Correlates of Auditory Decision-Making in Prefrontal, Auditory, and Basal Lateral Amygdala Cortical Areas.

Spatial selective listening and auditory choice underlie important processes including attending to a speaker at a cocktail party and knowing how (or whether) to respond. To examine task encoding and the relative timing of potential neural substrates underlying these behaviors, we developed a spatial selective detection paradigm for monkeys, and recorded activity in primary auditory cortex (AC), dorsolateral prefrontal cortex (dlPFC), and the basolateral amygdala (BLA). A comparison of neural responses among these three areas showed that, as expected, AC encoded the side of the cue and target characteristics before dlPFC and BLA. Interestingly, AC also encoded the choice of the monkey before dlPFC and around the time of BLA. Generally, BLA showed weak responses to all task features except the choice. Decoding analyses suggested that errors followed from a failure to encode the target stimulus in both AC and dlPFC, but again, these differences arose earlier in AC. The similarities between AC and dlPFC responses were abolished during passive sensory stimulation with identical trial conditions, suggesting that the robust sensory encoding in dlPFC is contextually gated. Thus, counter to a strictly PFC-driven decision process, in this spatial selective listening task AC neural activity represents the sensory and decision information before dlPFC. Unlike in the visual domain, in this auditory task, the BLA does not appear to be robustly involved in selective spatial processing.SIGNIFICANCE STATEMENT We examined neural correlates of an auditory spatial selective listening task by recording single-neuron activity in behaving monkeys from the amygdala, dorsolateral prefrontal cortex, and auditory cortex. We found that auditory cortex coded spatial cues and choice-related activity before dorsolateral prefrontal cortex or the amygdala. Auditory cortex also had robust delay period activity. Therefore, we found that auditory cortex could support the neural computations that underlie the behavioral processes in the task.

A Comparison of Auditory Oddball Responses in Dorsolateral Prefrontal Cortex, Basolateral Amygdala, and Auditory Cortex of Macaque.

The mismatch negativity (MMN) is an ERP component seen in response to unexpected "novel" stimuli, such as in an auditory oddball task. The MMN is of wide interest and application, but the neural responses that generate it are poorly understood. This is in part due to differences in design and focus between animal and human oddball paradigms. For example, one of the main explanatory models, the "predictive error hypothesis", posits differences in timing and selectivity between signals carried in auditory and prefrontal cortex (PFC). However, these predictions have not been fully tested because (1) noninvasive techniques used in humans lack the combined spatial and temporal precision necessary for these comparisons and (2) single-neuron studies in animal models, which combine necessary spatial and temporal precision, have not focused on higher order contributions to novelty signals. In addition, accounts of the MMN traditionally do not address contributions from subcortical areas known to be involved in novelty detection, such as the amygdala. To better constrain hypotheses and to address methodological gaps between human and animal studies, we recorded single neuron activity from the auditory cortex, dorsolateral PFC, and basolateral amygdala of two macaque monkeys during an auditory oddball paradigm modeled after that used in humans. Consistent with predictions of the predictive error hypothesis, novelty signals in PFC were generally later than in auditory cortex and were abstracted from stimulus-specific effects seen in auditory cortex. However, we found signals in amygdala that were comparable in magnitude and timing to those in PFC, and both prefrontal and amygdala signals were generally much weaker than those in auditory cortex. These observations place useful quantitative constraints on putative generators of the auditory oddball-based MMN and additionally indicate that there are subcortical areas, such as the amygdala, that may be involved in novelty detection in an auditory oddball paradigm.

Intrinsic Connections of the Core Auditory Cortical Regions and Rostral Supratemporal Plane in the Macaque Monkey.

