Effect of the dopamine D2 receptor T allele on response latency after mild traumatic brain injury

OBJECTIVE: The authors tested the hypothesis that the dopamine D2 receptor T allele (formerly described as the A1 allele) would be associated with poorer performance on memory and attention tasks following mild traumatic brain injury. METHOD: Thirty-nine patients with mild traumatic brain injury and 27 comparison subjects were genotyped. All subjects completed memory and attention tests, including the California Verbal Learning Test recognition task and the Continuous Performance Test. RESULTS: In both groups the T allele was associated with poorer performance on the California Verbal Learning Test recognition task. There was also a significant diagnosis-by-allele interaction on measures of response latency (Continuous Performance Test): the subjects with mild traumatic brain injury and the T allele had the worst performance. CONCLUSIONS: Genetic polymorphisms modulating central dopaminergic tone can affect cognitive outcome following mild traumatic brain injury.     

Procedural learning is impaired in Huntington's disease: evidence from the serial reaction time task.

The purpose of the study was to test the hypothesis that Huntington's disease (HD) is associated with impairment of procedural learning. We identified 13 patients with mild to moderate HD whose manual performance was still sufficiently intact to assess learning on the serial reaction time (SRT) task. Twelve age-matched neurologically normal control subjects were studied as well. The SRT task was a four-choice reaction time task in which the stimuli followed a sequence (10 items in length) which repeated itself 10 times during each of the first four blocks of trials. During the fifth block of trials, the stimuli were random. Learning was manifested by a reduction in response latency over the first four blocks and an increase in response latency in the fifth (random) block. Learning in this task has been demonstrated in other amnesics of other etiologies. The HD patients were significantly impaired on sequence-specific learning, using the log-transformed reaction time data (P less than 0.004). In addition, in an individual-by-individual analysis, five of the HD patients and none of the control subjects failed to show sequence-specific learning, a difference in proportions that was significant (P less than 0.04). No feature of the standard cognitive or motor assessment of the HD patients was associated with efficacy of procedural learning. HD, including patients with mild disease, was associated with a deficit in procedural learning, consistent with the hypothesis that the striatum plays a critical role in supporting procedural learning.     

Brain lesions in patients visiting a memory clinic with postconcussional sequelae after mild to moderate brain injury

Postconcussional disorder after a relatively mild head injury is common. Although a partial organic etiology is presumed, little imaging evidence exists for this assumption. In this study, patients with mild to moderate brain injury (median Glasgow Coma Scale score of 14) had more parenchymal brain lesions than control subjects (P=0.02). Additionally, the authors investigated the potential of quantifying brain injury by the magnetization transfer ratio (MTR). The curve amplitude of the MTR histogram was used as a measure of normal white matter. Patients had a lower curve amplitude than control subjects (P=0.008). This study provides evidence of persistent traumatic brain alterations in patients who sustained a relatively mild traumatic brain injury.     

Changes in brain activation patterns according to cross-training effect in serial reaction time task An functional MRI study

Cross-training is a phenomenon related to motor learning, where motor performance of the untrained limb shows improvement in strength and skill execution following unilateral training of the homologous contralateral limb. We used functional MRI to investigate whether motor performance of the untrained limb could be improved using a serial reaction time task according to motor sequential learning of the trained limb, and whether these skill acquisitions led to changes in brain activation patterns. We recruited 20 right-handed healthy subjects, who were randomly allocated into training and control groups. The training group was trained in performance of a serial reaction time task using their non-dominant left hand, 40 minutes per day, for 10 days, over a period of 2 weeks. The control group did not receive training. Measurements of response time and percentile of response accuracy were performed twice during pre- and post-training, while brain functional MRI was scanned during performance of the serial reaction time task using the untrained right hand. In the training group, prominent changes in response time and percentile of response accuracy were observed in both the untrained right hand and the trained left hand between pre- and post-training. The control group showed no significant changes in the untrained hand between pre- and post-training. In the training group, the activated volume of the cortical areas related to motor function (i.e., primary motor cortex, premotor area, posterior parietal cortex) showed a gradual decrease, and enhanced cerebellar activation of the vermis and the newly activated ipsilateral dentate nucleus were observed during performance of the serial reaction time task using the untrained right hand, accompanied by the cross-motor learning effect. However, no significant changes were observed in the control group. Our findings indicate that motor skills learned over the 2-week training using the trained limb were transferred to the opposite homologous limb, and motor skill acquisition of the untrained limb led to changes in brain activation patterns in the cerebral cortex and cerebellum.     

