Delayed Response Deficits Research Articles

Traumatic Prefrontal Encephalopathy and Amotivational Apathetic Syndrome: Revisiting the Historical Limitations of Standardized Neuropsychological Assessments

The field of neuropsychology has made significant gains regarding the development and implementation of diagnostic measures and assessment techniques for frontal lobe pathology. Nevertheless, it is becoming increasingly evident that the existing battery of tests remains relatively insensitive to the ever-growing range of functions known to be mediated by the prefrontal regions. In the present study, a 62 year-old gentleman was involved in a pedestrian motor vehicle accident and suffered bilateral prefrontal, left parietal, and left occipital trauma (as evidenced by magnetic resonance imaging (MRI) scans). Secondary to this accident, he complained of significant depression, thought disturbances, and paranoia, while family members reported additional personality changes. A consistent diagnosis of frontal lobe syndrome was established across three independent neuropsychological evaluations, in which his postrehabilitative scores on a range of standardized assessments were consistently above average, regardless of his significant social, affective, and motivational changes following the accident. This case demonstrates the limitations and insensitivity that current standardized measures still obtain for assessing prefrontal lobe injury. The results are interpreted within the context of test development relevant to neuroscience rather than strictly psychometric concerns. The importance of these constraints on the evaluation of frontal lobe syndrome is discussed within the context of traumatic brain injury from contact sports and military combat. For the healthy left frontal lobe, intentional acts involve substantial energy, the desire or intent to engage socially, and the intent to engage in positive affective and verbally interactive activities. These appear to be diminished with the amotivational syndrome arising from dysfunctional left frontal lobe origin and medial frontal pathology with reduced activation of social reward systems and dopaminergic pathways (25, 24). While the patient with left frontal pathology may present with diminished energy and behavioral slowing or inertia, heightened energy or impulsivity may result from right frontal pathology and, by inference, the release of left frontal systems (e.g., decreased caution). Both are described in the scientific literatures as delayed response deficits. However, with left frontal pathology the patient may initiate only following inordinate delays with behavioral slowing or bradykinesia, whereas the patient with right frontal pathology may initiate substantially prior to implementing the organizational planning or caution for successful task completion. Hypoactivity bradykinesia may derive from medial frontal lobe or left frontal lobe pathology and hyperactive or impulsive features with pathology within the homologous regions of the right frontal lobe supplementary motor or orbitofrontal cortex (24, 29). Neuropsychological comprehension of frontal lobe functioning has grown exponentially in scope and research specificity. In the early to mid 1900's, diagnoses of mental illness and abnormal emotionality began to shift towards the implication of dysfunction in specific brain regions. Potential solutions included surgical resection of the brain via frontal lobotomy or lobectomy, which rapidly grew in popularity. German physiologist Friedrich Goltz, in the late 1800's, ablated canine neocortex. Goltz's (23) reporting of character changes in his subjects influenced Swiss physician Gottlieb Burkhardt to translate this early medical intervention to human patients. Portuguese neurologist Egas Moniz (41) was

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.

Preservation of Prefrontal Cortical Volume in Behaviorally Characterized Aged Macaque Monkeys

Normal aging is frequently accompanied by a decline in cognitive capacities supported by the prefrontal cortex. The principal aim of the present study was to determine whether these impairments are coupled to morphometric alterations affecting the volume of the prefrontal cortex in an established nonhuman primate model. A large sample of 19 young (4–11 years old) and 40 aged (20–32 years old) rhesus monkeys was tested using a delayed response procedure known to require the functional integrity of area 46 of the prefrontal cortex. Aged monkeys displayed robust delayed response deficits that were specifically related to the demands of testing on memory. Modern stereological methods were then used to estimate the total volume of area 46 and the volume of layer I in brains from 21 young and aged monkeys. Prefrontal cortex volume was entirely preserved in the aged monkeys as a group and among the subset of aged subjects that displayed the most severe behavioral impairment. These findings indicate that gross morphometric alterations affecting cortical volume are unlikely to account for age-related decline in the information processing capacities of area 46 in primates. Taken together, current evidence instead suggests that changes in the functional connectivity of critical cortical circuits may contribute to normal cognitive aging.