In the ventral stream of the primate auditory cortex, cortico-cortical projections emanate from the primary auditory cortex (AI) along 2 principal axes: one mediolateral, the other caudorostral. Connections in the mediolateral direction from core, to belt, to parabelt, have been well described, but less is known about the flow of information along the supratemporal plane (STP) in the caudorostral dimension. Neuroanatomical tracers were injected throughout the caudorostral extent of the auditory core and rostral STP by direct visualization of the cortical surface. Auditory cortical areas were distinguished by SMI-32 immunostaining for neurofilament, in addition to established cytoarchitectonic criteria. The results describe a pathway comprising step-wise projections from AI through the rostral and rostrotemporal fields of the core (R and RT), continuing to the recently identified rostrotemporal polar field (RTp) and the dorsal temporal pole. Each area was strongly and reciprocally connected with the areas immediately caudal and rostral to it, though deviations from strictly serial connectivity were observed. In RTp, inputs converged from core, belt, parabelt, and the auditory thalamus, as well as higher order cortical regions. The results support a rostrally directed flow of auditory information with complex and recurrent connections, similar to the ventral stream of macaque visual cortex.

Extent of hippocampal atrophy predicts degree of deficit in recall.

Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition.

Hippocampal damage and memory impairment in congenital cyanotic heart disease.

Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalizability of this causal sequence, we examined a cohort of 41 children aged 8-16, who, having received the arterial switch operation to correct for transposition of the great arteries, had sustained significant neonatal cyanosis but were otherwise neurodevelopmentally normal. As predicted, the cohort had significant bilateral reduction of hippocampal volumes relative to the volumes of 64 normal controls. They also had significant, yet selective, impairment of episodic memory as measured by standard tests of memory, despite relatively normal levels of intelligence, academic attainment, and verbal fluency. Across the cohort, degree of memory impairment was correlated with degree of hippocampal atrophy suggesting that even as early as neonatal life no other structure can fully compensate for hippocampal injury and its special role in serving episodic long term memory. © 2017 Wiley Periodicals, Inc.

Hippocampal Volume Reduction in Humans Predicts Impaired Allocentric Spatial Memory in Virtual-Reality Navigation.

The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with "moderate" hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes. SIGNIFICANCE STATEMENT: In humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated spatial recall using a virtual environment in two groups of patients with hippocampal damage (moderate/severe) and a normal control group. The results showed that patients with severe hippocampal damage are impaired in learning and recalling allocentric spatial information. Furthermore, hippocampal volume reduction impaired allocentric navigation beyond what can be predicted by memory quotient as a widely used measure of general memory function.

A new neural framework for visuospatial processing.

The division of cortical visual processing into distinct dorsal and ventral streams is a key framework that has guided visual neuroscience. The characterization of the ventral stream as a 'What' pathway is relatively uncontroversial, but the nature of dorsal stream processing is less clear. Originally proposed as mediating spatial perception ('Where'), more recent accounts suggest it primarily serves non-conscious visually guided action ('How'). Here, we identify three pathways emerging from the dorsal stream that consist of projections to the prefrontal and premotor cortices, and a major projection to the medial temporal lobe that courses both directly and indirectly through the posterior cingulate and retrosplenial cortices. These three pathways support both conscious and non-conscious visuospatial processing, including spatial working memory, visually guided action and navigation, respectively.

Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence.

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life.

Differential coding of conspecific vocalizations in the ventral auditory cortical stream.

The mammalian auditory cortex integrates spectral and temporal acoustic features to support the perception of complex sounds, including conspecific vocalizations. Here we investigate coding of vocal stimuli in different subfields in macaque auditory cortex. We simultaneously measured auditory evoked potentials over a large swath of primary and higher order auditory cortex along the supratemporal plane in three animals chronically using high-density microelectrocorticographic arrays. To evaluate the capacity of neural activity to discriminate individual stimuli in these high-dimensional datasets, we applied a regularized multivariate classifier to evoked potentials to conspecific vocalizations. We found a gradual decrease in the level of overall classification performance along the caudal to rostral axis. Furthermore, the performance in the caudal sectors was similar across individual stimuli, whereas the performance in the rostral sectors significantly differed for different stimuli. Moreover, the information about vocalizations in the caudal sectors was similar to the information about synthetic stimuli that contained only the spectral or temporal features of the original vocalizations. In the rostral sectors, however, the classification for vocalizations was significantly better than that for the synthetic stimuli, suggesting that conjoined spectral and temporal features were necessary to explain differential coding of vocalizations in the rostral areas. We also found that this coding in the rostral sector was carried primarily in the theta frequency band of the response. These findings illustrate a progression in neural coding of conspecific vocalizations along the ventral auditory pathway.