Awareness of activity limitations and prediction of performance in patients with brain injuries and orthopedic disorders.

The aim of this study was to compare the accuracy of performance predictions in experimental tasks with patients' awareness of activity limitations. Participants were 24 patients with brain injuries (i.e., traumatic brain injury and cerebrovascular disorders) and 22 patients with orthopedic disorders. Prediction of performance was examined in a memory task (word list learning) and a motor task (finger tapping). Awareness of activity limitations was measured by comparing patients' self-ratings and staff ratings in the Patient Competency Rating Scale (PCRS). Results for the PCRS showed that patients with orthopedic disorders underestimated and patients with brain injuries (i.e., patients with TBI) overestimated their level of functioning in the total scale and the social/emotional subscale in comparison to staff ratings. Both patient groups agreed with staff ratings in physical/basic self-care items. In the predicted performance tasks a similar pattern could be observed: None of the groups showed an overestimation of performance in the motor task, whereas patients with brain injuries overestimated their competency in the memory task. However, the agreement between both awareness measures (PCRS, predicted performance) was only low, which indicates that they might measure different aspects or levels of self-awareness.     

Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study.

OBJECTIVE: To assess patterns of regional brain activation in response to varying working memory loads shortly after mild traumatic brain injury (MTBI). BACKGROUND: Many individuals complain of memory difficulty shortly after MTBI. Memory performance in these individuals can be normal despite these complaints. METHODS: Brain activation patterns in response to a working memory task (auditory n-back) were assessed with functional MRI in 12 MTBI patients within 1 month of their injury and in 11 healthy control subjects. RESULTS: Brain activation patterns differed between MTBI patients and control subjects in response to increasing working memory processing loads. Maximum intensity projections of statistical parametric maps in control subjects showed bifrontal and biparietal activation in response to a low processing load, with little additional increase in activation associated with the high load task. MTBI patients showed some activation during the low processing load task but significantly increased activation during the high load condition, particularly in the right parietal and right dorsolateral frontal regions. Task performance did not differ significantly between groups. CONCLUSION: MTBI patients differed from control subjects in activation pattern of working memory circuitry in response to different processing loads, despite similar task performance. This suggests that injury-related changes in ability to activate or to modulate working memory processing resources may underlie some of the memory complaints after MTBI.     

Involvement of Activation of Dopamineraic Neuronal System in Learning and Memory Deficits Associated with Experimental Mild Traumatic Brain Injury

Much evidence has indicated that a disturbance in dopamine neurotransmission following mild to moderate traumatic brain injury is involved in the development of post traumatic memory deficits. In the present study we examined the effects of a dopamine receptor agonist and some antagonists on latent learning and memory deficits associated with a concussive traumatic brain injury in mice. Anaesthetized animals were subjected to mild traumatic brain injury by dropping a weight onto the head, and a single-dose injection of apomorphine (0.3–3.0 mg/kg) or haloperidol (0.3–3.0 mg/kg) was made i.p. 15 min after the trauma. One week later, a water-finding task consisting of an acquisition trial, a retention test and a retest was employed to assess learning and memory functions. Mice that had received a traumatic brain injury were impaired in task performance, with prolonged latencies for finding and drinking in the retention test and retest. Administration of haloperidol but not of apomorphine significantly shortened the prolonged latency in both of the tests, indicating that antagonism of dopamine receptors is beneficial for the recovery of post traumatic memory deficits. In order to evaluate which receptor subtype plays the major role in this model, we examined the effects of SCH-23390 (0.03–0.3 mg/kg), a D1 receptor antagonist, and sulpiride (3.0–30 mg/kg), a D2 receptor antagonist, in the same experimental paradigm. The results showed that administration of sulpiride but not of SCH-23390 significantly improved the deficits in task performance, indicating that D2 receptors are the major site of action. However, combined treatment with SCH-23390 (0.03–0.3 mg/kg) and sulpiride (3.0 mg/kg) at doses that had no effect when the antagonists were given alone exerted a significant additive effect in improving these deficits, indicating that interaction between D1 and D2 receptors is involved in these processes. The present results suggest that a dopaminergic mechanism contributes to the memory dysfunction associated with traumatic brain injury.     