Neurosurgery for mental disorder: past and present

Carlyle Jacobsen and John Fulton, at Yale in the early and mid-1930s, investigated primate frontal lobe function. Following bilateral frontal lobecotomy, monkeys and chimpanzees developed a delayed-response deficit, being unable to perform tasks when there was a significant delay between the stimulus and the required response. There were accompanying behavioural changes, with the animals becoming more placid and lethargic and losing their characteristic inquisitive initiative. They became distractible, with difficulty in maintaining an attention set. They had great difficulty in adapting to changes in the directions of an already learned task, tending to perseverate.

Delayed response deficits induced by local injection of GABA antagonists (bicuculline and phaclofen) into area 46 in infant rhesus monkeys

In freely moving infant rhesus monkeys, a small amount of GABAa or GABAb antagonist (bicuculline methiodide (BMI) or phaclofen (PHAC)) was injected into the left- or right-side of Walker's area 46 (BMI, left-side 18 sites, right-side 15 sites; PHAC, left-side six sites, right-side five sites). Deficits in the performance of a 5-s delayed response task were then studied. Regardless of which side of the brain was injected, the correct performance rate was reduced for the hand used most often. An increase in the number of error trials was seen both in the primary, most used and non-primary, less used hands. In addition, the number of perseverative errors, using the primary and non-primary hands, also increased. BMI and PHAC produced similar reductions in performance and increased perseveration. With BMI, no clear difference was observed in performance reduction between the left- and right-side injections, while a difference was observed in the increase in the number of perseverative errors. In monkeys that primarily used their right hands, the right-side BMI injections induced more perseverative errors to the left position with the right hand, and left-side injections induced perseverative errors to both the left and right positions with both the left and right hands. In monkeys that primarily used their left hands, right-side BMI injections induced more perseverative errors to the left position with both the left and right hands and left-side injections induced, as seen in the right hand users, perseverative errors to both the left and right positions with both the left and right hands. Such lateral differences were not observed with PHAC. These results suggest that both GABAa and GABAb inhibition of area 46 are involved in the correct performance of a 5-s delayed response task.

Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys

Monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over long periods of time develop cognitive deficits without severe parkinsonian motor signs. In the present study we assessed the effects of the selective and full dopamine D-1 receptor agonist dihydrexidine on delayed response deficits in chronic low dose (CLD) MPTP-treated monkeys. Dihydrexidine caused a dose-dependent improvement in task performance, that could be blocked by the D-1 receptor antagonist SCH-23390. In addition to reducing the number of mistakes made during delayed response performance, dihydrexidine also improved task persistence. These data suggest that dihydrexidine may be useful in treating cognitive as well as motor deficits of parkinsonian.

Delayed-response deficit induced by local injection of the α 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys

Two young adult monkeys (Macaca mullata) were trained to perform a delayed-response task that required the monkeys to remember a cued spatial position (left or right) over a delay interval and then to make a response to the cued position. Local injection of the alpha 2-adrenergic antagonist yohimbine (10 micrograms in 2 microliters saline) into the dorsolateral prefrontal cortex (Walker's area 46 and area 9) impaired the performance of the delayed-response task, and it was without effect on the performance of the task if there was no delay between the cue and choice signals. The main performing error after injection of yohimbine was that the monkeys responded to uncued position with higher rate. Local injection of the alpha 1-adrenergic antagonist prazosin (10 microgram in 2 microliters saline) or the beta-adrenergic antagonist propranolol (10 micrograms in 2 microliters saline) into the same cortical areas induced no significant effect on the performance of the task. The present study suggests that prefrontal alpha 2-adrenoceptors play an important role in the spatial working memory in young adult monkeys.

Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic "scotomas"

The spatial memory functions of the monkey's prefrontal cortex were examined with oculomotor delayed-response (ODR) paradigms that required the animal to remember the spatial location of peripheral visual cues, while maintaining fixation on a central visual target during the presentation of each cue and during a subsequent 1.5-8 sec delay period. Four rhesus monkeys received unilateral or serial prefrontal lesions in and around the principal sulcus after they reached criterion performance on the ODR tasks. Unilateral lesions disrupted the performance of memory-guided eye movements to spatial cues in the visual field contralateral to the hemisphere in which the lesion was placed. Memory-guided eye movements to ipsilateral cues were mildly affected by unilateral lesions, and these lesions had little or no effect on performance in visually guided control tasks. With addition of a second lesion in the opposite hemisphere, the deficit was extended to include the opposite hemifield. The impairment was characterized by eye movements of inappropriate direction, and, excepting the one lesion that extended into the frontal eye field region of the arcuate sulcus, saccadic reaction times and velocities were the same before and after the lesions. The effect of the lesions was delay dependent: performance was rarely altered at the shortest (1.5 sec) delay but became progressively worse as the delay period was lengthened. The present results strengthen the evidence that the delayed-response deficits of monkeys with prefrontal lesions are caused by failure to maintain a transient memory "trace" in working memory, and indicate for the first time that working memory mechanisms are lateralized: memories for visuo-spatial coordinates in each hemifield are processed primarily in the contralateral prefrontal cortex. These findings provide evidence for the concept of mnemonic hemianopias and mnemonic scotomas, that is, memory deficits for particular hemifields or visual field locations, unaccompanied by simple sensory or motor deficits.

Delayed response deficits produced by local injection of bicuculline into the dorsolateral prefrontal cortex in Japanese macaque monkeys.

Bicuculline (10-30 micrograms, but usually 30 micrograms) was injected locally into 20 different sites in the dorsolateral prefrontal cortex (PFC) of 2 Japanese macaque monkeys, while they were performing a delayed response task. The task was initiated by the rotation of a handle to a central zone by the wrist joint and consisted of seven periods: an initial waiting period of 0.3 s, a pre-cue period (central green lamp of 1.0 s), a cue period (left or right green cue of 0.3 s), a delay period of 4.0 s (occasionally 1 s), a go period (central red lamp; rotation of the handle to either the left or right zone within 1.0 s), a hold period (holding of the handle in either the left or the right zone), and a final reward period. The parameters of the task performance, such as the frequency of correct trials, the frequency of directional error trials in which the monkeys rotated the handle in an incorrect direction during the go period, and the frequency of omission error trials, in which the monkeys did not rotate the handle during the go period, were examined before and after the injection of bicuculline. The injections of bicuculline induced a burst of multi-neuronal activity around the sites of injection. Within 5 min of an injection into one of 7 different sites in the PFC, three different kinds of performance deficit were observed: 1) an increase in the frequency of error responses during the go period in both left-cue and right-cue trials, after injection into the dorso-caudal portion of the principal sulcus (2 sites); 2) an increase in the frequency of directional error responses during the go period in either left-cue or right-cue trials, after injection into the bottom of the middle principal sulcus (3 sites), and 3) an increase in the frequency of omission of responses during the go period, after injection into the dorsal region of the caudal principal sulcus (2 sites). Injections at the remaining 13 sites did not induce any deficits, although injections into the dorsal bank of the principal sulcus (3 sites) induced a decrease in the frequency of the task trials as a result of prolonged intertrial intervals (ITIs). Our results suggest that locally disturbed neuronal activity in different small areas of the PFC induces different deficits in the performance of the delayed response task.(ABSTRACT TRUNCATED AT 400 WORDS)

Delayed response deficit in monkeys by locally disturbed prefrontal neuronal activity by bicuculline

Effects of local injection of a γ-aminobutyric acid antagonist, bicuculline (10–30 μg dissolved in saline) in the principal prefrontal cortex on the delayed response task were investigated in two monkeys. On a visual Go signal, the monkeys rotated a handle to the left or to the right (Go period) according to a visual cue (left or right; 1 s) presented 4 s earlier. Bicuculline induced bursting activity at the injected site 1–2 min after the injection and 5 min later the burst activity spread to nearby cortical areas (<4 mm diameter). Within 5 min after injection, the monkeys showed errors in Go periods, rotating the handle to the contralateral zone, regardless of the cue side. This tendency continued for 30–40 min and returned to the control level. Electromyographic recordings of forearm muscles did not show any changes. The effect was observed when the drug was injected into a circumscribed area of the bottom of the mid-principalis region. It appears that disturbed neuronal activity in a small group of cortical columns induces performance errors of specific direction of the delayed response.

Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys.

Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.

Effect of S-adenosyl-L-methionine (SAMe) on disturbances in hand movement and delayed response tasks after lesion of motor or prefrontal cortex in the monkey

Effects of SAMe on disturbances in trained hand movement tasks or a trained delayed response task after lesion in unilateral motor cortex (hand area) or bilateral dorsolateral prefrontal cortices were studied in the monkey. Following lesion, hand movement tasks or delayed response tasks were disturbed moderately or severely for one week to several months depending on the extent of lesion or nature of task. Although treatment with small doses of SAMe (10 mg/kg/day, i.m.) had no effect, treatment with moderate doses (SAMe, 20 or 30 mg/kg, i.m.) reduced impairment and promoted recovery from both disturbances. Even in the chronic stage (76-140 days after operation), SAMe (30 mg/kg/day, i.m.) facilitated recovery from delayed response deficits. Histological findings in the acute stage after cortical lesion in rats showed that SAMe (50 mg/kg/day, s.c.) augmented infiltration of activated phagocytic macrophages in lesioned sites. Data suggest that SAMe improves recovery from behavioral and histological disturbances due to brain damages.

Bilateral frontal lobe disease and selective delayed response deficits in humans.

The performance of patients with frontal lobe disease was compared with that of amnesic patients (with etiology of alcoholic Korsakoff's disease or surgically treated ruptured anterior communicating artery aneurysm) on tasks known to be sensitive to frontal lobe damage in nonhuman primates: delayed alternation (DA) and delayed response (DR). Alcoholic patients with no clinical memory impairment served as controls. Results showed that bilateral frontal lobe damage in humans is associated with impairment on both tasks. In addition, there was no relation between performances on DA and DR and performance on standardized tests of memory, a result strengthening the suggestion that the former tasks are not sensitive to anterograde amnesia in humans.

Bilateral frontal lobe disease and selective delayed response deficits in humans.

The performance of patients with frontal lobe disease was compared with that of amnesic patients (with etiology of alcoholic Korsakoff's disease or surgically treated ruptured anterior communicating artery aneurysm) on tasks known to be sensitive to frontal lobe damage in nonhuman primates: delayed alternation (DA) and delayed response (DR). Alcoholic patients with no clinical memory impairment served as controls. Results showed that bilateral frontal lobe damage in humans is associated with impairment on both tasks. In addition, there was no relation between performances on DA and DR and performance on standardized tests of memory, a result strengthening the suggestion that the former tasks are not sensitive to anterograde amnesia in humans.

Operant behavioral analysis of memory loss in monkeys with prefrontal lesions

The effects of dorsolateral prefrontal cortical ablation were examined in rhesus monkeys preoperatively trained to perform two versions of an indirect spatial delayed-response task. In one task (DR I), the stimulus keys that signaled the position of the reward were accessible throughout a trial. Thus, the monkeys could orient to the positive side (‘rehearse’) by continuing to press the correct key during the delay. The other task, DR II, was designed to disrupt bodily orientation and to prevent ‘rehearsal’. In this task the monkeys were required to press an extraneous upper key during the delay. After bilateral ablation of the prefrontal cortex, 3 out of the 4 monkeys easily regained preoperative levels of performance on the DR I task, but all subjects were markedly impaired in the DR II task on which they exhibited strong position preferences. These deficits were ameliorated by eliminating the position biases through training with short delay intervals followed by gradual increments in delay length. Analysis of the location of key presses during each phase of delayed-response trials showed that the monkeys press the correct key in the cue period even when they subsequently made incorrect responses. A consistent finding was that operated monkeys shifted their response to the incorrect key early in the delay period regardless of its duration, whenever the correct side was the nonpreferred side. These results support the idea that delayed-response deficits in monkeys with prefrontal lesions may be due in part to a defect in registering or encoding the correct spatial position in memory rather than to a loss in storage or retrieval processes.