Test of a motor theory of long-term auditory memory.

Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e.g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory-suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve.

Monkeys have a limited form of short-term memory in audition.

A stimulus trace may be temporarily retained either actively [i.e., in working memory (WM)] or by the weaker mnemonic process we will call passive short-term memory, in which a given stimulus trace is highly susceptible to "overwriting" by a subsequent stimulus. It has been suggested that WM is the more robust process because it exploits long-term memory (i.e., a current stimulus activates a stored representation of that stimulus, which can then be actively maintained). Recent studies have suggested that monkeys may be unable to store acoustic signals in long-term memory, raising the possibility that they may therefore also lack auditory WM. To explore this possibility, we tested rhesus monkeys on a serial delayed match-to-sample (DMS) task using a small set of sounds presented with ~1-s interstimulus delays. Performance was accurate whenever a match or a nonmatch stimulus followed the sample directly, but it fell precipitously if a single nonmatch stimulus intervened between sample and match. The steep drop in accuracy was found to be due not to passive decay of the sample's trace, but to retroactive interference from the intervening nonmatch stimulus. This "overwriting" effect was far greater than that observed previously in serial DMS with visual stimuli. The results, which accord with the notion that WM relies on long-term memory, indicate that monkeys perform serial DMS in audition remarkably poorly and that whatever success they had on this task depended largely, if not entirely, on the retention of stimulus traces in the passive form of short-term memory.

Two processes support visual recognition memory in rhesus monkeys.

A large body of evidence in humans suggests that recognition memory can be supported by both recollection and familiarity. Recollection-based recognition is characterized by the retrieval of contextual information about the episode in which an item was previously encountered, whereas familiarity-based recognition is characterized instead by knowledge only that the item had been encountered previously in the absence of any context. To date, it is unknown whether monkeys rely on similar mnemonic processes to perform recognition memory tasks. Here, we present evidence from the analysis of receiver operating characteristics, suggesting that visual recognition memory in rhesus monkeys also can be supported by two separate processes and that these processes have features considered to be characteristic of recollection and familiarity. Thus, the present study provides converging evidence across species for a dual process model of recognition memory and opens up the possibility of studying the neural mechanisms of recognition memory in nonhuman primates on tasks that are highly similar to the ones used in humans.

Differential effects of m1 and m2 receptor antagonists in perirhinal cortex on visual recognition memory in monkeys.

Microinfusions of the nonselective muscarinic antagonist scopolamine into perirhinal cortex impairs performance on visual recognition tasks, indicating that muscarinic receptors in this region play a pivotal role in recognition memory. To assess the mnemonic effects of selective blockade in perirhinal cortex of muscarinic receptor subtypes, we locally infused either the m1-selective antagonist pirenzepine or the m2-selective antagonist methoctramine in animals performing one-trial visual recognition, and compared these scores with those following infusions of equivalent volumes of saline. Compared to these control infusions, injections of pirenzepine, but not of methoctramine, significantly impaired recognition accuracy. Further, similar doses of scopolamine and pirenzepine yielded similar deficits, suggesting that the deficits obtained earlier with scopolamine were due mainly, if not exclusively, to blockade of m1 receptors. The present findings indicate that m1 and m2 receptors have functionally dissociable roles, and that the formation of new visual memories is critically dependent on the cholinergic activation of m1 receptors located on perirhinal cells.

Hierarchical auditory processing directed rostrally along the monkey's supratemporal plane.