Direct and indirect measures of verbal relational memory following anterior temporal lobectomy.

Medial temporal lobe (MTL) structures are implicated in forming conjunctions between events in order to form enduring relational memories; these memories are not evident using direct measures with varieties of amnesic subjects. Extratemporal brain structures are thought to be responsible for preserved memories, which are sometimes detectable using indirect measures. The present study tests this theory of multiple memory systems by examining whether preserved learning can be demonstrated for relational material in MTL-disordered subjects using an indirect measure which minimises conscious mediation of performance. The subjects had undergone anterior temporal lobectomy for relief of temporal lobe epilepsy: left-sided (LATL) cases had a mild verbal amnesia and right-sided (RATL) cases had better verbal memory, forming a comparison group. A direct measure of verbal relational memory was provided by successive trials of cued recall in a specially-constructed paired associate learning task with arbitrarily paired words; pairs consisted of either concrete or abstract words. LATL subjects performed worse than RATL subjects, and particularly so with abstract words. Following direct testing, memory for the pairings was measured indirectly using a masked recognition priming technique. RATL subjects showed savings in RT, demonstrating that masked priming can reveal evidence of the formation of conjunctions. Critically, LATL subjects showed no evidence of preserved learning with priming. Thus when MTL structures are damaged, relational memory appears to be affected without exception, consistent with the tenets of multiple memory systems theory.     

Altered brain activation in military personnel with one or more traumatic brain injuries following blast

Explosive blast is a frequent cause of traumatic brain injury (TBI) among personnel deployed to Afghanistan and Iraq. Functional magnetic resonance imaging (fMRI) with an event-related stimulus-response compatibility task was used to compare 15 subjects with mild, chronic blast-related TBI with 15 subjects who had not experienced a TBI or blast exposure during deployment. Six TBI subjects reported multiple injuries. Relative to the control group, TBI subjects had slightly slower responses during fMRI and increased somatic complaints and symptoms of post-traumatic stress disorder (PTSD) and depression. A between-group analysis indicated greater activation during stimulus-response incompatibility in TBI subjects within the anterior cingulate gyrus, medial frontal cortex, and posterior cerebral areas involved in visual and visual-spatial functions. This activation pattern was more extensive after statistically controlling for reaction time and symptoms of PTSD and depression. There was also a negative relationship between symptoms of PTSD and activation within posterior brain regions. These results provide evidence for increased task-related activation following mild, blast-related TBI and additional changes associated with emotional symptoms. Limitations of this study include no matching for combat exposure and different recruitment strategies so that the control group was largely a community-based sample, while many TBI subjects were seeking services.     

Long-term retention of implicitly acquired learning in patients with Alzheimer's disease.

This study examined retention of procedural learning, using the serial reaction time (SRT) task, over a 1- or 2-week delay in Alzheimer's disease (AD) patients and elderly control (EC) subjects. The SRT task is a four-choice reaction-time task consisting of blocks of 100 trials. A 10-item repeating sequence was embedded in the first four blocks of trials in session one and the first two blocks of session two. Sequence-specific learning was assessed in session one by comparing reaction time (RT) in the fourth block with a repeating sequence to a fifth block in session one in which the stimuli were randomly arranged. After excluding subjects with deficient session one learning, there were eight AD patients and 14 EC subjects who showed robust sequence-specific learning in session one. In these subjects, retention of sequence-specific learning over the 1- to 2-week delay was examined. The AD patients and EC subjects showed an equivalent change in RT across sessions, and all the AD patients lacked any declarative knowledge of the repeating sequence within the task. Individually, two of the eight AD patients appeared to deviate substantially from the others and from the EC subjects in their excess slowing of RT across sessions. Since six AD patients did show retention similar to the EC subjects, it is concluded that at least some AD patients show normal retention of implicitly acquired knowledge over a long delay. Preserved retention in some of the AD patients implies that it is mediated by brain structures that are not affected by the Alzheimer neuropathological process.     