The effect of ambient illumination on delayed-matching and delayed-response deficits from cooling dorsolateral prefrontal cortex

The possibility was examined that the delay-dependent increase in delayed matching-to-sample (DMS) and delayed-response (DR) errors induced by prefrontal cooling (FC) could be modified by changes in ambient illumination. Monkeys were tested in normal room lighting and in the dark with intratrial delays of 1–32 sec during FC and normal brain temperature (no cooling, NC). The results showed that FC increased errors and motor activity on trials with long intratrial intervals but had little effect with short delays. Ambient illumination had little effect during either FC or NC. The results are discussed in terms of relative differences in novelty of lighting or darkness with respect to the level of illumination during training.

Delayed-matching and delayed-response deficit from cooling dorsolateral prefrontal cortex in monkeys.

The hypothesis that the functional integrity of the dorsolateral prefrontal cortex is important for short-term memory of both spatial and nonspatial information was examined. Monkeys were tested in delayed matching-to-sample (DMS) and delayed-response (DR) tasks with delays of 0-32 sec. Testing was carried out under three different conditions: frontal cooling (FC), parietal cooling (PC), and normal temperature (noncooling, NC). Errors, reaction time, and motor activity were recorded. The proportion of correct responses decreased in NC as a function of the delay. This decrease was significantly accentuated by FC, whereas it was not modified by PC. At each delay, the decrement elicited by FC was as large in DR as in DMS. Reaction time and activity normally increased as a function of delay; these changes were enhanced by FC. The FC-induced decrements in proportion of correct responses suggest a faster loss from short-term memory of both spatial and nonspatial information.

Two-stage frontal lesion influences upon severity of delayed-response deficit

Seven groups of monkeys (total n = 33) underwent one- or two-stage bilateral aspirative removal of frontal cortical areas after acquisition of 5-sec spatial delayed response. Some animals were tested for retention as normals, and all were eventually tested under some postoperative condition. Relative to normal retention, one-stage dorsolateral removals produced severe deficits. Two-stage removals, divided into zones above or below the principal sulcus, generally yielded lesser severity, but this property was also influenced by the order and, to a lesser degree, the extent of these lesions. Some potential bases for the consequences of serial removals were discussed.

Delayed response deficits in squirrel monkeys with unilateral lesions in the midbrain reticular formation

Electrophysiological experiments suggest that the midbrain reticular formation plays a role in visual attention. However, behavioral tests of this hypothesis have been few and their results inconsistent. Squirrel monkeys with unilateral lesions in the midbrain reticular formation were compared to control animals in their performance on a delayed-response task and a visual pattern discrimination. Nystagmus, adduction of limbs, and lack of visual responsivity were noted a few days after the lesion was made, but these symptoms were transient and were not seen during delayed response testing. The monkeys with lesions had delayed response deficits when the baited food well was contralateral to the lesion and responses were delayed 10 sec or longer. They did not differ significantly from controls on the delayed response task when the baited food well was ipsilateral to the lesion or in learning the visual pattern discrimination. The delayed response task presumably measures the ability to maintain orienting responses, overtly or covertly, during the delay interval. This experiment suggests that the midbrain reticular formation facilitates orienting responses over long delays.

Delayed response deficits in neonatally asphyxiated rhesus monkeys

Rhesus monkeys, asphyxiated at the time of birth and tested at 10 months of age, were unable to perform a 5-sec delayed response task. They did as well as normal animals of the same age when no delay was introduced and could solve a black-white discrimination. It was concluded that the deficit was not of a cognitive nature, nor due to any sensory incapacity, but was truly one of short-term memory.