Connectional anatomical evidence suggests that the auditory core, containing the tonotopic areas A1, R, and RT, constitutes the first stage of auditory cortical processing, with feedforward projections from core outward, first to the surrounding auditory belt and then to the parabelt. Connectional evidence also raises the possibility that the core itself is serially organized, with feedforward projections from A1 to R and with additional projections, although of unknown feed direction, from R to RT. We hypothesized that area RT together with more rostral parts of the supratemporal plane (rSTP) form the anterior extension of a rostrally directed stimulus quality processing stream originating in the auditory core area A1. Here, we analyzed auditory responses of single neurons in three different sectors distributed caudorostrally along the supratemporal plane (STP): sector I, mainly area A1; sector II, mainly area RT; and sector III, principally RTp (the rostrotemporal polar area), including cortex located 3 mm from the temporal tip. Mean onset latency of excitation responses and stimulus selectivity to monkey calls and other sounds, both simple and complex, increased progressively from sector I to III. Also, whereas cells in sector I responded with significantly higher firing rates to the "other" sounds than to monkey calls, those in sectors II and III responded at the same rate to both stimulus types. The pattern of results supports the proposal that the STP contains a rostrally directed, hierarchically organized auditory processing stream, with gradually increasing stimulus selectivity, and that this stream extends from the primary auditory area to the temporal pole.

Pulvinar inactivation disrupts selection of movement plans.

The coordinated movement of the eyes and hands under visual guidance is an essential part of goal-directed behavior. Several cortical areas known to be involved in this process exchange projections with the dorsal aspect of the thalamic pulvinar nucleus, suggesting that this structure may play a central role in visuomotor behavior. Here, we used reversible inactivation to investigate the role of the dorsal pulvinar in the selection and execution of visually guided manual and saccadic eye movements in macaque monkeys. We found that unilateral pulvinar inactivation resulted in a spatial neglect syndrome accompanied by visuomotor deficits including optic ataxia during visually guided limb movements. Monkeys were severely disrupted in their visually guided behavior regarding space contralateral to the side of the injection in several domains, including the following: (1) target selection in both manual and oculomotor tasks, (2) limb usage in a manual retrieval task, and (3) spontaneous visual exploration. In addition, saccades into the ipsilesional field had abnormally short latencies and tended to overshoot their mark. None of the deficits could be explained by a visual field defect or primary motor deficit. These findings highlight the importance of the dorsal aspect of the pulvinar nucleus as a critical hub for spatial attention and selection of visually guided actions.

Effect of sound intensity on tonotopic fMRI maps in the unanesthetized monkey.

The monkey's auditory cortex includes a core region on the supratemporal plane (STP) made up of the tonotopically organized areas A1, R, and RT, together with a surrounding belt and a lateral parabelt region. The functional studies that yielded the tonotopic maps and corroborated the anatomical division into core, belt, and parabelt typically used low-amplitude pure tones that were often restricted to threshold-level intensities. Here we used functional magnetic resonance imaging in awake rhesus monkeys to determine whether, and if so how, the tonotopic maps and the pattern of activation in core, belt, and parabelt are affected by systematic changes in sound intensity. Blood oxygenation level-dependent (BOLD) responses to groups of low- and high-frequency pure tones 3-4 octaves apart were measured at multiple sound intensity levels. The results revealed tonotopic maps in the auditory core that reversed at the putative areal boundaries between A1 and R and between R and RT. Although these reversals of the tonotopic representations were present at all intensity levels, the lateral spread of activation depended on sound amplitude, with increasing recruitment of the adjacent belt areas as the intensities increased. Tonotopic organization along the STP was also evident in frequency-specific deactivation (i.e. "negative BOLD"), an effect that was intensity-specific as well. Regions of positive and negative BOLD were spatially interleaved, possibly reflecting lateral inhibition of high-frequency areas during activation of adjacent low-frequency areas, and vice versa. These results, which demonstrate the strong influence of tonal amplitude on activation levels, identify sound intensity as an important adjunct parameter for mapping the functional architecture of auditory cortex.

Species-specific calls evoke asymmetric activity in the monkey's temporal poles.