Long-term Retention of Implicitly Acquired Learning in Patients with Alzheimer's Disease

Abstract

This study examined retention of procedural learning, using the serial reaction time (SRT) task, over a 1- or 2-week delay in Alzheimer's disease (AD) patients and elderly control (EC) subjects. The SRT task is a four-choice reaction-time task consisting of blocks of 100 trials. A 10-item repeating sequence was embedded in the first four blocks of trials in session one and the first two blocks of session two. Sequence-specific learning was assessed in session one by comparing reaction time (RT) in the fourth block with a repeating sequence to a fifth block in session one in which the stimuli were randomly arranged. After excluding subjects with deficient session one learning, there were eight AD patients and 14 EC subjects who showed robust sequence-specific learning in session one. In these subjects, retention of sequence-specific learning over the 1- to 2-week delay was examined. The AD patients and EC subjects showed an equivalent change in RT across sessions, and all the AD patients lacked any declarative knowledge of the repeating sequence within the task. Individually, two of the eight AD patients appeared to deviate substantially from the others and from the EC subjects in their excess slowing of RT across sessions. Since six AD patients did show retention similar to the EC subjects, it is concluded that at least some AD patients show normal retention of implicitly acquired knowledge over a long delay. Preserved retention in some of the AD patients implies that it is mediated by brain structures that are not affected by the Alzheimer neuropathological process.     

Interference of left and right cerebellar rTMS with procedural learning

Increasing evidence suggests cerebellar involvement in procedural learning. To further analyze its role and to assess whether it has a lateralized influence, in the present study we used a repetitive transcranial magnetic stimulation interference approach in a group of normal subjects performing a serial reaction time task. We studied 36 normal volunteers: 13 subjects underwent repetitive transcranial magnetic stimulation on the left cerebellum and performed the task with the right (6 subjects) or left (7 subjects) hand; 10 subjects underwent repetitive transcranial magnetic stimulation on the right cerebellum and performed the task with the hand ipsilateral (5 subjects) or contralateral (5 subjects) to the stimulation; another 13 subjects served as controls and were not submitted to repetitive transcranial magnetic stimulation; 7 of them performed the task with the right hand and 6 with the left hand. The main results show that interference with the activity of the lateral cerebellum induces a significant decrease of procedural learning: Interference with the right cerebellar hemisphere activity induces a significant decrease in procedural learning regardless of the hand used to perform the serial reaction time task, whereas left cerebellar hemisphere activity seems more linked with procedural learning through the ipsilateral hand. In conclusion, the present study shows for the first time that a transient interference with the functions of the cerebellar cortex results in an impairment of procedural learning in normal subjects and it provides new evidences for interhemispheric differences in the lateral cerebellum.     

Robot-aided functional imaging: Application to a motor learning study

The purpose of this study was to examine the neural activity underlying an implicit motor learning task. In particular, our goals were to determine whether initial phases of procedural learning of a motor task involve areas of the brain distinct from those involved in later phases of learning the task, and what changes in neural activity coincide with performance improvement. We describe a novel integration of robotic technology with functional brain imaging and its use in this study of implicit motor learning. A portable robotic device was used to generate forces that disturbed the subjects' arm movements, thereby generating a “virtual mechanical environment” that the subjects learned to manipulate. Positron emission tomography (PET) was used to measure indices of neural activity underlying learning of the motor task. Eight healthy, right-handed male subjects participated in the study. Results support the hypothesis that different stages of implicit learning (early and late implicit learning) occur in an orderly fashion, and that distinct neural structures may be involved in these different stages. In particular, neuroimaging results indicate that the cortico-striatal loop may play a significant role during early learning, and that the cortico-cerebellar loop may play a significant role during late learning. Hum. Brain Mapping 6:59–72, 1998. © 1998 Wiley-Liss, Inc.     

