Frontal-striatal Circuits Research Articles

Dopamine and cognitive functioning in de novo subjects with Parkinson's disease: Effects of pramipexole and pergolide on working memory

Very few studies have investigated the relationship between dopaminergic therapy and working memory (WM) functioning in Parkinson's disease (PD) patients. The aim of the present study was to explore the effects of pharmacological treatment with pergolide (a D 1 + D 2 receptor agonist) and pramipexole (a D 2 + D 3 receptor agonist) on performance in visual–spatial, visual-object, and verbal WM tasks in PD patients. Participants included 19 “de novo” PD patients and 13 healthy controls (HC). The experimental task consisted of an n-back paradigm with verbal, visual-object, or visual–spatial stimuli. PD patients performed the task twice: after 18–24 h of therapy wash-out and after administration of pergolide (nine patients) or pramipexole (ten patients). HCs performed the task only once, without drug administration. Depending on how they performed in the “Off” and “On” therapy conditions, the nine PD patients each were classified into groups of low performers (i.e., performance on the n-back paradigm was below the median value of the experimental sample) and high performers (i.e., performance was above the median value). One PD patient was excluded from the analysis because his performance pattern clearly revealed that he was an outlier. In the low performer PD patients, administration of both pergolide and pramipexole improved accuracy on all WM tasks. No effect of the drugs was found in the high performer patients. The results of the present study show that stimulation of dopaminergic receptors improves high-level WM processes in PD patients, possibly by modulating activity in frontal–striatal circuits.

Poster 7: Memory for Temporal Sequences for the Early Detection of Cognitive Changes in Preclinical Huntington's Disease

Previous research implicates the prefrontal cortex in memory for temporal order. Since frontal-striatal circuits are disrupted early in Huntington's disease (HD), temporal order memory may be particularly sensitive to neuropathological changes in preclinical HD. Eighteen presymptomatic gene carriers, 18 age- and sex-matched normal controls, and 18 non-gene–carriers were administered a visuospatial temporal order memory task on a computerized radial eight-arm maze. Presymptomatic gene carriers were assigned to two groups consisting of presymptomatic gene carriers less than five years away from estimated age of onset (HD Close group, n = 10) and presymptomatic gene carriers more than five years away from estimated age of onset (HD Far group, n = 8). On the study phase, the participant was shown a random sequence of circles presented one at a time at the end of each of the eight arms. On the choice phase, the participant was presented with a circle at the end of two of the study phase arms and was asked to choose the circle that occurred earlier in the sequence. Parametric manipulations of the temporal metric were carried out by systematically changing the temporal separation lag between the two circles in the choice phase. As expected, all groups showed superior performance on distal temporal separation lags compared to proximal temporal separation lags. However, the HD Close group demonstrated impairments relative to the HD Far group, non-gene–carriers, and normal controls on more proximal temporal separation lags ( p

Fragile X syndrome—From genes to cognition

Fragile X syndrome (FXS), a single gene disorder with an expanded CGG allele on the X chromosome, is the most common form of inherited cognitive impairment. The cognitive deficit ranges from mild learning disabilities to severe intellectual disability. The phenotype includes hyperactivity, short attention span, emotional problems including anxiety, social avoidance, poor eye contact, and hyperarousal to sensory stimuli. Imaging studies in FXS have clarified the impact of the FMR1 mutation on brain development and function by documenting structural abnormalities, predominantly in the caudate nucleus and cerebellum, and functional deficits in the caudate, frontal-striatal circuits, and the limbic system. On the basis of current research results, a targeted treatment for FXS will be available in the near future. Currently, a number of psychopharmacological agents are helpful in treating many of the problems in FXS including hyperactivity, attention deficits, anxiety, episodic aggression, and hyperarousal. Although the targeted treatments aim at strengthening synaptic connections, it is essential that these treatments are combined with learning programs that address the cognitive deficits in FXS.

