance, and delayed extinction as compared to either reinforcer alone. Additional experiments, using partial reinforcement protocols and experiments in which one of the reinforcers was omitted after the animals had been previously trained with the combination of both reinforcers, indicated that appetitive and aversive reinforcers operated together but acted in different ways: in this particular experimental context, punishment appeared to be more effective for initial acquisition and reward more effective to maintain a high level of conditioned responses (CRs). The results imply that learning mechanisms in problem solving were maximally effective when the initial punishment of mistakes was combined with the subsequent rewarding of correct performance.

Click train encoding in primary and non-primary auditory cortex of anesthetized macaque monkeys.

We studied encoding of temporally modulated sounds in 28 multiunits in the primary auditory cortical field (AI) and in 35 multiunits in the secondary auditory cortical field (caudomedial auditory cortical field, CM) by presenting periodic click trains with click rates between 1 and 300 Hz lasting for 2-4 s. We found that all multiunits increased or decreased their firing rate during the steady state portion of the click train and that all except two multiunits synchronized their firing to individual clicks in the train. Rate increases and synchronized responses were most prevalent and strongest at low click rates, as expressed by best modulation frequency, limiting frequency, percentage of responsive multiunits, and average rate response and vector strength. Synchronized responses occurred up to 100 Hz; rate response occurred up to 300 Hz. Both auditory fields responded similarly to low click rates but differed at click rates above approximately 12 Hz at which more multiunits in AI than in CM exhibited synchronized responses and increased rate responses and more multiunits in CM exhibited decreased rate responses. These findings suggest that the auditory cortex of macaque monkeys encodes temporally modulated sounds similar to the auditory cortex of other mammals. Together with other observations presented in this and other reports, our findings also suggest that AI and CM have largely overlapping sensitivities for acoustic stimulus features but encode these features differently.

False recognition of emotional stimuli is lateralised in the brain: An fMRI study.

We have investigated whether the left (LH) and right (RH) hemisphere play a different role in eliciting false recognition (FR) and whether their involvement in this memory illusion depends on the emotional content of stimuli. Negative and neutral pictures (taken from IAPS) were presented in the divided-visual field paradigm. Subjects task was to indicate whether the pictures had already been presented or not during the preceding study phase. FR rate was much higher for the RH than the LH presentations. In line, FR resulted in activations mainly in the right prefrontal cortex (PFC) for either RH or LH presentations. Emotional content of stimuli facilitated the formation of false memories and strengthened the involvement of the right PFC in FR induction.

Dynamics of cortical theta activity correlates with stages of auditory avoidance strategy formation in a shuttle-box.

By comparing behavioral performance and cortical theta activity (4-8 Hz) on a trial by trial basis we examined how the different behavioral stages of tone-induced avoidance learning in the shuttle-box may be distinguishable by theta power as a potential correlate of changing strategies of information processing. Electrocorticograms with pronounced theta content were recorded across the cortical surface of gerbils during avoidance learning and analyzed in each trial in conjunction with reaction times and unconditioned and conditioned responses. The focus of theta analysis in this paradigm with a 5-s delay between tone and foot-shock onsets was on the 14-s periods after hurdle crossing where feedback information from a trial is available. The strongest theta activity occurred in stage 1 of initial tone conditioning which was sharply reduced to a minimum during stage 2 of optimization of unconditioned escape responses from the foot shock. A few initial successful avoidance responses gave rise to a reversal of the decline of theta activity that later reached a second maximum. A systematic increase of theta activity during this stage 3 of avoidance conditioning was found for the occasional trials with unconditioned responses and not for the increasing number of conditioned responses suggesting that error processing is a major correlate of this new increase of theta power. After the second maximum the theta power slowly declined together with a further improvement of behavioral performance indicating that stage 4 of retrieval of the consolidated avoidance response was reached. The results suggest that behind a previously reported general trend of decreasing theta power with increasing performance in this paradigm there is a hidden microstructure of theta activity across trials which separates stages of avoidance conditioning and is partially mirrored by known changes of prefrontal dopamine release.

Multisensory processing via early cortical stages: Connections of the primary auditory cortical field with other sensory systems.