Apolipoprotein E epsilon 4 and short-term recovery from predominantly mild brain injury

OBJECTIVE: To determine whether APOE genotype explained variability in short-term recovery from predominantly mild traumatic brain injury (TBI). METHODS: A total of 87 adult patients presenting with mild or moderate TBI to a shock trauma center were enrolled prospectively. A battery of 13 neuropsychological tests was administered twice, at approximately 3 and 6 weeks after injury. Eighty of 87 patients were successfully genotyped for APOE using a buccal swab technique. RESULTS: Ninety percent of study patients had mild TBI (Glasgow Coma Scale score of 13 to 15); 18 (22.5%) had one APOE epsilon 4 and none had two epsilon 4 alleles. After adjusting for potential confounders, patients positive for the APOE epsilon 4 allele had lower mean scores on 12 of 13 neuropsychological outcomes at visit 1 compared with APOE epsilon 4-negative patients. Two of the differences were significant (grooved pegboard test, p = 0.005; paced auditory serial addition task 2.8-second trial, p = 0.004). At visit 2, APOE epsilon 4-positive patients had lower adjusted mean scores on 11 of the 13 neuropsychological outcomes. None of the differences was significant. CONCLUSIONS: APOE genotype may influence the severity of the acute injury. However, with no consistent pattern to the recovery curves, it is not clear if APOE genotype influences the rate of recovery.     

Diffuse axonal injury due to traumatic brain injury alters inhibition of imitative response tendencies

It is well known that traumatic brain injury particularly affects the frontal lobes. Consequently, patients often suffer from executive dysfunction and behavioral disturbances. Accordingly, our study aimed at investigating patients after traumatic brain injury with two tasks involving different functional processes and structural networks supported by the frontal lobes. Two paradigms were applied: the Stroop color-word task and a task in which subjects had to inhibit imitative response tendencies. We selected a patient group solely with diffuse axonal injury, as this type of injury is homogenous and is correlated with cognitive dysfunction more than focal contusions. To evaluate long-term effects most relevant for rehabilitation, we selected a patient group whose brain injuries dated back several years. Our results show that patients with diffuse axonal injury inhibited imitative responses more successfully than control subjects, whereas executive processes examined with the Stroop task were unaltered. Interestingly, impairments were tightly correlated both with the length of the post-traumatic amnesia predicting outcome in traumatic brain injury and with behavioral disturbances. Impairments in the imitation-inhibition task may indicate alterations in an anterior frontomedian neural network even years after traumatic brain injury.     

Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study

A dysfunction of the fronto-striatal loop has been associated with obsessive-compulsive disorder (OCD). Functional imaging studies suggest that reversal learning is affected by deficits in fronto-striatal brain areas and thus should be impaired in patients with OCD. The authors compared patients with OCD and healthy comparison subjects on a reversal learning task. Correlation analyses and group comparisons showing prolonged reaction times of different response parameters are associated with increasing severity of compulsions. The reversal learning task has been shown to be associated with ventral fronto-striatal brain activation by functional magnetic resonance imaging (fMRI) in healthy comparison subjects. The purpose of this article is to suggest that the reversal learning task can be used as a neuropsychiatric measurement of the ventral fronto-striatal dysfunction in OCD.     

