Mild cognitive impairment in prediagnosed Huntington disease.

BACKGROUND: Cognitive decline has been reported in Huntington disease (HD), as well as in the period before diagnosis of motor symptoms (i.e., pre-HD). However, the severity, frequency, and characterization of cognitive difficulties have not been well-described. Applying similar cutoffs to those used in mild cognitive impairment (MCI) research, the current study examined the rates of subtle cognitive dysfunction (e.g., dysfunction that does not meet criteria for dementia) in pre-HD. METHODS: Using baseline data from 160 non-gene-expanded comparison participants, normative data were established for cognitive tests of episodic memory, processing speed, executive functioning, and visuospatial perception. Cutoff scores at 1.5 standard deviations below the mean of the comparison group were then applied to 575 gene-expanded pre-HD participants from the observational study, PREDICT-HD, who were stratified by motor signs and genetic risk for HD. RESULTS: Nearly 40% of pre-HD individuals met criteria for MCI, and individuals closer to HD diagnosis had higher rates of MCI. Nonamnestic MCI was more common than amnestic MCI. Single-domain MCI was more common than multiple-domain MCI. Within the nonamnestic single-domain subtype, impairments in processing speed were most frequent. CONCLUSIONS: Consistent with the Alzheimer disease literature, MCI as a prodromal period is a valid concept in pre-HD, with nearly 40% of individuals showing this level of impairment before diagnosis. Future studies should examine the utility of MCI as a marker of cognitive decline in pre-HD.

The effects of stimulus modality and frequency of stimulus presentation on cross-modal distraction.

Selective attention produces enhanced activity (attention-related modulations [ARMs]) in cortical regions corresponding to the attended modality and suppressed activity in cortical regions corresponding to the ignored modality. However, effects of behavioral context (e.g., temporal vs. spatial tasks) and basic stimulus properties (i.e., stimulus frequency) on ARMs are not fully understood. The current study used functional magnetic resonance imaging to investigate selectively attending and responding to either a visual or auditory metronome in the presence of asynchronous cross-modal distractors of 3 different frequencies (0.5, 1, and 2 Hz). Attending to auditory information while ignoring visual distractors was generally more efficient (i.e., required coordination of a smaller network) and less effortful (i.e., decreased interference and presence of ARMs) than attending to visual information while ignoring auditory distractors. However, these effects were modulated by stimulus frequency, as attempting to ignore auditory information resulted in the obligatory recruitment of auditory cortical areas during infrequent (0.5 Hz) stimulation. Robust ARMs were observed in both visual and auditory cortical areas at higher frequencies (2 Hz), indicating that participants effectively allocated attention to more rapidly presented targets. In summary, results provide neuroanatomical correlates for the dominance of the auditory modality in behavioral contexts that are highly dependent on temporal processing.

From preparation to online control: reappraisal of neural circuitry mediating internally generated and externally guided actions.

Action plans internally generated (IG) from memory are thought to be regulated by the supplementary motor area (SMA), whereas plans externally guided (EG) online using sensory cues are believed to be controlled by the premotor cortex. This theory was investigated in an event-related fMRI study that separated the time course of activation before and during movement to distinguish advance planning from online control. In contrast to prevailing theory, the SMA was not more important for online control of IG actions. EG movement was distinguished from IG movement by greater activation in a more distributed right hemisphere parietal-frontal network than previously reported. Comparisons between premovement and movement periods showed that frontostriatal networks are central for preparing actions before movement onset. However, unlike cortical and cerebellar regions, the basal ganglia exhibited planning-related activity before, but not during, movement. These findings indicate that the basal ganglia mediate planning and online control processes in different ways and suggest a specific role for the striatum in internally planning sequences of actions before they are implemented.

Commonalities and differences among vectorized beamformers in electromagnetic source imaging.

A number of beamformers have been introduced to localize neuronal activity using magnetoencephalography (MEG) and electroencephalography (EEG). However, currently available information about the major aspects of existing beamformers is incomplete. In the present study, detailed analyses are performed to study the commonalities and differences among vectorized versions of existing beamformers in both theory and practice. In addition, a novel beamformer based on higher-order covariance analysis is introduced. Theoretical formulas are provided on all major aspects of each beamformer; to examine their performance, computer simulations with different levels of correlation and signal-to-noise ratio are studied. Then, an empirical data set of human MEG median-nerve responses with a large number of neuronal generators is analyzed using the different beamformers. The results show substantial differences among existing MEG/EEG beamformers in their ways of describing the spatial map of neuronal activity. Differences in performance are observed among existing beamformers in terms of their spatial resolution, false-positive background activity, and robustness to highly correlated signals. Superior performance is obtained using our novel beamformer with higher-order covariance analysis in simulated data. Excellent agreement is also found between the results of our beamformer and the known neurophysiology of the median-nerve MEG response.

The evolution of brain activation during temporal processing.

