Volumetric mesoscopic electrophysiology: a new imaging modality for the non-human primate.

The primate brain is a densely interconnected organ whose function is best understood by recording from the entire structure in parallel, rather than parts of it in sequence. However, available methods either have limited temporal resolution (functional magnetic resonance imaging), limited spatial resolution (macroscopic electroencephalography), or a limited field of view (microscopic electrophysiology). To address this need, we developed a volumetric, mesoscopic recording approach ( MePhys ) by tessellating the volume of a monkey hemisphere with 992 electrode contacts that were distributed across 62 chronically implanted multi-electrode shafts. We showcase the scientific promise of MePhys by describing the functional interactions of local field potentials between the more than 300,000 simultaneously recorded pairs of electrodes. We find that a subanesthetic dose of ketamine -believed to mimic certain aspects of psychosis- can create a pronounced state of functional disconnection and prevent the formation of stable large-scale intrinsic states. We conclude that MePhys provides a new and fundamentally distinct window into brain function whose unique profile of strengths and weaknesses complements existing approaches in synergistic ways.

Formation and decay of auditory short-term memory in the macaque monkey.

Echoic memory (EM) is a short-lived, precategorical, and passive form of auditory short-term memory (STM). A key hallmark of EM is its rapid exponential decay with a time constant between 1 and 2 s. It is not clear whether auditory STM in the rhesus, an important model system, shares this rapid exponential decay. To resolve this shortcoming, two rhesus macaques were trained to perform a delayed frequency discrimination task. Discriminability of delayed tones was measured as a function of retention duration and the number of times the standard had been repeated before the target. Like in the human, our results show a rapid decline of discriminability with retention duration. In addition, the results suggest a gradual strengthening of discriminability with repetition number. Model-based analyses suggest the presence of two components of auditory STM: a short-lived component with a time constant on the order of 550 ms that most likely corresponds to EM and a more stable memory trace with time constants on the order of 10 s that strengthens with repetition and most likely corresponds to auditory recognition memory. NEW & NOTEWORTHY This is the first detailed quantification of the rapid temporal dynamics of auditory short-term memory in the rhesus. Much of the auditory information in short-term memory is lost within the first couple of seconds. Repeated presentations of a tone strengthen its encoding into short-term memory. Model-based analyses suggest two distinct components: an echoic memory homolog that mediates the rapid decay and a more stable but less detail-rich component that mediates strengthening of the trace with repetition.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-ᴅ-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment.

BACKGROUND: Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7-24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. RESULTS: Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-α are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM-Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. CONCLUSIONS: Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-d-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus.

Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ∼65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions.

Altered activity-based sleep measures in rhesus monkeys following cocaine self-administration and abstinence.

BACKGROUND: Impairments in sleep and cognitive function have been observed in patients with substance abuse disorders and may be potential factors contributing to drug relapse. In addition, sleep disruption may itself contribute to cognitive deficits. In the present study we examined the impact of prolonged cocaine self-administration and abstinence on actigraphy-based measures of night-time activity in rhesus macaques as an inferential measure of sleep, and determined whether sleep-efficiency correlated with cognitive impairments in the same subjects on drug free days. METHODS: Actigraphy data was obtained from a group of rhesus macaques intravenously self-administering cocaine (n=6) and a control group (n=5). Periods were evaluated during which the mean cumulative doses of cocaine were 3.0+0.0 and 4.5+0.2mg/kg/day for 4days (Tuesday-Thursday) each week. RESULTS: Actigraphy-based sleep efficiency decreased during days of cocaine self-administration in a dose-dependent manner. Consistent with this observation, sleep became more fragmented. Activity-based sleep efficiency normalized during the weekend without cocaine prior to cognitive assessment on Monday. The magnitude of activity-based sleep disruption during self-administration did not correlate with the level of cognitive impairment on drug free days. With continued self-administration, the impact of cocaine on activity-based sleep efficiency declined indicating the development of tolerance. CONCLUSIONS: Cocaine self-administration disrupted sleep efficiency in rhesus macaques as measured by actigraphy, but normalized quickly in the absence of cocaine. The cognitive impairment observed on drug free days was unlikely to be related to disruption of the nightly activity patterns on days of cocaine self-administration.

Latent vulnerability in cognitive performance following chronic cocaine self-administration in rhesus monkeys.

