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The neurodevelopmental frontostriatal disorders: evolutionary adaptiveness and anomalous lateralization.

The frontostriatal system (dorsolateral prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate, supplementary motor area, and associated basal-ganglia structures) is subject to a range of neurodevelopmental disorders: Tourette's syndrome (TS), obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), autism, and probably depression. The system is responsible for our adaptive responses (initiation, execution, or withholding) to environmental situations, and the above disorders, involving effectively excessive release or withholding of various types of response, are all a consequence of changes in specific frontostriatal regions. The disorders all have a genetic component, and their persistence in the genome indicates that their clinical manifestations may also be associated, perhaps in low levels in close relatives, with certain adaptive advantages in given situations. Thus autism is associated with computational careers, depression with literary creativity, SCZ with lateral thinking and the Odyssean personality, ADHD with an Ice-Age readiness to respond, OCD with a focused range of interests, and TS with competitive sports and jazz improvisation. The disorders are all highly comorbid, and which one predominantly manifests may depend on how the frontostriatal system happens to be compromised as a result of inherited genetic predispositions and environmental contingency. We review the adaptive nature of the various subclinical manifestations and the evidence for concomitant phenomena (possibly epiphenomena): alterations in structural, functional, and behavioral lateralization in each syndrome. Indeed it is not clear that altered lateralization in frontostriatal disorders of a neurodevelopmental origin generally has any adaptive significance; it may often simply serve as a marker for altered regulatory function of the frontostriatal system, alterations which in low genetic dosage or penetrance continue to play an adaptive role in clinically unaffected close relatives of probands, but which, in high dosage or penetrance in the probands themselves, are generally deleterious.

Adaptation, Physiological↗

Isolating the mnemonic component in spatial delayed response: a controlled PET 15O-labeled water regional cerebral blood flow study in normal humans.

In this study we attempted to elucidate the neural network involved in maintaining spatial information over short delays by means of the PET 15O-labeled water method for measuring regional cerebral blood flow. To isolate the mnemonic component of delayed response processing we designed a control task isomorphic to the experimental task (in which the subject remembered the location of four targets in an array over a 7 s delay) and controlled for spatial encoding. Fourteen normal subjects participated in the study. Regional cerebral blood flow (rCBF) data were analyzed using statistical parametric mapping, a data-driven approach which canvasses the whole brain for significantly activated pixels in the experimental vis-à-vis the control task, and a hypothesis driven region of interest approach involving comparisons of control and experimental conditions using normalized rCBF data. We found convergent evidence for a spatially distinct but functionally related network in which dorsolateral prefrontal cortex and extrastriate occipital cortex were activated by the experimental task vis-à-vis the control task, as well as evidence for superior parietal and supplementary motor area cortical activation. These findings suggest that anterior components of the network may be involved in mnemonic rehearsal functions, while posterior components may store critical perceptual attributes of the memoranda.

Adult↗

Changes in regional cerebral blood flow related to line bisection discrimination and visual attention using HMPAO-SPECT.

Behavioral tasks requiring visual-spatial discrimination such as line bisection are used clinically to assess right hemisphere function, yet the anatomical substrate of line bisection has yet to be elucidated by functional imaging. In the current study, nine right-handed, healthy adult subjects underwent split-dose technetium-99m-hexamethylpropylene amine oxime single photon emission tomography during performance of two visual tasks. Statistical parametric maps that represented significant changes in regional cerebral blood flow (rCBF) for each task were generated. Increases in rCBF were seen in the right dorsolateral prefrontal cortex, the insula, and the superior temporal lobe with a line-bisection discrimination task, whereas increases in the visual association areas, the posterior cingulate gyrus bilaterally, and the anterior cingulate gyrus on the right were seen with a similar control task which required sustained visual attention, but no visual spatial discrimination. We conclude that distinct areas in the nondominant hemisphere can be shown to be active during performance of line-bisection discrimination and sustained visual attention.

Adult↗

Mapping voxel-based statistical power on parametric images.