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

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

Neuropsychological and hypothalamic–pituitary-axis function in female patients with melancholic and non-melancholic depression

Executive function deficits in depression implicate involvement of frontal-striatal circuits. However, studies of hypothalamic-pituitary-axis (HPA) function suggest that stress-related brain changes of hippocampus may also implicate prefrontal-hippocampal circuits, which may explain the profile of both executive dysfunction and memory deficits. In this study we examined the performance of patients with major depressive disorder (MDD) on tasks of memory and executive function in relation to melancholic features and to cortisol levels. Our hypothesis was that raised cortisol levels in melancholic patients would correlate with these deficits. Forty female MDD patients, 20 having melancholic features (MEL vs. Non-MEL), and 20 sex-age- and education-matched normal controls were investigated using the Cambridge neuropsychological test automated battery (CANTAB), to assess memory (paired associative learning, PAL; short-term recognition memory, SRM) and executive (intradimensional/extradimensional set-shifting, ID/ED; Stockings of Cambridge, SOC) functions. Plasma and salivary cortisol levels were measured. The MDD patients performed worse than controls on PAL and both executive tasks. The MEL group differed from controls on all tests, and differed from the non-MEL only at the ED stage of the ID/ED task. Patient cortisol levels were within the normal range and did not correlate with neuropsychological performance for any group. MDD patients showed neuropsychological deficits on tasks of executive function and memory, supporting the model of frontal-temporal dysfunction. MEL vs. non-MEL performed worse overall and demonstrated a qualitative difference in set shifting, perhaps implicating more extensive prefrontal involvement. Cortisol levels did not correlate with depression severity or the observed deficits.

Neural correlates of cognitive inflexibility during task-switching in obsessive-compulsive disorder

A deficit in cognitive flexibility is acknowledged as a cognitive trait for obsessive-compulsive disorder (OCD). However, no investigations to date have used a cognitive activation paradigm to specify the neural correlates of this deficit in OCD. The objective of this study was to clarify how abnormal brain activities relate to cognitive inflexibility in OCD, using a task-switching paradigm. A task-switching paradigm which has two kinds of task-set was applied to 21 patients with OCD and 21 healthy subjects of matching age, IQ and sex, during an event-related functional magnetic resonance imaging experiment. Compared with the healthy subjects, patients with OCD exhibited a significantly higher error rate in task-switch trials (P < 0.05). Healthy controls showed significant activation in various areas, including dorsal frontal-striatal regions, during task-switching, whereas patients with OCD showed no activation in these areas. Significant differences were also observed in the dorsal frontal-striatal regions and ventromedial prefrontal and right orbitofrontal cortexes between patients with OCD and healthy controls. Correlation analysis indicated that the activations of orbitofrontal cortex were related with the performance in both groups and also with the activation of anterior cingulate cortex in the OCD group. These findings replicate previous studies of cognitive inflexibility in OCD and provide neural correlates related to a task-switching deficit in OCD. The results suggest that impaired task-switching ability in OCD patients might be associated with an imbalance in brain activation between dorsal and ventral frontal-striatal circuits.

Recent advances in structural and functional brain imaging studies of attention-deficit/hyperactivity disorder

The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naïve, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD.

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis

Multiple theories of Attention-Deficit/Hyper-activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.