Timing is crucial to many aspects of human performance. To better understand its neural underpinnings, we used event-related fMRI to examine the time course of activation associated with different components of a time perception task. We distinguished systems associated with encoding time intervals from those related to comparing intervals and implementing a response. Activation in the basal ganglia occurred early, and was uniquely associated with encoding time intervals, whereas cerebellar activation unfolded late, suggesting an involvement in processes other than explicit timing. Early cortical activation associated with encoding of time intervals was observed in the right inferior parietal cortex and bilateral premotor cortex, implicating these systems in attention and temporary maintenance of intervals. Late activation in the right dorsolateral prefrontal cortex emerged during comparison of time intervals. Our results illustrate a dynamic network of cortical-subcortical activation associated with different components of temporal information processing.

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.

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.

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.

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.

Neuropsychological functioning following a spinal cord injury.

Studies indicate that 10-60% of the spinal cord injury (SCI) population retains residual cognitive deficits following the injury. However, previous studies have not used a comprehensive neuropsychological battery and/or a well-matched control group. In addition, no study has determined if cognitive deficits continue more than one year after injury. The present study addressed these limitations by comparing the performance of a chronic SCI group (Mean = 17 years post-injury) and a well-matched control group in four cognitive areas. Memory, visuospatial skills, attention/executive functioning, and processing speed were assessed. Results from a discriminant function analysis indicated that information processing speed best differentiated between the SCI and control groups. Twenty-nine percent of the SCI group performed 1 to 2 standard deviations below the control group mean. These results could not be attributed to psychological status or history of alcohol consumption. The findings emphasize the importance of neuropsychological evaluation after SCI.

Limb-sequencing deficits after left but not right hemisphere damage.

The performance of right and left hemisphere stroke patients was compared to normal control groups on a task where subjects alternately hit two targets which varied in size from 0.5 to 6.5 cm. The stroke patients used the arm ipsilateral to damage, and the control groups used the same arm as their respective stroke group. Lesion size and location were similar for the two stroke groups. No deficits were found for the right hemisphere stroke group. The left stroke group's tapping speed was not slower at the smallest target, but became progressively slower relative to the control group's as target size increased. Variability in tapping speed increased as target size increased for all except the left stroke group. While the entire left stroke group was as accurate as their controls, the apraxic, but not nonapraxic, patients made more errors on smaller targets only. Two explanations for these findings both emphasize the left hemisphere's special role in motor programming; one focuses upon its dominance for movements which are independent of sensory feedback and the other emphasizes its specialization for processing rapid temporal information.

Effects of aging on planning and implementing arm movements.

In Experiments 1 and 2, aiming movements were performed with and without visual feedback in young and elderly adults. The initial (acceleration and deceleration phases) and secondary movement components were analyzed. Although deceleration phase accuracy decreased without visual feedback in both age groups, accuracy diminished as movement amplitude increased only in the elderly. This suggested that the elderly were more dependent on visual feedback to modify motor programs for longer duration movements. Velocity also increased less with increasing amplitude and target size in the elderly, which was related to impaired preprogramming (acceleration phase) and implementation (deceleration phase) of higher forces. This conclusion was confirmed directly in Experiment 2 because only the deceleration phase was affected by the removal of visual feedback of arm position when availability of visual information could not be predicted before movement.

Skill learning in the elderly: diminished implicit and explicit memory for a motor sequence.

Explicit and implicit memory for a cognitive-motor sequence was studied in elderly and young adults. Implicit memory was examined in a serial reaction-time paradigm in which sequences of hand postures repeated cyclically, then shifted to random sequences. Two control groups received random sequences throughout. Movement times (MTs) across the first 4 blocks did not improve more in the elderly-repeated than in the elderly-random group. In contrast, the young-repeated group showed greater improvement in MT across these blocks than the young-random group. MT was less affected in the elderly than in the young by shifts between repeated and random sequences, indicating impaired implicit memory. Explicit memory, which was assessed by free recall and cued recall, also was impaired in the elderly. Diminished implicit memory in the elderly could not be explained solely by the possible intrusion of conscious recollection strategies.

Motor sequencing with left hemisphere damage. Are some cognitive deficits specific to limb apraxia?

Sixteen left-hemisphere stroke patients, who were apraxic or nonapraxic, and 17 control subjects performed sequences of hand postures that varied in the number of different postures (repetitive and heterogeneous) and sequence length (one to five). Performance of the left hand (ipsilateral to stroke) was compared with a control group using the left hand. All stroke patients had slower reaction times and were slower to execute single hand postures, but the apraxic group was not slower than the nonapraxic group. Both the apraxic and the nonapraxic groups had similar problems scheduling or timing motor programs for both sequence types such that inter-response times were more affected by sequence length than the control group. However, only the apraxic group showed abnormalities in preprogramming heterogeneous sequences. The apraxic group also made more errors and had longer movement times (MTs) than for the other groups, but only for heterogeneous sequences containing more than three hand postures. The nonapraxic group did not show slower MTs or greater errors, regardless of the type or the length of sequences. These results suggested deficits in encoding, generating single movements and in scheduling or timing a series of actions which generally attributable to left hemisphere damage. However, abnormalities in temporal organization processes prior to and during movement were specific to apraxia. The dissociation between the two stroke groups on some but not all aspects of sequencing has implications for different cognitive mechanisms supporting motor sequencing.