Double dissociation of the roles of the left and right prefrontal cortices in anticipatory regulation of action.

Recent actions can benefit or disrupt our current actions and the prefrontal cortex (PFC) is thought to play a major role in the regulation of these actions before they occur. The left PFC has been associated with overcoming interference from past events in the context of language production and working memory. The right PFC, and especially the right IFG, has been associated with preparatory inhibition processes. But damage to the right PFC has also been associated with impairment in sustaining actions in motor intentional disorders. Moreover, bilateral dorsolateral PFC has been associated with the ability to maintain task-sets, and improve the performance of current actions based on previous experience. However, potential hemispheric asymmetries in anticipatory regulation of action have not yet been delineated. In the present study, patients with left (n=7) vs. right (n=6) PFC damage due to stroke and 14 aged- and education-matched controls performed a picture naming and a verbal Simon task (participants had to say "right" or "left" depending on the color of the picture while ignoring its position). In both tasks, performance depended on the nature of the preceding trial, but in different ways. In the naming task, performance decreased if previous pictures were from the same rather than from different semantic categories (i.e., semantic interference effect). In the Simon task, performance was better for both compatible (i.e., response matching the position of the stimulus) and incompatible trials when preceded by a trial of the same compatibility (i.e. Gratton effect) relative to sequential trials of different compatibility. Left PFC patients were selectively impaired in picture naming; they had an increased semantic interference effect compared to both right PFC patients and aged-matched controls. Conversely, right PFC patients were selectively impaired in the Simon task compared to controls or left PFC patients; they showed no benefit when sequential trials were compatible (cC vs. iC trials) or a decreased Gratton effect. These results provide evidence for a double dissociation between left and right PFC in the anticipatory regulation of action. Our results are in agreement with a preponderant role of the left PFC in overcoming proactive interference from competing memory representations and provide evidence that the right PFC, plays a role in sustaining goal-directed actions consistent with clinical data in right PFC patients with motor intentional disorders.

Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis.

The retrogenesis model of Alzheimer's disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.

Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement.

Ideomotor limb apraxia, a disorder of goal-directed movement, has been attributed to lesions in the frontal and parietal lobes, but the role of subcortical structures is less certain. In order to determine its prevalence in a disorder affecting the basal ganglia and corticostriatal connections, we examined imitation of hand gestures in Huntington's disease (HD) patients. We also assessed the relationship between apraxia and cognitive and motor dysfunction in an effort to better understand the neural underpinnings of apraxia in HD. If damage restricted to the basal ganglia produces ideomotor limb apraxia, then we would expect to find evidence of apraxia in patients who were early in the disease course when selective striatal damage is most common. Such a pattern, however, was not found in our sample. Instead, patients with greater neurological impairment and with a longer duration of disease were more likely than less affected patients to demonstrate apraxia. Apraxia was not related to severity of chorea, but was associated with greater impairment in eye movements, voluntary movements, and verbal fluency. These findings suggest that apraxia in HD results from damage to the corticostriate pathways and the basal ganglia rather than from damage restricted to the basal ganglia.

Neural representations of skilled movement.

The frontal and parietal cortex are intimately involved in the representation of goal-directed movements, but the crucial neuroanatomical sites are not well established in humans. In order to identify these sites more precisely, we studied stroke patients who had the classic syndrome of ideomotor limb apraxia, which disrupts goal-directed movements, such as writing or brushing teeth. Patients with and without limb apraxia were identified by assessing errors imitating gestures and specifying a cut-off for apraxia relative to a normal control group. We then used MRI or CT for lesion localization and compared areas of overlap in those patients with and without limb apraxia. Patients with ideomotor limb apraxia had damage lateralized to a left hemispheric network involving the middle frontal gyrus and intraparietal sulcus region. Thus, the results revealed that discrete areas in the left hemisphere of humans are critical for control of complex goal-directed movements.

Specialized neural systems underlying representations of sequential movements.