Using a classic technique based on the noncentral F-distribution method for computing statistical power, we developed a general approach to the estimation of voxel-based power in functional brain image data analysis. We applied this method to PET data from a large sample (N = 40) of subjects performing the Wisconsin Card Sorting (WCST) paradigm analyzed with SPM95, produced statistical power maps for a range of samples sizes and smoothing filter widths, and examined the effects of sample size and image smoothing on the expected reliability of activation findings. At an uncorrected alpha of 0.01, a fixed filter size of 10 mm3, and a range of power thresholds, maps revealed that the power to reject the null hypothesis in brain regions implicated in the task at Ns of 5 and 10 may not be sufficient to ensure reliable replication of significant findings and so should be interpreted with caution. At sample sizes approaching 20 subjects, sufficient power was found in the right dorsolateral prefrontal cortex (BA 46/9), right and left inferior parietal lobule (BA 40), and left inferior temporal lobe (BA 37), comprising the cortical network typically observed during the WCST. Filter size needed to maximize power varied widely, but systematically, across the brain, tending to follow known neuroanatomical landmarks. Statistical power considerations in brain imaging studies are critical for controlling the rate of false negatives and assuring reliable detection of cognitive activation. The variation of filter size for maximizing power across the brain suggests that the underlying neuroanatomy of functional units is an important consideration in the a priori selection of filter size.

Algorithms↗

Reproducibility of fMRI results across four institutions using a spatial working memory task.

Four U.S. sites formed a consortium to conduct a multisite study of fMRI methods. The primary purpose of this consortium was to examine the reliability and reproducibility of fMRI results. FMRI data were collected on healthy adults during performance of a spatial working memory task at four different institutions. Two sets of data from each institution were made available. First, data from two subjects were made available from each site and were processed and analyzed as a pooled data set. Second, statistical maps from five to eight subjects per site were made available. These images were aligned in stereotactic space and common regions of activation were examined to address the reproducibility of fMRI results when both image acquisition and analysis vary as a function of site. Our grouped and individual data analyses showed reliable patterns of activation in dorsolateral prefrontal cortex and posterior parietal cortex during performance of the working memory task across all four sites. This multisite study, the first of its kind using fMRI data, demonstrates highly consistent findings across sites.

Adult↗

A developmental functional MRI study of spatial working memory.

Functional magnetic resonance imaging (fMRI) was used to examine patterns of cortical activity in children during performance of a spatial working memory task. Six children (8-10 years) and six adults (19-26 years) searched a linear array of four boxes for the appearance of a dot. In the visual blocks, participants made no response. In the motor blocks, participants were instructed to indicate the location of the dot on each trial using a button-press response. In the working memory blocks, participants were instructed to indicate at which location the dot had appeared 1 or 2 trials previously. Both children and adults showed activity in the left precentral and postcentral gyri, as well as the right cerebellum for the motor condition as compared to the visual condition. Comparison of the memory and motor conditions revealed reliable activity in the right superior frontal gyrus (BA 8), right dorsolateral prefrontal cortex (BA 10/46), right superior parietal cortex, and bilateral inferior parietal cortex for both adults and children. These results suggest that spatial working memory tasks activate very similar cortical regions for school-age children and adults. The findings differ from previous imaging studies of nonspatial working memory tasks in that the prefrontal activations observed in the current work tend to be more dorsal. Results are discussed in light of the significant behavioral performance differences observed between child and adult participants.

Adult↗

Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation.

We used multislice functional magnetic resonance imaging (fMRI) to investigate the association between behavioral and neurophysiological measures of working memory task performance in 20 right-handed male healthy volunteers. Images were acquired over a 5-min period at 1.5 Tesla. We used a periodic design, alternating 30-s blocks of the "n-back" working memory task with 30-s blocks of a sensorimotor control task to activate verbal working memory systems. The power of functional response to the task was estimated by sinusoidal regression at each voxel. The relationship between power of fMRI response and mean reaction time over all 11 working memory trials was explored by multiple regression, with age and mean reaction time to the control task as covariates, at voxel and regional levels of analysis. All subjects were able to perform the n-back task accurately. A spatially distributed network was activated, including dorsolateral prefrontal cortex, inferior frontal gyrus, lateral premotor cortex, and supplementary motor area (SMA) in the frontal lobes. More posteriorly, there were major foci of activation in parietal and occipitoparietal cortex, precuneus, lingual, and fusiform gyri of the ventral occipital lobe, inferior temporal gyrus, and cerebellum. The power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex (Talairach coordinates in x, y, z (mm) 35, -44, 37 and -32, -56, 42), indicating that subjects who found the task difficult, and responded with a slower reaction time, tended to activate these regions more powerfully. One interpretation of this regionally specific relationship between prolonged reaction time and increased power of posterior parietal activation is consistent with prior studies identifying similar areas of parietal cortex as the site of the phonological storage function in verbal working memory.