Functional neuroanatomy of successful paired associate learning in Alzheimer's disease

OBJECTIVE: The purpose of the study was to develop a strategy for functional imaging of neurodegenerative disorders that overcomes confounds associated with differential performance between patient and comparison groups. METHOD: Functional magnetic resonance imaging was used to examine responses to increasing difficulty of visuospatial paired associate learning in 12 patients with mild probable Alzheimer's disease and 12 age-matched healthy comparison subjects. Performance was matched across groups by only examining successful encoding and retrieval attempts. Adjustment for task difficulty was made on an individual basis so that the patients with Alzheimer's disease and the comparison subjects performed at the same relative levels of difficulty. RESULTS: A network of lateral and medial frontoparietal and occipital regions was engaged in all subjects during successful associative learning. As task difficulty increased, blood-oxygen-level-dependent responses increased linearly in occipitoparietal regions during encoding and retrieval. Differential activations in patients with Alzheimer's disease and comparison subjects were small and were found only when an uncorrected statistical threshold was used. CONCLUSIONS: By controlling for confounds of varying task difficulty and subsequent performance, remarkably similar brain activations were identified during successful paired associate learning in patients with Alzheimer's disease and in healthy comparison subjects. The study methods provide a useful model for further applications of functional imaging involving cognitive activation paradigms in the study of neuropsychiatric disorders.     

Functional anatomy of visuo-spatial working memory during mental rotation is influenced by sex, menstrual cycle, and sex steroid hormones

Recent observations indicate that sex and level of steroid hormones may influence cortical networks associated with specific cognitive functions, in particular visuo-spatial abilities.

The present study probed the influence of sex, menstrual cycle, and sex steroid hormones on 3D mental rotation and brain function using 3-T fMRI. Twelve healthy women and 12 men were investigated. Menstrual cycle and hormone levels were assessed. The early follicular and midluteal phase of the menstrual cycle were chosen to examine short-term cyclical changes.

Parietal and frontal areas were activated during mental rotation in both sexes. Significant differences between men and women were revealed in both phases of menstrual cycle. In men we observed a significant correlation of activation levels with testosterone levels in the left parietal lobe (BA 40). In women, a cycle-dependent correlation pattern was observed for testosterone: brain activation correlated with this male hormone only during the early follicular phase. In both cycle phases females’ brain activation was significantly correlated with estradiol in frontal and parietal areas.

Our study provides evidence that fMRI-related activity during performance of cognitive tasks varies across sex and phases of the menstrual cycle. The variation might be partly explained by better task performance in men, but our results indicate that further explanations like basic neuronal or neurovascular effects modulated by steroid hormones must be considered. Both estradiol and testosterone levels may influence fMRI signals of cognitive tasks, which should affect selection of subjects for future fMRI studies.     

Evaluation of serial EEG recordings and auditory brainstem responses in the early preterm infants]

EEGs were recorded serially throughout the neonatal period and auditory brainstem responses (ABRs) in the late neonatal period in 105 preterm infants with the gestational age of less than 33 weeks and birth weights of less than 1,750g in order to study the relation between abnormal findings and neurological outcome. A study of serial EEG recordings revealed that a disorganized pattern following severe depression of background EEG activities was closely associated with deep white matter injuries detected by ultrasonography and that infants showing such features are likely to suffer from cerebral palsy. On the other hand, a dysmature pattern was often observed following prolonged mild depression, although no abnormalities were apparent on ultrasonography. This EEG pattern was more often associated with mental impairment. Any findings of ABRs were not associated with adverse outcome. We conclude that serial EEG recordings during the neonatal period in preterm infants are useful in clarifying the extent and nature of brain injury as well as future developmental problems.     

Errorless learning of novel routes through a virtual town in people with acquired brain injury

Impaired route learning is a common consequence of acquired brain injury (ABI) but has received little attention in the research literature. Errorless learning may be a method of facilitating the learning of routes but this is unclear as previous studies of errorless learning have focused mainly on verbal skills and the only previous study involving route learning was based upon a pencil and paper task. In the present study we therefore use virtual reality to explore the benefits of errorless learning for routes in an ecologically valid task. Twenty people with acquired brain injury learned two routes, of equivalent difficulty, around a virtual town based upon the city of Nice. For one route, full guidance was provided throughout the learning trials in an errorless learning paradigm; the other route was learned using a procedure that allowed for trial and error. Route recall following the errorless learning condition was significantly more accurate than recall after errorful learning. This suggests that the benefits of errorless over errorful learning in acquired brain injury rehabilitation extend beyond verbal learning tasks to the practical task of route memorisation.