It is still a popular view that primary sensory cortices are unimodal, but recent physiological studies have shown that under certain behavioral conditions primary sensory cortices can also be activated by multiple other modalities. Here, we investigate the anatomical substrate, which may underlie multisensory processes at the level of the primary auditory cortex (field AI), and which may, in turn, enable AI to influence other sensory systems. We approached this issue by means of the axonal transport of the sensitive bidirectional neuronal tracer fluorescein-labeled dextran which was injected into AI of Mongolian gerbils (Meriones unguiculatus). Of the total number of retrogradely labeled cell bodies (i.e. cells of origin of direct projections to AI) found in non-auditory sensory and multisensory brain areas, approximately 40% were in cortical areas and 60% in subcortical structures. Of the cell bodies in the cortical areas about 82% were located in multisensory cortex, viz., the dorsoposterior and ventroposterior, posterior parietal cortex, the claustrum, and the endopiriform nucleus, 10% were located in the primary somatosensory cortex (hindlimb and trunk region), and 8% in secondary visual cortex. The cortical regions with retrogradely labeled cells also contained anterogradely labeled axons and their terminations, i.e. they are also target areas of direct projections from AI. In addition, the primary olfactory cortex was identified as a target area of projections from AI. The laminar pattern of corticocortical connections suggests that AI receives primarily cortical feedback-type inputs and projects in a feedforward manner to its target areas. Of the labeled cell bodies in the subcortical structures, approximately 90% were located in multisensory thalamic, 4% in visual thalamic, and 6% in multisensory lower brainstem structures. At subcortical levels, we observed a similar correspondence of retrogradely labeled cells and anterogradely labeled axons and terminals in visual (posterior limitans thalamic nucleus) and multisensory thalamic nuclei (dorsal and medial division of the medial geniculate body, suprageniculate nucleus, posterior thalamic cell group, zona incerta), and in the multisensory nucleus of the brachium of the inferior colliculus. Retrograde, but not anterograde, labeling was found in the multisensory pontine reticular formation, particularly in the reticulotegmental nucleus of the pons. Conversely, anterograde, but no retrograde, labeling was found in the visual laterodorsal and lateroposterior thalamic nuclei, in the multisensory peripeduncular, posterior intralaminar, and reticular thalamic nuclei, as well as in the multisensory superior and pericentral inferior colliculi (including cuneiform and sagulum nucleus), pontine nuclei, and periaqueductal gray. Our study supports the notion that AI is not merely involved in the analysis of auditory stimulus properties but also in processing of other sensory and multisensory information. Since AI is directly connected to other primary sensory cortices (viz. the somatosensory and olfactory ones) multisensory information is probably also processed in these cortices. This suggests more generally, that primary sensory cortices may not be unimodal.

Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine.

Using microdialysis from medial prefrontal cortex of gerbils during aversive auditory conditioning in the shuttle-box we have previously shown a transient increase of dopamine efflux correlated with the establishment of avoidance behavior. We hypothesized that the acquisition of a new behavioral strategy is generally accompanied by this extra prefrontal dopamine release. The present experiment aimed at further testing this hypothesis. In a pre-training period in the shuttle-box the gerbils acquired an active avoidance response by generalizing two different tone signals to a GO-meaning (change of shuttle-box compartment). Thereafter, they were subjected in relearning sessions to differentially associate the known tone stimuli with GO- and NOGO- (no change of shuttle-box compartment) conditions, respectively. The following formation of discrimination behavior led to a similar extra dopamine increase as found during establishment of the avoidance strategy. This significant enhancement was limited to rapidly relearning individuals. Furthermore, the dopamine increase attenuated in these animals with increasing performance during the course of the discrimination training, similar to the retrieval stage of the avoidance strategy. Therefore, the dopamine system seems to be critically involved in the initial formation of associations for new behavioral strategies, i.e. learning. We assume that the prefrontal dopamine increase during initial learning of the complex discrimination behavior indicates an involvement of working memory principles and a goal-directed formation of a behavioral strategy.

Analysis of evoked and emergent patterns of stimulus-related auditory cortical activity.

Cortical activity contains both evoked patterns and emergent patterns of stimulus-related activity. Here we compared evoked and emergent patterns in the primary auditory cortex, field AI, of the gerbil by studying the differential effects of diluting spatial information about the patterns on their geometric dissimilarity by randomly removing channels from the recording data. This identified the sets of most relevant channels for the discrimination of stimuli in both types of patterns. In the evoked patterns the sets of most discriminative channels were found to be focally organized at locations corresponding to the thalamically relayed input into the cortical tonotopic map. In the emergent patterns the sets of most discriminative channels were broadly distributed and held no apparent relationship to the tonotopic map. The results indicate the coexistence in the same neuronal tissue of a topographic mapping principle for the evoked activity and a holographic mapping principle for the emergent activity.

Early and late patterns of stimulus-related activity in auditory cortex of trained animals.