RATIONALE: Cocaine use is associated with cognitive impairment which impacts treatment outcome. A clearer understanding of those deficits, and whether particular environments exacerbate them, is needed. OBJECTIVES: This study evaluated whether previously observed domain-specific cognitive deficits persisted following a 3-month cessation from chronic cocaine self-administration, as well as the impact of novel and cocaine-associated attentional distractors. METHODS: Control and experimental groups of monkeys performed stimulus discrimination, stimulus reversal, and delayed match-to-sample (DMS) tasks. After establishing post-cocaine baseline performance, we examined general distractibility in both groups, using brief novel distractors counterbalanced across each task. After testing the novel distractor, an identical approach was used for exposure to an appetitive distractor previously associated with cocaine in the experimental group or water in the control group. RESULTS: Post-administration baseline performance was equivalent between groups on all tasks. In the cocaine group, stimulus discrimination was unaffected by either distractor, whereas reversal performance was disrupted by both the novel and appetitive distractors. DMS performance was impaired in the cocaine group in the presence of the novel distractor. The control group's performance was not affected by the presentation of either distractor on any task. CONCLUSION: Our results reveal that despite normalized performance between groups, there exists in the cocaine group a domain-specific latent vulnerability of cognitive performance to impairment by environmental distractors. The pattern of vulnerability recapitulates the frank impairments seen in drug-free animals during an active self-administration phase. A greater impact of the cocaine-associated distractor over the novel one was not observed.

Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory.

Cocaine users display a wide range of cognitive impairments. Because treatment outcome is dependent on baseline cognitive ability, it is clinically important to understand the underlying neurobiology of these deficits. Therefore, it is crucial to determine whether cocaine exposure by itself is an etiological factor and, if so, to determine the overall nature of cognitive deficits associated with cocaine use. This will help to guide therapeutic approaches that address cognitive components of cocaine use to improve treatment outcome. We used rhesus monkeys in a longitudinal study in which 14 animals were characterized before assignment to matched control (n = 6) and cocaine self-administration (n = 8) groups. Self-administration took place on 4 consecutive days/week over 9 months, with a maximum (and typical) daily cumulative intake of 3.0 mg/kg. Weekly cognitive assessments (total of 36) were conducted after a 72 h drug-free period. We used a stimulus discrimination task with reversal to evaluate associative learning and the cognitive control/flexibility needed to adapt to changes in reward contingencies. After extended self-administration, initial accuracy on the stimulus discrimination indicated intact associative learning. However, animals were impaired at maintaining high levels of accuracy needed to reach criterion and initiate the reversal. Increasing the reward contrast between stimuli permitted evaluation of reversal performance and revealed striking deficits in the cocaine group. Impairments in visual working memory were also observed using a delayed match-to-sample task. These results suggest a combination of generalized, possibly attentional, impairments, along with a more specific cognitive control impairment implicating orbitofrontal cortex dysfunction.

The acute impact of ethanol on cognitive performance in rhesus macaques.

Decreased cognitive control over prepotent responses has been hypothesized to contribute to ethanol-induced behavioral disinhibition. However, the effects of ethanol on specific cognitive domains associated with decision making have not been extensively studied. We examined the impact of acute ethanol administration on cognitive performance of nonhuman primates. Studies were conducted using 0.2, 0.5, and 1 g/kg intravenous ethanol in rhesus macaques performing touch screen-based tasks examining stimulus discrimination, stimulus reversal, and stimulus response performance. The impact on attentional processing was also evaluated. Ethanol reduced the accuracy of reversal performance marginally at 0.2 g/kg and significantly at 0.5 g/kg. This effect was selective given an absence of impairment on the stimulus discrimination and stimulus response tasks at these doses. Performance on stimulus discrimination was impaired at 1.0 g/kg, which prevented determination of reversal performance. Analysis of post-error response times demonstrated that error processing was impaired at both 0.2 and 0.5 g/kg. Ethanol also increased the number of omissions and delayed responses on an attentional task, suggesting more frequent attentional lapses. These data demonstrate that cognitive function mediated by specific prefrontal cortical brain regions is particularly sensitive to ethanol and suggest specific cognitive mechanisms that may underlie harmful decisions made at low doses of ethanol.