Adult↗

The functional neuroanatomy of simple calculation and number repetition: A parametric PET activation study.

We examined cerebral activation patterns with positron emission tomography (PET) in 12 right-handed normal volunteers while they were completing simple calculation tasks or merely repeating numbers. Using a parametric experimental design, during calculation we found activation in the medial frontal/cingulate gyri, left dorsolateral prefrontal cortex, left anterior insular cortex and right anterior insular cortex/putamen, left lateral parietal cortex, and the medial thalamus. Number repetition engaged bilateral inferior sensorimotor cortex, bilateral temporal areas, and left inferior frontal cortex. These results suggest a functional anatomical network for simple calculation, which includes aspects of attention, auditory, and motor processing and the phonological store and articulatory loop components of working memory; they add some support for a special role of the parietal cortex in calculation tasks.

Adult↗

Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections.

Cross-correlation of low-frequency temporal fluctuations (<0.08 Hz) was used to correlate widely separated anatomic regions during continuous performance of a spatial working memory task. The regions of highest correlation to right-hemisphere dorsolateral prefrontal cortex correspond to the regions of largest baseline signal change in a conventional block-style functional MRI paradigm. Additionally, it is shown that the correlations between elements of the functional network increase during performance of a task that activates the network when compared to a task that does not directly stimulate the functionally connected network.

Attention↗

Cortical networks recruited for time perception: a monkey positron emission tomography (PET) study.

The presence of an "internal clock" in the brain has been assumed to underlie the information processing related to time. This clock plays a critical role in time keeping and time perception, which are closely associated with integrated functions in the brain. To identify the brain areas recruited for time keeping and time perception, we performed positron emission tomography (PET) studies with rhesus monkeys to measure regional cerebral blood flow (rCBF) as an index of neural activity during time discrimination tasks of different durations ranging from 400 to 1500 ms. Changes in rCBF that covaried significantly with the durations of the target being perceived by subjects were found in the dorsolateral prefrontal cortex (DLPFC), the posterior part of the inferior parietal cortex, basal ganglia, and posterior cingulate cortex. Furthermore, a loss of neuronal function in the DLPFC caused by a local application of bicuculline resulted in the selective reduction of performance in time discrimination tasks. The results indicate that a neural network composed of the posterior inferior parietal cortex to the DLPFC plays a crucial role in the temporal monitoring process in time perception.

Animals↗

Functional specificity of superior parietal mediation of spatial shifting.

Using event-related functional magnetic resonance imaging (fMRI) we determined how brain activity changes when an attended target shifts its location. In the main experiment, a white square could appear at 10 possible eccentricities along the horizontal meridian. It remained on the screen for a variable period of time and then changed location. At any time the stimulus could dim briefly. Subjects had to press a button when the stimulus dimmed. In order to perform this task attention had to be locked onto the target and shift with it. Half of the runs were performed overtly and half covertly. The event of interest consisted of the shift in the location of the attentional target. The state of maintained attention occurring in between the shifts constituted the baseline. The superior parietal gyrus was activated bilaterally in response to attentional shifts. No other area showed a significant response to shifting. On the left side the amplitude of the superior parietal response correlated positively with the distance of the shift. On the right side a significant correlation was present only for overt shifts. In a separate experiment we compared the maintaining of attention at a single spatial location to passive fixation: the frontal eye fields, anterior cingulate, right dorsolateral prefrontal cortex, and inferior parietal lobule were significantly activated, indicating that the absence of a shift-related response in these areas in the main experiment was due to the fact that they were equally activated by maintaining and shifting attention. The response to spatial shifts and the correlation with the distance between the original and the new location points to a specific role of the superior parietal gyrus in shifting the locus of spatial attention.

