Preclinical Huntington's disease: compensatory brain responses during learning

Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.     

Impaired sequence learning in carriers of the DYT1 dystonia mutation

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age-matched controls. Regional differences in brain function during task performance were assessed with simultaneous H(2) (15)O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning.     

Effects of levodopa infusion on motor activation responses in Parkinson's disease

BACKGROUND: Clinical improvement with levodopa therapy for PD is associated with specific regional changes in cerebral glucose metabolism. However, it is unknown how these effects of treatment in the resting state relate to alterations in brain function that occur during movement. In this study, the authors used PET to assess the effects of levodopa on motor activation responses and determined how these changes related to on-line recordings of movement speed and accuracy. METHODS: Seven right-handed PD patients were scanned with H(2)15O/PET while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed during "on" and "off" states with an individually titrated constant rate levodopa infusion; movements were kinematically controlled across treatment conditions. RESULTS: Levodopa improved "off" state UPDRS motor ratings (34%; p < 0.006) and movement time (18%; p = 0.001). Spatial errors worsened during levodopa infusion (24%; p = 0.02). Concurrent regional cerebral blood flow (rCBF) recordings revealed significant enhancement of motor activation responses in the posterior putamen bilaterally (p < 0.001), left ventral thalamus (p < 0.002), and pons (p < 0.005). Movement time improvement with treatment correlated with rCBF increases in the left globus pallidus and left ventral thalamus (p < 0.01). By contrast, the increase in spatial errors correlated with rCBF increases in the cerebellar vermis (p < 0.01). CONCLUSION: These results suggest that levodopa infusion may improve aspects of motor performance while worsening others. Different components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways may underlie motor improvement and adverse motoric effects of levodopa therapy for PD.     

The dynamic network subserving the three phases of cognitive procedural learning

Cognitive procedural learning is characterized by three phases (cognitive, associative, and autonomous), each involving distinct processes. We performed a behavioral study and a positron emission tomography (PET) activation study using the Tower of Toronto task. The aim of the behavioral study was to determine cognitive predictors for the length of each of the three learning phases, in order to preselect subjects for the PET study. The objective of the second study was to describe the cerebral substrates subtending these three phases. Contrasted with a reference (motor) task, the cognitive phase activated the prefrontal cortex, cerebellum, and parietal regions, all of which became less active as learning progressed. The associative phase was characterized by the activation of the occipital regions, right thalamus, and caudate nucleus. During the autonomous phase, new regions were involved, including the left thalamus and an anterior part of the cerebellum. These results, by employing a direct comparison between phases, provide the first evidence of the involvement and the time course of activation of different regions in each learning phase, in accordance with current models of cognitive procedural learning. The involvement of a frontoparietal network suggests the use of strategies in problem solving during the cognitive phase. The involvement of the occipital regions during the associative and autonomous phase suggests the intervention of mental imagery. Lastly, the activation of the cerebellum during the autonomous phase is consistent with the fact that performance in this phase is determined by psychomotor abilities.     

Learning-related fMRI activation associated with a rotational visuo-motor transformation

The unique ability to learn transformed or altered visuo-motor relationships during motor learning (visuo-motor transformation learning) has engaged researchers for over a century. Compared to other forms of motor learning (e.g., sequence learning), little is known about plasticity in the cortical and/or subcortical systems involved. We used fMRI to isolate region-specific activation changes during the learning of a visuo-motor (joystick) task under a simple transformation (90 degree rotation of visual feedback). Distributed brain systems were engaged in the learning process. In particular, we found evidence of a learning-dependent transition from early activation of the posterior parietal cortex to later distributed cortico-subcortical-cerebellar responses (in the temporal and occipital cortices, basal ganglia, cerebellum and thalamus). The role of the posterior parietal cortex may relate specifically to the acquisition of the transformation, while that of the fusiform and superior temporal gyri may reflect higher level visual and visuo-spatial processing underlying consolidation. Learning-related increases in cerebellar responses are consistent with its proposed role in the acquisition of internal models of the motor apparatus. These learning-related changes suggest a role for interacting neural systems involving the co-operation of cortico-cortico, cortico-cerebellar and cortico-basal ganglia loops during visuo-motor transformation learning.     

Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET.

The functional anatomy of motor skill acquisition was investigated in six normal human subjects who learned to perform a pursuit rotor task with their dominant right hand during serial positron emission tomography (PET) imaging of relative cerebral blood flow (relCBF). The effect of motor execution, rather than learning, was identified by a comparison of four motor performance scans with two control scans (eye movements only). Motor execution was associated with activation of a distributed network involving cortical, striatonigral, and cerebellar sites. Second, the effect of early motor learning was examined. Performance improved from 17% to 66% mean time on target across the four PET scans obtained during pursuit rotor performance. Across the same scans, significant longitudinal increases of relCBF were located in the left primary motor cortex, the left supplementary motor area, and the left pulvinar thalamus. The results demonstrate that changes of regional cerebral activity associated with early learning of skilled movements occur in sites that are a subset of a more widely distributed network that is active during motor execution.     

Pallidal stimulation for parkinsonism: improved brain activation during sequence learning

We used (15)O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes.     

Functional correlates of pallidal stimulation for Parkinson's disease

We measured regional cerebral blood flow with H2 15O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinson's disease. Six right-handed patients with Parkinson's disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication-free state. Internal globus pallidus deep brain stimulation improved off-state United Parkinson's Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention.     

Analysis of single-subject data sets with a low number of PET scans

We present a procedure for the statistical analysis of single-subject PET data sets with a low number of scans (six total, two scans for each of three conditions) and describe the results of applying this method of analysis on the PET data of 10 normal subjects, performing a motor task, with six scans per subject. Development of this procedure, which combines well-established methods of statistical analysis in functional neuroimaging (a pooled estimate of variance and spatial-extent-based analysis), was motivated by the need for a statistical, individual analysis of PET data sets with a low number of scans from stroke patients in which the location and extent of an infarct varied from subject-to-subject. The results of this spatial-extent-based, single-subject analysis of PET data (including coregistration of significant PET activation to every individual's MRI image and transformation into Talairach space) showed activation in all major cortical motor areas, while no activation was detected in small structures such as the putamen and thalamus. Individual variability in the pattern of statistically significant regions of activation across 10 normal subjects, performing the same motor task, was observed. The results obtained in this study from individual analysis of a low number of PET scans of normal subjects are consistent with previous results of group PET analysis of normal subjects performing similar motor tasks, and these current results indicate that this procedure can help in the examination of PET data sets demanding a single-subject analysis (e.g., involving stroke). Hum. Brain Mapping 5:445–453, 1997. © 1997 Wiley-Liss, Inc.     

APOE-dependent PET patterns of brain activation in Alzheimer disease

Using H2(15)O PET, the authors imaged 13 patients with Alzheimer disease (AD) while performing a serial nonverbal recognition memory task. Patterns of brain activation differed as a function of APOE genotype: epsilon4 carriers exhibited lower activation in the left lingual gyrus and higher activation in left cuneus, precuneus, parahippocampal, and right precentral gyrus. The APOE genotype seems to play a role in cerebral physiologic activity even after onset of clinical manifestations of AD.     

Activation of non-primary motor areas during a complex finger movement task revealed by functional magnetic resonance imaging

We examined the brain activation induced by a complex finger movement task using functional magnetic resonance imaging (fMRI) with echo planar imaging (EPI). Imaging planes were set up for the observation of non-primary motor areas. Among five normal males examined, four subjects naive to the task showed activations in contralateral primary and supplementary motor areas and the ipsilateral superior anterior part of the cerebellar hemisphere. Also, the bilateral premotor areas and the contralateral ventrolateral nucleus of thalamus were occasionally activated. No changes were observed in the putamen and globus pallidus. The subject accustomed to the task showed activation in the narrow areas of the contralateral primary motor and supplementary motor and premotor areas but not in the cerebellum. These results suggest that fMRI has nearly the same degree of detectability to that of positron emission tomography (PET) in regard to motor functions.     

Functional imaging of sequence learning in Parkinson's disease

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.     

Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele).

OBJECTIVE: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. METHODS: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. RESULTS: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. CONCLUSION: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.     

