Severity of Ongoing Post-Concussive Symptoms as a Predictor of Cognitive Performance Following a Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury. METHOD: 203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8-18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1-11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (~4 months) phase. RESULTS: Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not. CONCLUSIONS: The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.

Compressed Timeline of Recent Experience in Monkey Lateral Prefrontal Cortex.

Cognitive theories suggest that working memory maintains not only the identity of recently presented stimuli but also a sense of the elapsed time since the stimuli were presented. Previous studies of the neural underpinnings of working memory have focused on sustained firing, which can account for maintenance of the stimulus identity, but not for representation of the elapsed time. We analyzed single-unit recordings from the lateral prefrontal cortex of macaque monkeys during performance of a delayed match-to-category task. Each sample stimulus triggered a consistent sequence of neurons, with each neuron in the sequence firing during a circumscribed period. These sequences of neurons encoded both stimulus identity and elapsed time. The encoding of elapsed time became less precise as the sample stimulus receded into the past. These findings suggest that working memory includes a compressed timeline of what happened when, consistent with long-standing cognitive theories of human memory.

Investigating the diagnostic accuracy of a paper-and-pencil and a computerized cognitive test battery for pediatric mild traumatic brain injury.

OBJECTIVE: This study assessed classification accuracy of paper-and-pencil and computerized cognitive batteries at subacute (SA; 1-11 days) and early chronic (EC; ∼4 months) phases of pediatric mild traumatic brain injury (pmTBI). Two statistical approaches focused on single-subject performance (individual task scores, total impairments) were used to maximize clinical utility. METHOD: Two hundred thirty-five pmTBI and 169 healthy controls (HC) participants aged 8-18 were enrolled, with a subset (190 pmTBI; 160 HC) returning for the EC visit. The paper-and-pencil battery included several neuropsychological tests selected from recommended common data elements, whereas computerized testing was performed with the Cogstate Brief Battery. Hierarchical logistic regressions (base model: Parental education and premorbid reading abilities; full model: Base model and cognitive testing variables) were used to examine sensitivity/specificity, with diagnosis as the dependent variable. RESULTS: Number Sequencing and Cogstate One-Card Learning accuracy significantly predicted SA diagnosis (full model accuracy = 71.6%-71.7%, sensitivity = 80.6%-80.8%, specificity = 59.1%-59.6%), while only immediate recall was significant at EC visit (accuracy = 68.5%, sensitivity = 74.6%, specificity = 61.5%). Other measures (Letter Fluency, Cogstate Detection, and One-Card Learning accuracy) demonstrated higher proportions of impairment for pmTBI subacutely (pmTBI: 11.5%-19.8%; HC: 3.7%-6.1%) but did not improve classification accuracy. Evidence of multiple impairments across the entire testing battery significantly predicted diagnosis at both visits (full model accuracy = 66.2%-68.6%, sensitivity = 71.2%-78.9%, specificity = 54.3%-61.5%). CONCLUSIONS: Current results suggest similar modest diagnostic accuracy for computerized and paper-and-pencil batteries across multiple pmTBI phases. Moreover, findings suggest the total number of impairments may be more clinically useful than any single test or cognitive domain in terms of diagnostic accuracy at both assessment points. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Rapid association learning in the primate prefrontal cortex in the absence of behavioral reversals.

The PFC plays a central role in our ability to learn arbitrary rules, such as "green means go." Previous experiments from our laboratory have used conditional association learning to show that slow, gradual changes in PFC neural activity mirror monkeys' slow acquisition of associations. These previous experiments required monkeys to repeatedly reverse the cue-saccade associations, an ability known to be PFC-dependent. We aimed to test whether the relationship between PFC neural activity and behavior was due to the reversal requirement, so monkeys were trained to learn several new conditional cue-saccade associations without reversing them. Learning-related changes in PFC activity now appeared earlier and more suddenly in correspondence with similar changes in behavioral improvement. This suggests that learning of conditional associations is linked to PFC activity regardless of whether reversals are required. However, when previous learning does not need to be suppressed, PFC acquires associations more rapidly.

Comparison of primate prefrontal and premotor cortex neuronal activity during visual categorization.