Adult↗

The inhibition of imitative response tendencies.

Recent neurocognitive studies show that perception and execution of actions are intimately linked. The mere observation of an action seems to evoke a tendency to execute that action. Since such imitative response tendencies are not adaptive in many everyday situations imitative response tendencies usually have to be inhibited. These inhibitory processes have never been investigated using brain imaging techniques. Former work on response inhibition and interference control has focused on paradigms such as the Stroop task or the go/no-go task. We have carried out an event-related functional magnetic resonance imaging study in order to investigate the cortical mechanisms underlying the inhibition of imitative responses. The experiment employs a simple response task in which subjects were instructed to execute predefined finger movements (tapping or lifting of the index finger) in response to an observed congruent or incongruent finger movement (tapping or lifting). A comparison of brain activation in incongruent and congruent trials revealed strong activation in the dorsolateral prefrontal cortex (middle frontal gyrus) and activation in the right frontopolar cortex and the right anterior parietal cortex, as well as in the precuneus. These results support the assumption of prefrontal involvement in response inhibition and extend this assumption to a "new" class of prepotent responses, namely, to imitative actions.

Adult↗

The synchronization of the human cortical working memory network.

A verbal reasoning problem at the intersection of verbal working memory, problem-solving, and language comprehension was examined using event-related fMRI to distinguish differences in the differential timing of the response of the various cortical regions that compose the working memory network. Problems were developed such that the process demand as well as the timing of the manipulation of the contents of working memory (i.e., a demanding computation) was varied. Activation was observed in several regions including the dorsolateral prefrontal cortex, the inferior frontal gyrus, and the parietal lobe. Examination of the MR amplitude response revealed that the regions do not all activate simultaneously; instead, their activation time courses reveal differential responses that correspond to their theoretical processing role in the problem-solving task. The coordination of cortical area responses reveals how the various cortical regions synchronize and collaborate in order to accomplish a given cognitive function.

Adult↗

The neural basis for categorization in semantic memory.

We asked young adults to categorize written object descriptions into one of two categories, based on a rule or on overall similarity, while we monitored regional brain activity with functional magnetic resonance imaging (fMRI). We found significantly greater recruitment of left dorsolateral prefrontal cortex for rule-based categorization in direct comparison with similarity-based categorization. Recruitment of right ventral frontal cortex and thalamus was uniquely associated with rule-based categorization as well. These observations lend support to the claim that executive functions such as working memory, inhibitory control, and selective attention contribute to rule-based categorization. Right inferior parietal activation was uniquely associated with similarity-based categorization. This region may play an important role in overall feature configuration that is important for this form of categorization. We found other brain regions recruited for both rule-based and similarity-based categorization: Anterior cingulate cortex may support the implementation of executive functions during situations with competing response alternatives; and left inferior parietal cortex may be related to the integration of feature knowledge about objects represented in modality-specific association cortices. We also administered a degraded-similarity condition where the task of categorizing a written object description was made more difficult by perceptually degrading the stimulus materials. The degraded condition and the rule-based condition, but not the similarity-based condition, were associated with caudate activation. The caudate may support resource demands that are not specific for a particular categorization process. These findings associate partially distinct large-scale neural networks with different forms of categorization in semantic memory.

Adolescent↗

Voxel-based morphometry reveals increased gray matter density in Broca's area in male symphony orchestra musicians.

Broca's area is a major neuroanatomical substrate for spoken language and various musically relevant abilities, including visuospatial and audiospatial localization. Sight reading is a musician-specific visuospatial analysis task, and spatial ability is known to be amenable to training effects. Musicians have been reported to perform significantly better than nonmusicians on spatial ability tests, which is supported by our findings with the Benton judgement of line orientation (JOL) test (P < 0.001). We hypothesised that use-dependent adaptation would lead to increased gray matter density in Broca's area in musicians. Voxel-based morphometry (VBM) and stereological analyses were applied to high-resolution 3D MR images in male orchestral musicians (n = 26) and sex, handedness, and IQ-matched nonmusicians (n = 26). The wide age range (26 to 66 years) of volunteers permitted a secondary analysis of age-related effects. VBM with small volume correction (SVC) revealed a significant (P = 0.002) region of increased gray matter in Broca's area in the left inferior frontal gyrus in musicians. We observed significant age-related volume reductions in cerebral hemispheres, dorsolateral prefrontal cortex subfields bilaterally and gray matter density in the left inferior frontal gyrus in controls but not musicians; a positive correlation between JOL test score and age in musicians but not controls; a positive correlation between years of playing and the volume of gray matter in a significant region identified by VBM in under-50-year-old musicians. We suggest that orchestral musical performance promotes use-dependent retention, and possibly expansion, of gray matter involving Broca's area and that this provides further support for shared neural substrates underpinning expressive output in music and language.