Cerebrocerebellar relationship during behavioral activation: a PET study

The effect of behavioral activation on cerebral and cerebellar glucose metabolism was studied in normal subjects when performing either a verbal memory task or a tactile somatosensory task. Each subject was also studied in a resting state control condition, either 1 h earlier or later than the activation task. Compared to the resting state, both tasks produced asymmetrical metabolic activation, which was opposite in direction within the cerebral and cerebellar hemispheres. In both tasks, the difference of activation of CMRglc in the right and left hemispheres in the cerebellum was negatively correlated with that in the sensory-motor region. This apparently coupled metabolic activation of one cerebellum and areas within the opposite cerebral hemisphere represents the inverse of the crossed cerebellar diaschisis phenomenon commonly observed when a vascular lesion affects one cerebral hemisphere and hypometabolism occurs in the opposite cerebellum. Because these correlations were selective and concordant with known anatomical connections, and were found in two different tasks, they suggest strong functional connections between these specific brain regions.     

Basal ganglia hypoactivity during grip force in drug naïve Parkinson's disease

The basal ganglia (BG) are impaired in Parkinson's disease (PD), but it remains unclear which nuclei are impaired during the performance of motor tasks in early‐stage PD. Therefore, this study was conducted to determine which nuclei function abnormally, and whether cortical structures are also affected by early‐stage PD. The study also determined if cerebellar hyperactivity is found early in the course of PD. Blood oxygenation level dependent activation was compared between 14 early‐stage drug‐naïve PD patients and 14 controls performing two precision grip force tasks using functional magnetic resonance imaging at 3 T. The grip tasks used in this study were chosen because both tasks are known to provide robust activation in BG nuclei, and the two tasks were similar except that the 2‐s task required more switching between contraction and relaxation than the 4‐s task. The 4‐s task revealed that PD patients were hypoactive relative to controls only in putamen and external globus pallidus, and thalamus. In the 2‐s task, PD patients were hypoactive throughout all BG nuclei, thalamus, M1, and supplementary motor area. There were no differences in cerebellar activation between groups during either task. Regions of interest analysis revealed that the hypoactivity observed in PD patients during the 2‐s task became more pronounced over time as patients performed the task. This suggests that a motor task that requires switching can accentuate abnormal activity throughout all BG nuclei of early‐stage, drug‐naive PD, and that the abnormal activity becomes more pronounced with repeated task performance in these patients. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease

OBJECTIVES—The metabolic changes in the brain of symptomatic subjects affected with Machado-Joseph disease have been previously documented using PET with fluorine-18-fluorodeoxyglucose (FDG). The aim of this study was to evaluate these changes in asymptomatic Machado-Joseph disease gene carriers.
METHODS—Seven asymptomatic MachadoJoseph disease gene carriers, identified using a molecular test, and 10 normal control subjects were recruited for PET studies using FDG. Regional uptake ratios of FDG were calculated from the radioactivity of the cerebellar hemispheres, brainstem, and the temporal, parietal and occipital cortices, divided by the activity in the thalamus.
RESULTS—In comparison with data obtained from normal control subjects, there was significantly decreased FDG utilisation in the cerebellar hemispheres, brainstem, and occipital cortex, and increased FDG metabolism in the parietal and temporal cortices of asymptomatic Machado-Joseph disease gene carriers, suggesting preclinical disease activity. Discriminant analysis of regional FDG uptake correctly classified genetic status (Machado-Joseph disease mutation carriers v mutation negative subjects) in 25 of 25 subjects (100% sensitivity and 100% specificity), and clinical status (asymptomatic mutation carriers v symptomatic patients) in 14 of 15 subjects (100% sensitivity and 85.7% specificity).
CONCLUSION— Subclinical changes of FDG consumption, as measured by non-invasive PET, can act as an objective marker of preclinical disease activity in Machado-Joseph disease.