The ease by which movements are combined into skilled actions depends on many factors, including the complexity of movement sequences. Complexity can be defined by the surface structure of a sequence, including motoric properties such as the types of effectors, and by the abstract or sequence-specific structure, which is apparent in the relations amongst movements, such as repetitions. It is not known whether different neural systems support the cognitive and the sensorimotor processes underlying different structural properties of sequential actions. We investigated this question using whole-brain functional magnetic resonance imaging (fMRI) in healthy adults as they performed sequences of five key presses involving up to three fingers. The structure of sequences was defined by two factors that independently lengthen the time to plan sequences before movement: the number of different fingers (1-3; surface structure) and the number of finger transitions (0-4; sequence-specific structure). The results showed that systems involved in visual processing (extrastriate cortex) and the preparation of sensory aspects of movement (rostral inferior parietal and ventral premotor cortex (PMv)) correlated with both properties of sequence structure. The number of different fingers positively correlated with activation intensity in the cerebellum and superior parietal cortex (anterior), systems associated with sensorimotor, and kinematic representations of movement, respectively. The number of finger transitions correlated with activation in systems previously associated with sequence-specific processing, including the inferior parietal and the dorsal premotor cortex (PMd), and in interconnecting superior temporal-middle frontal gyrus networks. Different patterns of activation in the left and right inferior parietal cortex were associated with different sequences, consistent with the speculation that sequences are encoded using different mnemonics, depending on the sequence-specific structure. In contrast, PMd activation correlated positively with increases in the number of transitions, consistent with the role of this area in the retrieval or preparation of abstract action plans. These findings suggest that the surface and the sequence-specific structure of sequential movements can be distinguished by distinct distributed systems that support their underlying mental operations.

American Board of Clinical Neuropsychology special presentation: The American Board of Clinical Neuropsychology (ABCN), 2000 update.

This paper updates neuropsychologists on the process of obtaining board certification in clinical neuropsychology through the American Board of Clinical Neuropsychology (ABCN), a specialty board operating under the auspices of the American Board of Professional Psychology (ABPP). At this time, the ABPP and ABCN have certified 406 clinical neuropsychologists, which makes it the largest board-certification organization in clinical neuropsychology. This article details the advantages of board certification through the ABCN and the four steps which must be passed in order to obtain board certification. These steps are: credential review, written examination, work sample, and oral examination.

Spatial deficits in ideomotor limb apraxia. A kinematic analysis of aiming movements.

Ideomotor limb apraxia is a classic neurological disorder manifesting as a breakdown in co-ordinated limb control with spatiotemporal deficits. We employed kinematic analyses of simple aiming movements in left hemisphere-damaged patients with and without limb apraxia and a normal control group to examine preprogramming and response implementation deficits in apraxia. Damage to the frontal and parietal lobes was more common in apraxics, but neither frontal nor parietal damage was associated with different arm movement deficits. Limb apraxia was associated with intact preprogramming but impaired response implementation. The response implementation deficits were characterized by spatial but not temporal deficits, consistent with decoupling of spatial and temporal features of movement in limb apraxia. While the apraxics' accuracy was normal when visual feedback was available, it was impaired when visual feedback of either target location or hand position was unavailable. This finding suggests that ideomotor limb apraxia is associated with disruption of the neural representations for the extrapersonal (spatial location) and intrapersonal (hand position) features of movement. The non-apraxic group's normal kinematic performance demonstrates that the deficits demonstrated in the apraxic group are not simply a reflection of left hemisphere damage per se.

Neural underpinnings of temporal processing: a review of focal lesion, pharmacological, and functional imaging research.

The mechanisms by which the brain times events and stores them in memory for later use is increasingly of interest to neuroscientists. There are a variety of neurological disorders in which skilled behaviors are not coordinated and appear less than fluent, which may suggest a disorder in temporal processing. In this review, two influential models are described which suggest timing deficits may be due to impairments in a timekeeping mechanism or various nontemporal processes such as motor implementation, memory, and attention. We then review focal lesion, pharmacological, and functional imaging approaches to understanding the neural underpinnings of temporal processing. Converging findings from these approaches provide support for the role of the basal ganglia in timekeeping operations. Likewise, focal lesion and some functional imaging studies are compatible with a timekeeping role of the cerebellum, though specific regions within the cerebellum that control timing operations have not been identified. In contrast, the results from recent focal lesion research suggests the right middle-frontal and inferior-parietal cortices comprise a pathway that supports attention and working memory operations, which are crucial for timing. Functional imaging data provide some converging evidence for this proposal. Functional imaging work also indicates that a right superior-temporal inferior-frontal pathway sometimes aids timing through subvocal nonlinguistic rehearsal processes. These distributed pathways maintain timekeeping operations in working memory and store representations of temporal events, which is crucial for skilled performance.

Temporal processing in the basal ganglia.