Previous work has shown that neurons in the PFC show selectivity for learned categorical groupings. In contrast, brain regions lower in the visual hierarchy, such as inferior temporal cortex, do not seem to favor category information over information about physical appearance. However, the role of premotor cortex (PMC) in categorization has not been studied, despite evidence that PMC is strongly engaged by well-learned tasks and reflects learned rules. Here, we directly compare PFC neurons with PMC neurons during visual categorization. Unlike PFC neurons, relatively few PMC neurons distinguished between categories of visual images during a delayed match-to-category task. However, despite the lack of category information in the PMC, more than half of the neurons in both PFC and PMC reflected whether the category of a test image did or did not match the category of a sample image (i.e., had match information). Thus, PFC neurons represented all variables required to solve the cognitive problem, whereas PMC neurons instead represented only the final decision variable that drove the appropriate motor action required to obtain a reward. This dichotomy fits well with PFC's hypothesized role in learning arbitrary information and directing behavior as well as the PMC's role in motor planning.

The nature and rate of cognitive maturation from late childhood to adulthood.

To better understand the nature and rate of cognitive change across adolescence, the Cogstate Brief Battery (CBB) was utilized to assess psychomotor function, attention, working memory, and visual learning in individuals aged 10-18 years old. Since all CBB tasks have equivalent perceptual, motor, and linguistic demands as well as being appropriate for both children and adults, this approach allowed direct across-age comparison of multiple cognitive domains. Exponential decreases in reaction time and linear increases in accuracy were observed across adolescent development in a cross-sectional sample of 38,778 individuals and confirmed in a 5788 individual longitudinal sample with 1-year repeat assessments. These results have important implications for the repeated assessment of cognition during development where expected maturational changes in cognition must be accounted for during cognitive testing.

Comparison of Cognitive Performance on the Cogstate Brief Battery When Taken In-Clinic, In-Group, and Unsupervised.

OBJECTIVE: Repeat cognitive assessment comparing post-injury performance to a pre-injury baseline is common in concussion management. Although post-injury tests are typically administered in clinical settings, baseline tests may be conducted individually with one-on-one supervision, in a group with supervision, or without supervision. The extent to which these different test settings affect cognitive performance is not well understood. To assess if performance on the Cogstate Brief Battery (CBB) differs across these settings, tests completed individually with one-on-one supervision were compared to those taken either in a group with supervision or individually but without supervision. METHOD: A crossover study design was utilized to account for any effect of individual variability or test order to provide an unbiased examination of the effect of test setting on cognitive performance. Young adult participants completed an individually supervised test either before or after also completing a group or unsupervised test. RESULTS: CBB scores from the same individuals were not significantly different across test settings. Effect sizes ranged in magnitude from .09 to .12 for supervised versus unsupervised tests and from .01 to .37 for individual versus group tests across CBB tasks. CONCLUSION: These results suggest that cognitive testing with the CBB in alternate settings can provide valid cognitive data comparable to data obtained during individually supervised testing.

Detecting cognitive impairment after concussion: sensitivity of change from baseline and normative data methods using the CogSport/Axon cognitive test battery.

Concussion-related cognitive impairments are typically evaluated with repeated neuropsychological assessments where post-injury performances are compared with pre-injury baseline data (baseline method). Many cases of concussions, however, are evaluated in the absence of baseline data by comparing post-injury performances with normative data (normative method). This study aimed to compare the sensitivity and specificity of these two methods using the CogSport/Axon test battery. Normative data and reliable change indices were computed from a non-injured athlete sample (n = 235). Test-retest data from non-injured (n = 260) and recently concussed (n = 29) athlete samples were then used to compare the two methods. The baseline method was found to be more sensitive than the normative method, and both methods had high specificity and overall correct classification rates. This suggests that while the normative method identifies most cases of recent concussions, the baseline method remains a more precise approach to assessing concussion-related cognitive impairments.

Representation of multiple, independent categories in the primate prefrontal cortex.

Neural correlates of visual categories have been previously identified in the prefrontal cortex (PFC). However, whether individual neurons can represent multiple categories is unknown. Varying degrees of generalization versus specialization of neurons in the PFC have been theorized. We recorded from lateral PFC neural activity while monkeys switched between two different and independent categorical distinctions (Cats versus Dogs, Sports Cars versus Sedans). We found that many PFC neurons reflected both categorical distinctions. In fact, these multitasking neurons had the strongest category effects. This stands in contrast to our lab's recent report that monkeys switching between competing categorical distinctions (applied to the same stimulus set) showed independent representations. We suggest that cognitive demands determine whether PFC neurons function as category "multitaskers."