Epidural electrocorticograms over the right auditory cortex (field AI) were measured using implanted 18-channel (3 x 6) electrode arrays in four animals (Mongolian gerbil) trained to discriminate between a rising and a falling frequency modulated tone (frequency range 2-4 kHz). Using a previously introduced classification procedure, transient patterns of cortical activity suitable to discriminate between the rising and the falling modulation were identified. Early (locked to stimulus onset) and late (emerging at variable times poststimulus) patterns could be differentiated. Deletion of increasing numbers of randomly selected electrodes was used to determine a critical density of recording channels required to capture the discriminative power of the early and late patterns. Statistical analysis of the classification revealed a sigmoid dependence of the discriminative power from the number of remaining electrodes with an inflection point at 12 electrodes. The analysis of the minima of the classification statistic revealed that in the early patterns discriminative information was focal on regions corresponding to the tonotopic representation of the stimuli, whereas in late patterns this information seemed to be distributed nonfocally across larger cortical regions. This analysis supports the previous notion of the coexistence of topographically organized activity states related to the physical stimulus features and nontopographically organized states determined largely by intrinsic factors (Ohl et al. 2001).

Form-from-motion: MEG evidence for time course and processing sequence.

The neural mechanisms and role of attention in the processing of visual form defined by luminance or motion cues were studied using magnetoencephalography. Subjects viewed bilateral stimuli composed of moving random dots and were instructed to covertly attend to either left or right hemifield stimuli in order to detect designated target stimuli that required a response. To generate form-from-motion (FFMo) stimuli, a subset of the dots could begin to move coherently to create the appearance of a simple form (e.g., square). In other blocks, to generate form-from-luminance (FFLu) stimuli that served as a control, a gray stimulus was presented superimposed on the randomly moving dots. Neuromagnetic responses were observed to both the FFLu and FFMo stimuli and localized to multiple visual cortical stages of analysis. Early activity in low-level visual cortical areas (striate/early extrastriate) did not differ for FFLu versus FFMo stimuli, nor as a function of spatial attention. Longer latency responses elicited by the FFLu stimuli were localized to the ventral-lateral occipital cortex (LO) and the inferior temporal cortex (IT). The FFMo stimuli also generated activity in the LO and IT, but only after first eliciting activity in the lateral occipital cortical region corresponding to MT/V5, resulting in a 50-60 msec delay in activity. All of these late responses (MT/V5, LO, and IT) were significantly modulated by spatial attention, being greatly attenuated for ignored FFLu and FFMo stimuli. These findings argue that processing of form in IT that is defined by motion requires a serial processing of information, first in the motion analysis pathway from V1 to MT/V5 and thereafter via the form analysis stream in the ventral visual pathway to IT.

Phonetic perception and the temporal cortex.

Recent functional neuroimaging studies have emphasized the role of the different areas within the left superior temporal sulcus (STS) for the perception of various speech stimuli. We report here the results of three independent studies additionally demonstrating hemodynamic responses in the vicinity of the planum temporale (PT). In these studies we used consonant-vowel (CV) syllables, tones, white noise, and vowels as acoustic stimuli in the context of whole-head functional magnetic resonance imaging, applying a long TR to attenuate possible masking effects by the scanner noise. To summarize, we obtained the following results for the contrasts comparing hemodynamic responses obtained during the perception of CV syllables compared to tones or white noise: (i) stronger activation in the vicinity of the left PT with two distinct foci of activation, one in a lateral position and the other more medial in the vicinity of Heschl's sulcus; (ii) stronger activation in the vicinity of the right PT; and (iii) stronger bilateral activation within the mid-STS. Further contrasts revealed the following findings: (iv) stronger bilateral activation to CV syllables than to vowels in the medial PT, (v) stronger left-sided activation to CV syllables than to vowels in the mid-STS, and (vi) stronger activation to CV syllables with voiceless initial consonants than to CV syllables with voiced initial consonants in the left medial PT. The results are compatible with the hypothesis that the STS contains neurons specialized for speech perception. However, these results also emphasize the role of the PT in the analysis of phonetic features, namely the voice-onset-time. Yet this does not mean that the PT is solely specialized for phonetic analysis. We hypothesize rather that the PT contains neurons specialized for the analysis of rapidly changing cues as was suggested by P. Tallal et al. (1993, Ann. N. Y. Acad. Sci. 682: 27-47).

Short-term functional plasticity in the human auditory cortex: an fMRI study.

Applying functional magnetic resonance imaging (fMRI) techniques, hemodynamic responses elicited by sequences of pure tones of 950 Hz (standard) and deviant tones of 952, 954, and 958 Hz were measured before and 1 week after subjects had been trained at frequency discrimination for five sessions (over 1 week) using an oddball procedure. The task of the subject was to detect deviants differing from the standard stimulus. Frequency discrimination improved during the training session for three subjects (performance gain: T+) but not for three other subjects (no performance gain: T-). Hemodynamic responses in the auditory cortex comprising the planum temporale, planum polare and sulcus temporalis superior significantly decreased during training only for the T+ group. These activation changes were strongest for those stimuli accompanied by the strongest performance gain (958 and 954 Hz). There was no difference with respect to the hemodynamic responses in the auditory cortex for the T- group and the control group (CO) who did not received any pitch discrimination training. The results suggest a plastic reorganization of the cortical representation for the trained frequencies which can be best explained on the basis of 'fast learning' theories.