This study investigated the role of the basal ganglia in timing operations. Nondemented, medicated Parkinson's disease (PD) patients and controls were tested on 2 motor-timing tasks (paced finger tapping at a 300- or 600-ms target interval), 2 time perception tasks (duration perception wherein the interval between the standard tone pair was 300 or 600 ms), and 2 tasks that controlled for the auditory processing (frequency perception) demands of the time perception task and the movement rate (rapid tapping) in the motor-timing task. Using A.M. Wing and A.B. Kristofferson's (1973) model, the total variability in motor timing was partitioned into a clock component, which reflects central timekeeping operations, and a motor delay component, which estimates random variability due to response implementation processes. The PD group was impaired at both target intervals of the time perception and motor-timing tasks. Impaired motor timing was due to elevated clock but not motor delay variability. The findings implicate the basal ganglia and its thalamocortical connections in timing operations.

Cortical networks underlying mechanisms of time perception.

Precise timing of sensory information from multiple sensory streams is essential for many aspects of human perception and action. Animal and human research implicates the basal ganglia and cerebellar systems in timekeeping operations, but investigations into the role of the cerebral cortex have been limited. Individuals with focal left (LHD) or right hemisphere (RHD) lesions and control subjects performed two time perception tasks (duration perception, wherein the standard tone pair interval was 300 or 600 msec) and a frequency perception task, which controlled for deficits in time-independent processes shared by both tasks. When frequency perception deficits were controlled, only patients with RHD showed time perception deficits. Time perception competency was correlated with an independent test of switching nonspatial attention in the RHD but not the LHD patients, despite attention deficits in both groups. Lesion overlays of patients with RHD and impaired timing showed that 100% of the patients with anterior damage had lesions in premotor and prefrontal cortex (Brodmann areas 6, 8, 9, and 46), and 100% with posterior damage had lesions in the inferior parietal cortex. All LHD patients with normal timing had damage in these same regions, whereas few, if any, RHD patients with normal timing had similar lesion distributions. These results implicate a right hemisphere prefrontal-inferior parietal network in timing. Time-dependent attention and working memory functions may contribute to temporal perception deficits observed after damage to this network.

Profiles of cognitive functioning in chronic spinal cord injury and the role of moderating variables.

A traumatic spinal cord injury (SCI) is accompanied by a documented moderate to severe head injury in significant numbers of SCI patients. In a previous study (Dowler et al., 1995), cognitive deficits were found in 41% of the SCI individuals who were studied with a chronic injury from a traumatic event. The present study investigated whether clinically useful subtypes of normal and impaired cognition could be identified in a chronic (M = 17 years postinjury) SCI sample using a cluster analysis of neuropsychological test performance. A battery of 16 neuropsychological tests was administered to 91 SCI patients and 75 control participants. Composite scores, reflecting performance in different cognitive domains, were derived from a factor analysis of the battery, and these scores were then used in the cluster analysis. A six-cluster solution generated the most distinct and clinically relevant SCI group profiles. Two of the cognitive profiles were characterized by normal functioning in all cognitive domains, but they were distinguished by differences in performance levels. The remaining four SCI groups (60% of the sample) showed clinically significant deficits in one or more cognitive domains, with different groups showing moderate attention and processing speed deficits, mild deficits in processing speed, executive processing difficulties, or moderate memory impairments. Though age and premorbid intellectual ability were strong predictors of the cognitive profiles of some SCI groups, when these factors were controlled, the findings suggested that the patterns of cognitive impairment were likely due to a potential concomitant head injury.

Lidocaine pharmacokinetics and toxicity in newborn pigs.