Perception of alcohol intoxication shows acute tolerance while executive functions remain impaired.

Several psychological constructs (e.g., subjective perception of intoxication, visuomotor speed) display acute tolerance to alcohol, that is, show improvement at declining blood alcohol concentrations (BACs) relative to equivalent rising BACs. However, methodological challenges emerge when attempting to make such comparisons across limbs of the BAC curve, which have proven a barrier to advancing research on acute tolerance. To date, no studies have made multiple comparisons across the entire BAC trajectory. This study employs experimental procedures that overcome some of these difficulties, offering a clearer picture of recovery of impairment for subjective perception of intoxication and cognitive performance and the relationship between them. Twenty participants were assessed at multiple time points over 2 days. Continuous subjective perception of intoxication ratings and cognitive data derived from a computerized measure were paired with a novel analytic paradigm, which allowed comparisons at identified BACs. Results showed acute tolerance for individuals' subjective perception of intoxication and for performance on cognitive tasks measuring visuomotor speed and learning efficiency (recovery from impairment). In contrast, performance on measures of executive function and short-term memory showed no significant difference between limbs at exact concentrations (no recovery from impairment). Therefore, despite participants feeling less intoxicated over time, many cognitive functions remained impaired. The implication for these findings in terms of drunken driving behavior are substantial, suggesting that people may be likely to drive once they subjectively perceive that they have recovered from the acute intoxicating effects of alcohol, despite the persistence of "higher order" cognitive impairments.

Comparison of saccade-associated neuronal activity in the primate central mesencephalic and paramedian pontine reticular formations.

The oculomotor system must convert signals representing the target of an intended eye movement into appropriate input to drive the individual extraocular muscles. Neural models propose that this transformation may involve either a decomposition of the intended eye displacement signal into horizontal and vertical components or an implicit process whereby component signals do not predominate until the level of the motor neurons. Thus decomposition models predict that premotor neurons should primarily encode component signals while implicit models predict encoding of off-cardinal optimal directions by premotor neurons. The central mesencephalic reticular formation (cMRF) and paramedian pontine reticular formation (PPRF) are two brain stem regions that likely participate in the development of motor activity since both structures are anatomically connected to nuclei that encode movement goal (superior colliculus) and generate horizontal eye movements (abducens nucleus). We compared cMRF and PPRF neurons and found they had similar relationships to saccade dynamics, latencies, and movement fields. Typically, the direction preference of these premotor neurons was horizontal, suggesting they were related to saccade components. To confirm this supposition, we studied the neurons during a series of oblique saccades that caused "component stretching" and thus allowed the vectorial (overall) saccade velocity to be dissociated from horizontal component velocity. The majority of cMRF and PPRF neurons encoded component velocity across all saccades, supporting decomposition models that suggest horizontal and vertical signals are generated before the level of the motoneurons. However, we also found novel vectorial eye velocity encoding neurons that may have important implications for saccade control.

Neurones associated with saccade metrics in the monkey central mesencephalic reticular formation.

Neurones in the central mesencephalic reticular formation (cMRF) begin to discharge prior to saccades. These long lead burst neurones interact with major oculomotor centres including the superior colliculus (SC) and the paramedian pontine reticular formation (PPRF). Three different functions have been proposed for neurones in the cMRF: (1) to carry eye velocity signals that provide efference copy information to the SC (feedback), (2) to provide duration signals from the omnipause neurones to the SC (feedback), or (3) to participate in the transformation from the spatial encoding of a target selection signal in the SC into the temporal pattern of discharge used to drive the excitatory burst neurones in the pons (feed-forward). According to each respective proposal, specific predictions about cMRF neuronal discharge have been formulated. Individual neurones should: (1) encode instantaneous eye velocity, (2) burst specifically in relation to saccade duration but not to other saccade metrics, or (3) have a spectrum of weak to strong correlations to saccade dynamics. To determine if cMRF neurones could subserve these multiple oculomotor roles, we examined neuronal activity in relation to a variety of saccade metrics including amplitude, velocity and duration. We found separate groups of cMRF neurones that have the characteristics predicted by each of the proposed models. We also identified a number of subgroups for which no specific model prediction had previously been established. We found that we could accurately predict the neuronal firing pattern during one type of saccade behaviour (visually guided) using the activity during an alternative behaviour with different saccade metrics (memory guided saccades). We suggest that this evidence of a close relationship of cMRF neuronal discharge to individual saccade metrics supports the hypothesis that the cMRF participates in multiple saccade control pathways carrying saccade amplitude, velocity and duration information within the brainstem.