Optical imaging of neural activity in multiple auditory cortical fields of guinea pigs.

Neural activity of multiple fields in the auditory cortex of anesthetized guinea pigs in response to pure tones was visualized by optical recording using a voltage-sensitive dye (RH795). Ten auditory fields were identified based on the tonotopic organization and response latency: the core fields consisting of the primary (AI) and secondary (AII) fields and surrounding belt areas consisting of dorso-anterior (DA), dorsal (D), dorso-posterior (DP), posterior (P), ventro-posterior (VP), ventro-medial (VM), ventro-anterior (VA) and ventral (V) fields. Tonotopic organization was observed in all the fields apart from DA, D, DP and V. Spatio-temporal displays suggest that the auditory information spreads from the core fields of AI and AII to belt fields via three distinct (dorsocaudal, caudal and ventrorostral) pathways.

Auditory perception of laughing and crying activates human amygdala regardless of attentional state.

Adequate behavioral responses to socially relevant stimuli are often impaired after lesions of the amygdala. Such lesions concern especially the recognition of facial and sometimes of vocal expression of emotions. Using low-noise functional magnetic resonance imaging (fMRI), we investigated in which way the amygdala, auditory cortex and insula are involved in the processing of affective nonverbal vocalizations (Laughing and Crying) in healthy humans. The same samples of male and female Laughing and Crying were presented in different experimental conditions: Simply listening to the stimuli, self-induction of the corresponding emotions while listening, and detection of artificial pitch shifts in the same stimuli. All conditions activated the amygdala similarly and bilaterally, whereby the amount of activation was larger in the right amygdala. The auditory cortex was more strongly activated by Laughing than by Crying with a slight right-hemisphere advantage for Laughing, both likely due to acoustic stimulus features. The insula was bilaterally activated in all conditions. The mean signal intensity change with stimulation was much larger in the amygdala than in auditory cortex and insula. The amygdala results seem to be in accordance with the right-hemisphere hypothesis of emotion processing which may not be applicable as strongly to the level of auditory cortex or insula.

Change in pattern of ongoing cortical activity with auditory category learning.

Humans are able to classify novel items correctly by category; some other animals have also been shown to do this. During category learning, humans group perceptual stimuli by abstracting qualities from similarity relationships of their physical properties. Forming categories is fundamental to cognition and can be independent of a 'memory store' of information about the items or a prototype. The neurophysiological mechanisms underlying the formation of categories are unknown. Using an animal model of category learning, in which frequency-modulated tones are distinguished into the categories of 'rising' and 'falling' modulation, we demonstrate here that the sorting of stimuli into these categories emerges as a sudden change in an animal's learning strategy. Electro-corticographical recording from the auditory cortex shows that the transition is accompanied by a change in the dynamics of cortical stimulus representation. We suggest that this dynamic change represents a mechanism underlying the recognition of the abstract quality (or qualities) that defines the categories.

Comparative electrophysiological and hemodynamic measures of neural activation during memory-retrieval.

The spatial and temporal characteristics of the brain processes underlying memory retrieval were studied with both event-related potentials (ERP) and positron emission tomography (PET) techniques. Subjects studied lists of 20 words and then performed episodic (old/new judgment) or semantic (living/nonliving decision) retrieval tasks on multiple four-item test lists, each lasting 10 sec. The PET and ERP measurements at test were assessed in relation to both the task (episodic vs. semantic) and the item (old vs. new or living vs. nonliving). Episodic retrieval was associated with increased blood flow in the right frontal lobe (Brodmann Area 10) and a sustained, slowly developing positive ERP shift recorded from the right frontopolar scalp. Semantic retrieval was associated with increased blood flow in the left frontal (Area 45) and temporal (Area 21) lobes but no clear ERP concomitant. The two retrieval tasks also differed from each other in the ERPs to single items in an early (300-500 ms) time window. Item-related comparisons yielded convergent results mainly if the retrieved information was relevant to the given task (e.g., old/new items during episodic retrieval and living/nonliving items during semantic retrieval). Episodically retrieved old items were associated with increased blood flow in the left medial temporal lobe and a transient increase in the amplitude of the late positive component (500-700 ms) of the ERP. Semantically retrieved living items were associated with increased blood flow in the left frontal cortex and anterior cingulate and a transient late frontal slow wave (700-1,500 ms) in the ERPs. These results indicate that the brain regions engaged in memory retrieval are active in either a sustained or transient manner. They map task-related processes to sustained and item-related processes to transient neural activity. But they also suggest that task-related factors can transiently affect early stages of item processing.