     

Neural intersections of the phonological,visual magnocellular and motor/cerebellar systems in normal readers: Implications for imaging studies on dyslexia

We used fMRI to explore the extent of the anatomical overlap of three neural systems that the literature on developmental dyslexia associates with reading: the auditory phonological, the visual magnocellular, and the motor/cerebellar systems. Twenty‐eight normal subjects performed four tasks during fMRI scans: word and pseudoword reading, auditory rhyming for letter names, visual motion perception, and a motor sequence learning task. We found that the left occipitotemporal cortex (OTC), which previous studies reported to be dysfunctional in dyslexia, can be fractionated into different functional areas: an anterior and lateral area that was activated by both reading and auditory rhyming tasks; a posterior area that was commonly activated by both the reading and the motion perception task and a medial/intermediate area, including the so‐called Visual Word Form Area, which was specifically activated by the reading task. These results show that the left OTC is an area of segregated convergence of different functional systems. We compared our results with the hypoactivation pattern reported for reading in a previous cross‐cultural PET study on 36 dyslexic subjects from three countries. The region of decreased activation in dyslexia overlapped with regions that are specific for reading and those activated during both the auditory rhyming task and the single word and pseudoword reading task described in the present fMRI study. No overlap was found with the activation patterns for the visual motion perception task or for the motor sequence learning task. These observations challenge current theories of dyslexia. Hum Brain Mapp 34:2669–2687, 2013. © 2012 Wiley Periodicals, Inc.     

Role of the cerebellum in implicit motor skill learning: a PET study

To depict neural substrates of implicit motor learning, regional cerebral blood flow was measured using positron emission tomography (PET) in 13 volunteers in the rest condition and during performance of a unimanual two-ball rotation task. Subjects rotated two balls in a single hand; a slow rotation (0.5 Hz) was followed by two sessions requiring as rapid rotation as possible. The process was repeated four times by a single hand (Block 1) and then by the opposite hand (Block 2). One group of volunteers began with the right hand (n = 7), and the other with the left (n = 6). Performance was assessed by both quickness and efficiency of movements. The former was assessed with the maximum number of rotation per unit time, and the latter with the electromyographic activity under constant speed of the movement. Both showed learning transfer from the right hand to the left hand. Activation of cerebrum and cerebellum varied according to hand. Activation common to both hands occurred in the bilateral dorsal premotor cortex and parasagittal cerebellum, right inferior frontal gyms, left lateral cerebellum and thalamus, supplementary motor area, and cerebellar vermis. The left lateral cerebellum showed the most prominent activation on the first trial of the novel task, and hence may be related the early phase of learning, or "what to do" learning. Left parasagittal cerebellum activity diminished with training both in first and second blocks, correlating inversely with task performance. This region may therefore be involved in later learning or "how to do" learning. The activity of these regions was less prominent with prior training than without it. Thus the left cerebellar hemisphere may be related to learning transfer across hands.     

Functional neuroanatomy of the human near/far response to blur cues: eye-lens accommodation/vergence to point targets varying in depth

The purpose of this study was to identify the networks involved in the regulation of visual accommodation/vergence by contrasting the cortical functions subservient to eye-lens accommodation with those evoked by foveal fixation. Neural activity was assessed in normal volunteers by changes in rCBF measured with PET. Thirteen right-handed subjects participated in three monocular tasks: (i) resting with eyes closed; (ii) sustained foveal fixation upon a LED at 1.2 m (0.83 D); and (iii) accommodating alternately on a near (24 cm, 4.16 D) vs. a far (3.0 m, 0.33 D) LED alternately illuminated in sequential 2 s epochs. The contrast between the conditions of near/far accommodation and of constant foveal fixation revealed activation in cerebellar hemispheres and vermis; middle and inferior temporal cortex (BA 20, 21, 37); striate cortex and associative visual areas (BA 17/18). Comparison of the condition of constant fixation with the condition of resting with closed eyes indicated activation of cerebellar hemispheres and vermis; visual cortices (BA 17/18); a right hemisphere dominant network encompassing prefrontal (BA 6, 9, 47), superior parietal (BA 7), and superior temporal (BA 40) cortices; and bilateral thalamus. The contrast between the conditions of near/far accommodation with closed-eye rest reflected an incremental summation of the activations found in the previous comparisons (i.e. activations associated with constant fixation). Neural circuits activated selectively during the near/far response to blur cues over those during constant visual fixation, occupy posterior structures that include occipital visual regions, cerebellar hemispheres and vermis, and temporal cortex.