In newborn infants suffering from perinatal asphyxia seizures, lidocaine (LD) has proved to be an effective anticonvulsant. At high concentrations, however, LD can itself cause convulsions. The convulsive concentration of LD (LD(conv)) varies among species. The aim of this study was to describe LD pharmacokinetics and to define the LD(conv) in awake newborn pigs. Eighteen Land race newborn pigs aged 12-60 h, weight 1.0-2.5 kg, were enrolled. LD, 2 mg/kg intravenous (IV) bolus, (n = 11) was given to estimate pharmacokinetic variables. Continuous LD infusion 2 mg x kg(-1) x min(-1) IV (n = 5) and repeated bolus doses of 15 mg/kg (n = 4) were given until electroencephalogram-confirmed seizures appeared. After the bolus injection, the elimination half-life for LD was 0.87-5.44 h. Increasing plasma concentration (LD(pl)) during infusion resulted in sedation after 5-10 min and in shivering, nystagmus, neck extension, tonic-clonic seizures at LD(conv) of 40.6 +/- 12.7 mg/L (mean +/- SD). The unbound LD(pl) at seizures was 4.4 +/- 2.4 mg/L. Younger animals convulsed at higher LD(conv) (r2 = 0.85). LD pharmacokinetics in newborn pigs were found to be dose-dependent at high plasma concentrations. At lower plasma concentrations, LD pharmacokinetics appeared to be linear. The central nervous system is the primary target for the toxic effect of LD in awake newborn pigs. LD neurotoxicity is age-dependent, and younger pigs convulse at a higher LD(conv).

Distributed neural systems underlying the timing of movements.

Timing is essential to the execution of skilled movements, yet our knowledge of the neural systems underlying timekeeping operations is limited. Using whole-brain functional magnetic resonance imaging, subjects were imaged while tapping with their right index finger in synchrony with tones that were separated by constant intervals [Synchronization (S)], followed by tapping without the benefit of an auditory cue [Continuation (C)]. Two control conditions followed in which subjects listened to tones and then made pitch discriminations (D). Both the S and the C conditions produced equivalent activation within the left sensorimotor cortex, the right cerebellum (dorsal dentate nucleus), and the right superior temporal gyrus (STG). Only the C condition produced activation of a medial premotor system, including the caudal supplementary motor area (SMA), the left putamen, and the left ventrolateral thalamus. The C condition also activated a region within the right inferior frontal gyrus (IFG), which is functionally interconnected with auditory cortex. Both control conditions produced bilateral activation of the STG, and the D condition also activated the rostral SMA. These results suggest that the internal generation of precisely timed movements is dependent on three interrelated neural systems, one that is involved in explicit timing (putamen, ventrolateral thalamus, SMA), one that mediates auditory sensory memory (IFG, STG), and another that is involved in sensorimotor processing (dorsal dentate nucleus, sensorimotor cortex).

Cognitive-motor learning in Parkinson's disease.

Procedural learning deficits are common in Parkinson's disease (PD), but contradictory results have been reported in rotary pursuit learning. This article compared rotary pursuit learning in 2 nondemented PD groups and 2 normal control (NC) groups, using a between-subjects group design in which 3 rotation speeds were presented either randomly or in blocks. The pattern of learning differed between the randomized and the blocked conditions in the NC, but not in the PD groups. Learning was impaired in the PD group in the random condition only. Memory, visuospatial, or executive skills were not associated with the PD group's poorer learning in the randomized context. Results show that procedural learning deficits are not universal with basal ganglia abnormalities but rather depend on the specific cognitive requirements of the learning context.

Posthypoxic hypothermia in newborn piglets.

The purpose of this study was to determine whether mild hypothermia after a moderate hypoxic-ischemic insult reduces the extent of brain damage. Hypoxia was achieved in newborn piglets (n = 24; age, 14-72 h) by abrupt reduction of the inspired oxygen concentration (FiO2) to the maximum concentration (approximately 6%) giving low amplitude (< 7.0 microV) EEG. FiO2 was temporarily increased if heart rate, blood pressure, or end expiratory partial pressure of alveolar CO2 (PAco2) were markedly reduced. This intermittently resulted in EEG amplitude greater than 7 microV, the EEG traces were therefore later examined to determine the duration of low amplitude EEG. After 45 min of hypoxia, the animals were randomized to normothermia (39 degrees C) or hypothermia (35 degrees C) for 3 h. Hypothermia was achieved by applying packs containing ice water. Neurologic assessments and EEG recordings were performed regularly until 3 d when the brains were perfusion fixed. Histologic damage in cortex/white matter, cerebellum, hippocampus, basal ganglia, and thalamus was graded by a pathologist blind to treatment allocation. We found that the severity of brain damage (by histopathologic and neurologic evaluation) was not significantly different when the piglets were normothermic after hypoxia compared with the group made hypothermic. Increased duration of low amplitude EEG and seizure activity were associated with increased damage. When controlling for duration of hypoxia and excluding seizures, piglets undergoing hypothermia had approximately 50% less severe histopathologic damage in cortex/white matter, cerebellum, and hippocampus than those kept normothermic. Thalamus and basal ganglia had no or minor damage. It was concluded that there was no general beneficial effect of postinsult hypothermia. However, when controlling for the duration of the insult and occurrence of seizures, hypothermia reduced the severity of brain damage. This indicates a significant neuroprotective effect of 3 h of mild hypothermia on moderate, but not severe, hypoxic-ischemic insults.

Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment.

Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents. Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = 0.19-0.29) and better visuospatial performance with higher plasma ascorbate (r = 0.22). Concurrent dietary protein in 1986 correlated significantly (rs = 0.25-0.26) with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = 0.18-0.22). Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = 0.19-0.28). Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging.

Hemispheric asymmetry of movement.

Studies in brain-damaged patients indicate that the left hemisphere in right-handers is specialized for controlling cognitive-motor tasks in both arms. Recent functional imaging data support this conclusion, with the finding that ipsilateral, as well as contralateral, movements activate the left, but not the right, motor cortex or association areas of either hemisphere. Future studies must aspire to identify the mechanisms for this asymmetry.

A piglet survival model of posthypoxic encephalopathy.

The aim of this study was to produce a neonatal piglet model which, avoiding vessel ligation, exposed the whole animal to hypoxia and produced dose-dependent clinical encephalopathy and neuropathologic damage similar to that seen after birth asphyxia. Twenty-three piglets were halothane-anesthetized. Hypoxia was induced in 19 piglets by reducing the fractional concentration of inspired oxygen (FiO2) to the maximum concentration at which the EEG amplitude was below 7 microV (low amplitude) for 17-55 min. There were transient increases in Fio2 to correct bradycardia and hypotension. Posthypoxia, the piglets were extubated when breathing was stable. Four were sham-treated controls. We aimed at 72-h survival; seven died prematurely due to posthypoxic complications. EEG and a videotaped itemized neurologic assessment were recorded regularly. We found that 95% of the animals showed neuropathologic damage. The duration of low amplitude EEG during the insult and the arterial pH at the end of the insult correlated with cortical/white matter damage; r = 0.75 and 0.81, respectively. Early postinsult EEG background amplitude (r = 0.86 at 3 h) and neurologic score (r = 0.79 at 8 h) correlated with neuropathology. Epileptic seizures in seven animals were always associated with severe neuropathologic damage. We conclude that EEG-controlled hypoxia and subsequent intensive care enabled the animals to survive with an encephalopathy which correlated with the cerebral hypoxic insult. The encephalopathy was clinically, electrophysiologically, and neuropathologically similar to that in the asphyxiated term infant. This model is suitable for examining mechanisms of damage and evaluation of potential protective therapies after birth asphyxia.

MAC for halothane and isoflurane during normothermia and hypothermia in the newborn piglet.

BACKGROUND: Halothane and isoflurane are frequently used in studies of perinatal hypoxia and ischemia. Little information exists on the minimum alveolar concentration (MAC) necessary to prevent movement to a painful stimulus in newborn pigs and no information on the effects of hypothermia on MAC in pigs. Hypothermia is currently investigated as a posthypoxic neuroprotective intervention. METHODS: The MAC of halothane and isoflurane necessary to prevent movement when a 25 cm hemostatic clamp was applied to the tail were determined in six 20-48-hour-old piglets, and when the same stimulus was applied to the hoof. MAC for halothane was first determined at 39 degrees C, then at 35 degrees C, whereafter halothane was discontinued and MAC for isoflurane determined first at 35 degrees C and then at 39 degrees C. RESULTS: In all six piglets MAC was lower at 35 degrees C than at 39 degrees C for both anesthetics with both tail and hoof determination, lower for halothane than isoflurane for both stimuli at both temperatures, and lower for tail than hoof determination for both anesthetics at both temperatures. For halothane at 39 degrees C, mean (SD) MAC hoof was 0.82 (0.05)% vs tail 0.60 (0.12)%, and at 35 degrees C, hoof 0.65 (0.06)% vs tail 0.42 (0.10)%. For isoflurane at 39 degrees C, MAC hoof was 2.47 (0.28)% vs tail 1.83 (0.28)%, and at 35 degrees C, hoof was 1.83 (0.18)% vs tail 0.85 (0.25)%. CONCLUSION: In the newborn piglet, MAC should be determined by hoof clamp, MAC of isoflurane is approximately three times that of halothane, and both are reduced during hypothermia.