Mortimer Mishkin’s research while affiliated with National Institute of Mental Health, National Institutes of Health and other places

Despite bilateral hippocampal damage dating to perinatal or early-childhood period, and severely-impaired episodic memory that unfolds in later childhood, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganise to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40% while the atrophy of the uncus was moderate (−23%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions, such that the greater the damage, the more likely it is that surrounding cortical areas will be recruited to rescue the putative functions of the damaged subregions. Our findings document for the first time not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.

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.

The hippocampus is critical for cognitive memory and spatial processing but what are the specific functions of the different hippocampal subregions in humans? Can we provide evidence of functional correlations between cognitive performance and volumes of residual hippocampal subregions in patients with hippocampal damage? Here, we studied a large cohort of patients with Developmental Amnesia. These patients present with severe, bilateral damage to the hippocampus resulting from neonatal exposure to hypoxic-ischemic episodes. We used magnetic resonance imaging to estimate the volume of three hippocampal subregions: the Uncus, the Subiculum, and the CA-fields-dentate gyrus. We show that the level of volume reduction of the Uncus correlates positively with recall performance in patients. Also, we show that the level of volume reduction of the Subiculum correlates positively with spatial performance in patients. Altogether, these paradoxical findings suggest that following hippocampal damage of early onset, the brain is more likely to compensate for hippocampal function when the damage is more severe.

Auditory selective listening and decision making underlies important processes, including attending to a single speaker in a crowded room, often referred to as the cocktail party problem. To examine the neural mechanisms underlying these behaviors, we developed a novel auditory selective listening paradigm for monkeys. In this task, monkeys had to detect a difficult to discriminate target embedded in noise when presented in a pre-cued location (either left or right) and ignore it if it was in the opposite location. While the animals carried out the task we recorded neural activity in primary auditory cortex (AC), dorsal lateral prefrontal cortex (dlPFC) and the basal lateral amygdala (BLA), given that these areas have been implicated in auditory decision making, selective listing, and/or reward-guided decision making. There were two main findings in the neural data. First, primary AC encoded the side of the cue and target, and the monkey's choice, before either dlPFC or the amygdala. The BLA encoded cue and target variables negligibly, but was engaged at the time of the monkey's choice. Second, decoding analyses suggested that errors followed primarily from a failure to encode the target stimulus in both AC and PFC, but earlier in AC. Thus, AC neural activity is poised to represent the sensory volley and decision making during selective listening before dlPFC, and they both precede activity in BLA.

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.

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.

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the ‘KE family’, who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene’s early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech. Electronic supplementary material The online version of this article (10.1007/s12311-018-0989-3) contains supplementary material, which is available to authorized users.

Animals and humans rapidly detect specific features of sounds, but the time courses of the underlying neural response for different stimulus categories is largely unknown. Furthermore, the intricate functional organization of auditory information processing pathways is poorly understood. Here, we computed neuronal response latencies from simultaneously recorded spike trains and local field potentials (LFPs) along the first two stages of cortical sound processing, primary auditory cortex (A1) and lateral belt (LB), of awake, behaving macaques. Two types of response latencies were measured for spike trains as well as LFPs: (1) onset latency, time-locked to onset of external auditory stimuli; and (2) selection latency, time taken from stimulus onset to a selective response to a specific stimulus category. Trial-by-trial LFP onset latencies predominantly reflecting synaptic input arrival typically preceded spike onset latencies, assumed to be representative of neuronal output indicating that both areas may receive input environmental signals and relay the information to the next stage. In A1, simple sounds, such as pure tones (PTs), yielded shorter spike onset latencies compared to complex sounds, such as monkey vocalizations (“Coos”). This trend was reversed in LB, indicating a hierarchical functional organization of auditory cortex in the macaque. LFP selection latencies in A1 were always shorter than those in LB for both PT and Coo reflecting the serial arrival of stimulus-specific information in these areas. Thus, chronometry on spike-LFP signals revealed some of the effective neural circuitry underlying complex sound discrimination.