It has often been proposed that the vocal calls of monkeys are precursors of human speech, in part because they provide critical information to other members of the species who rely on them for survival and social interactions. Both behavioural and lesion studies suggest that monkeys, like humans, use the auditory system of the left hemisphere preferentially to process vocalizations. To investigate the pattern of neural activity that might underlie this particular form of functional asymmetry in monkeys, we measured local cerebral metabolic activity while the animals listened passively to species-specific calls compared with a variety of other classes of sound. Within the superior temporal gyrus, significantly greater metabolic activity occurred on the left side than on the right, only in the region of the temporal pole and only in response to monkey calls. This functional asymmetry was absent when these regions were separated by forebrain commissurotomy, suggesting that the perception of vocalizations elicits concurrent interhemispheric interactions that focus the auditory processing within a specialized area of one hemisphere.

Resection of the medial temporal lobe disconnects the rostral superior temporal gyrus from some of its projection targets in the frontal lobe and thalamus.

Auditory memory in the monkey does not appear to extend beyond the limits of working memory. It is therefore surprising that this ability is impaired by medial temporal lobe (MTL) resections, because such lesions spare working memory in other sensory modalities. To determine whether MTL ablations might have caused the auditory deficit through inadvertent transection of superior temporal gyrus (STG) projections to its downstream targets, and, if so, which targets might have been compromised, we injected anterograde tracer (biotinylated dextran amine) in the STG of both the normal and MTL-lesioned hemispheres of split-brain monkeys. Interhemispheric comparison of label failed to show any effect of the MTL ablation on efferents from caudal STG, which projects to the inferior prefrontal convexity. However, the ablation did consistently interrupt the normally dense projections from rostral STG to both the ventral medial prefrontal cortex and medial thalamic nuclei. The findings support the possibility that the auditory working memory deficit after MTL ablation is due to transection of downstream auditory projections, and indicate that the candidate structures for mediating auditory working memory are the ventral medial prefrontal cortical areas, the medial thalamus, or both.

Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning.

Monkeys trained in either one-trial recognition at 8- to 10-min delays or multi-trial discrimination habits with 24-h intertrial intervals received systemic cholinergic and dopaminergic antagonists, scopolamine and haloperidol, respectively, in separate sessions. Recognition memory was impaired markedly by scopolamine but not at all by haloperidol, whereas habit formation was impaired markedly by haloperidol but only minimally by scopolamine. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories versus slow acquisition but durable retention of habits.

Frontal and Insular Input to the Dorsolateral Temporal Pole in Primates: Implications for Auditory Memory.

The temporal pole (TP) has been involved in multiple functions from emotional and social behavior, semantic processing, memory, language in humans and epilepsy surgery, to the fronto-temporal neurodegenerative disorder (semantic) dementia. However, the role of the TP subdivisions is still unclear, in part due to the lack of quantitative data about TP connectivity. This study focuses in the dorsolateral subdivision of the TP: area 38DL. Area 38DL main input originates in the auditory processing areas of the rostral superior temporal gyrus. Among other connections, area 38DL conveys this auditory highly processed information to the entorhinal, rostral perirhinal, and posterior parahippocampal cortices, presumably for storage in long-term memory (Muñoz-López et al., 2015). However, the connections of the TP with cortical areas beyond the temporal cortex suggest that this area is part of a wider network. With the aim to quantitatively determine the topographical, laminar pattern and weighting of the lateral TP afferents from the frontal and insular cortices, we placed a total of 11 tracer injections of the fluorescent retrograde neuronal tracers Fast Blue and Diamidino Yellow at different levels of the lateral TP in rhesus monkeys. The results showed that circa 50% of the total cortical input to area 38DL originates in medial frontal areas 14, 25, 32, and 24 (25%); orbitofrontal areas Pro and PAll (15%); and the agranular, parainsular and disgranular insula (10%). This study sets the anatomical bases to better understand the function of the dorsolateral division of the TP. More specifically, these results suggest that area 38DL forms part of the wider limbic circuit that might contribute, among other functions, with an auditory component to multimodal memory processing.