Temporal characteristics of neurons in the central mesencephalic reticular formation of head unrestrained monkeys.

The accompanying paper demonstrated two distinct types of central mesencephalic reticular formation (cMRF) neuron that discharged before or after the gaze movement: pre-saccadic or post-saccadic. The movement fields of pre-saccadic neurons were most closely associated with gaze displacement. The movement fields of post-saccadic neurons were most closely associated with head displacement. Here we examine the relationships of the discharge patterns of these cMRF neurons with the temporal aspects of gaze or head movement. For pre-saccadic cMRF neurons with monotonically open movement fields, we demonstrate that burst duration correlated closely with gaze duration. In addition, the peak discharge of the majority of pre-saccadic neurons was closely correlated with peak gaze velocity. In contrast, discharge parameters of post-saccadic neurons were best correlated with the time of peak head velocity. However, the duration and peak discharge of post-saccadic discharge was only weakly related to the duration and peak velocity of head movement. As a result, for the majority of post-saccadic neurons the discharge waveform poorly correlated with the dynamics of head movement. We suggest that the discharge characteristics of pre-saccadic cMRF neurons with monotonically open movement fields are similar to that of direction long-lead burst neurons found previously in the paramedian portion of the pontine reticular formation (PPRF; Hepp and Henn 1983). In light of their anatomic connections with the PPRF, these pre-saccadic neurons could form a parallel pathway that participates in the transformation from the spatial coding of gaze in the superior colliculus (SC) to the temporal coding displayed by excitatory burst neurons of the PPRF. In contrast, closed and non-monotonically open movement field pre-saccadic neurons could play a critical role in feedback to the SC. The current data do not support a role for post-saccadic cMRF neurons in the direct control of head movements, but suggest that they may serve a feedback or reafference function, providing a signal of current head amplitude to upstream regions involved in head control.

Spatial characteristics of neurons in the central mesencephalic reticular formation (cMRF) of head-unrestrained monkeys.

Prior studies of the central portion of the mesencephalic reticular formation (cMRF) have shown that in head-restrained monkeys, neurons discharge prior to saccades. Here, we provide a systematic analysis of the patterns of activity in cMRF neurons during head unrestrained gaze shifts. Two types of cMRF neurons were found: presaccadic neurons began to discharge before the onset of gaze movements, while postsaccadic neurons began to discharge after gaze shift onset and typically after the end of the gaze shift. Presaccadic neuronal responses were well correlated with gaze movements, while the discharge of postsaccadic neurons was more closely associated with head movements. The activity of presaccadic neurons was organized into gaze movement fields, while the activity of postsaccadic neurons was better organized into movement fields associated with head displacement. We found that cMRF neurons displayed both open and closed movement field responses. Neurons with closed movement fields discharged before a specific set of gaze (presaccadic) or head (postsaccadic) movement amplitudes and directions and had a clear distal boundary. Neurons with open movement fields discharged for gaze or head movements of a specific direction and also for movement amplitudes up to the limit of measurement (70 degrees). A subset of open movement field neurons displayed an increased discharge with increased gaze shift amplitudes, similar to pontine burst neurons, and were called monotonically increasing open movement field neurons. In contrast, neurons with non-monotonically open movement fields demonstrated activity for all gaze shift amplitudes, but their activity reached a plateau or declined gradually for gaze shifts beyond specific amplitudes. We suggest that presaccadic neurons with open movement fields participate in a descending pathway providing gaze signals to medium-lead burst neurons in the paramedian pontine reticular formation, while presaccadic closed movement field neurons may participate in feedback to the superior colliculus. The previously unrecognized group of postsaccadic cMRF neurons may provide signals of head position or velocity to the thalamus, cerebellum, or spinal cord.