Adult↗

Glucose metabolism in psychiatric disorders: how can we facilitate comparisons among studies?

Positron emission tomography (PET) offers a possibility to study brain function and its relationship to psychiatric disorders. Clinical studies have demonstrated that several psychiatric diseases are coupled with changes in brain glucose metabolism. Schizophrenia seems to involve a lower metabolism in wide areas of the brain--both cortical and subcortical structures. Depression probably involves dysfunction of the metabolism in dorsolateral prefrontal cortex. Obsessive compulsive disorder, panic disorder, anorexia nervosa and the experience of anxiety may involve increased metabolic rates. The results from the different studies do not allow quantitative comparisons or detailed analyses because of large differences in experimental and clinical methodology. The term Good Clinical PET Practice (GCPP) is suggested to encourage standardization in clinical investigations. GCPP includes standardization of both experimental factors (lumped constant, arterialization, purity of tracer, regions of interest, relative rates) and clinical factors (state of the subject, wakefulness, anxiety, gender, course of the disease) in PET performance.

Brain↗

Prefrontal unit activity during associative learning in the monkey.

Single unit activity was recorded from the dorsolateral prefrontal cortex of two monkeys which were trained on a stimulus-reward association task. The monkeys were trained on a reaction time task overlapped with a classical conditioning paradigm. The sequential events of the task were as follows: (1) lever pressing to start the trial; (2) presentation of a visual cue for 1 s; (3) delay period of 1 s; (4) imperative stimulus presentation; and (5) release of the lever by the animal. The visual cue signaled whether or not a drop of fruit juice would be given (its associative significance) for the animal's release response instead of signaling what response the animal should perform (its behavioral significance). In this task, the animal had to release the lever even on the trial where no juice was given in order to advance to the next trial. A total of 423 units showed activity changes in relation to one or more of the task events, such as the cue presentation, delay, release response and reward delivery. Among 313 units which showed cue-related activity changes, 179 units showed differential activity in relation to the different cues. A majority of them (Type M; n = 120) showed activity changes in relation to whether the cue indicated juice delivery or not, independent of its physical properties. The activity of 13 units (Type P) was related to the physical properties of the stimulus, and the activity of the remaining 46 units (Type MP) appeared to be related to both aspects of the stimulus. Sustained activity changes during the delay period were observed in 68 Type M, in 3 Type P and in 24 Type MP units. The results suggest that the prefrontal cortex plays important roles in the stimulus-reward association and that prefrontal units are involved in higher order information processing, extracting and retaining the "associative significance" of the stimulus independent of its physical properties.

Animals↗

Age-related changes in cerebral blood flow activation during a Card Sorting Test.

To determine the age-related changes in the neural processing involved in the Modified Card Sorting Test (MCST), we measured cerebral blood flow (CBF) during performance of the MCST and of the number-matching task in young and elderly subjects using positron emission tomography. Compared with that during the number-matching task, CBF during the MCST was increased in the left dorsolateral prefrontal cortex (DLPFC), left inferior parietal lobule, and left striate and prestriate cortices in both age groups. However, CBF activation in these areas was significantly lower in the elderly subjects than the young subjects. Furthermore, CBF activation was reduced in the left DLPFC, right parahippocampal gyrus, and prestriate cortex in proportion to the increase in the number of perseverative errors with aging. These results suggest that the impaired MCST performance in elderly subjects may be due, in part, to dysfunction of the network involving certain cortical areas such as the prefrontal and parahippocampal cortices, although the essential neural circuits for MCST performance were still preserved even in the elderly subjects.

Adult↗