Neuroimaging in Obsessive-Compulsive Disorder

Neurobiological models of obsessive-compulsive disorder (OCD) have emphasized the mediation of clinical symptoms by aberrant frontal-striatal circuits. A recent neurobiological model for normal human emotion perception has proposed distinct ventral and dorsal processing systems corresponding with differential levels of emotion perception. This construct appears also relevant for elucidating the pathophysiology of OCD, being an anxiety disorder. In the present paper, we present a comprehensive review of the neuroimaging literature in OCD, with the aim of critically appraising the current status of imaging-based knowledge on neurophysiological factors in the pathogenesis of OCD, along with the methodological possibilities and limitations of each imaging paradigm for OCD research. Moreover, we intend to relate these experimental findings to the frontal-striatal model and to the model of normal emotion perception. Results of imaging studies point to the need for adjustments in current models, with respect to the involvement of frontalstriatal circuits in OCD, as a ventral-dorsal dissociation may be distinguished. Moreover, data from pediatric OCD patient samples have commenced to shed light on developmental characteristics of OCD. Furthermore, longitudinal designs, in combination with pre-post treatment comparisons, are of great value for assessing the state-trait duality. Finally, the use of multimodal study designs holds great promise for the near future. Keywords: obsessive-compulsive disorder, review, pathophysiology, neurobiological models, neuroimaging

Shifting-Related Brain Magnetic Activity in Attention-Deficit/Hyperactivity Disorder

Current theories suggest a role for frontal-striatal circuits in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). We used magnetoencephalography (MEG) to measure event-related brain activity during a simplified version of the Wisconsin Card Sorting Test in children with DSM-IV combined type ADHD (ADHD-C) or predominantly inattentive type ADHD (ADHD-PI) and in age- and intelligence-matched control children. In control children, set-shifting cues evoked a higher degree of activation in the medial temporal lobe (MTL) between 200 and 300 msec than non-shifting cues, with MTL activation predicting later activity in left anterior cingulate cortex (ACC) (at 400-500 msec). This MTL-ACC response pattern was diminished in children with ADHD. By contrast, children with ADHD showed early activity in regions barely activated in control children, such as left inferior parietal lobe and posterior superior temporal gyrus. These preliminary data support theories of frontal dysfunction in ADHD but also suggest that deficits in higher-level functions might be secondary to disruptions in earlier limbic processes.

Cortical and subcortical brain regions involved in rule-based category learning

The brain regions contributing to rule-based category learning were examined using fMRI. Participants categorized single lines that varied in length and orientation into one of two categories. Category membership was based on the length of the line. Results indicated that left frontal and parietal regions were differentially activated in those participants who learned the task as compared to those who did not. Further, the head of the caudate displayed relative decreases in activation on incorrect trials relative to correct trials. The involvement of this latter structure is likely related to (1) processing an error signal, or (2) volitional switching between potential category rules. Results are consistent with theories suggesting that a frontal-striatal circuit is involved in rule-based category learning.

Human Category Learning

Much recent evidence suggests some dramatic differences in the way people learn perceptual categories, depending on exactly how the categories were constructed. Four different kinds of category-learning tasks are currently popular-rule-based tasks, information-integration tasks, prototype distortion tasks, and the weather prediction task. The cognitive, neuropsychological, and neuroimaging results obtained using these four tasks are qualitatively different. Success in rule-based (explicit reasoning) tasks depends on frontal-striatal circuits and requires working memory and executive attention. Success in information-integration tasks requires a form of procedural learning and is sensitive to the nature and timing of feedback. Prototype distortion tasks induce perceptual (visual cortical) learning. A variety of different strategies can lead to success in the weather prediction task. Collectively, results from these four tasks provide strong evidence that human category learning is mediated by multiple, qualitatively distinct systems.

Un modèle neurobiologique de la perception et de l'estimation du temps

Frontal-striatal circuits provide an important neurobiological substrate for timing and time perception as well as for working memory. In this review, we outline recent theoretical and empirical work to suggest that interval timing and working memory rely not only on the same anatomic structures, but also on the same neural representation of a specific stimulus. In the striatal beat-frequency model, cortical neurons fire in an oscillatory fashion to form representations of stimuli, and striatal medium spiny neurons detect those patterns of cortical firing that occur co-incident to important temporal events. Information about stimulus identity can be extracted from the specific cortical networks that are involved in the representation, and information about duration can be extracted from the relative phase of neural firing. The properties derived from these neurobiological models fit well with the psychophysics of timing and time perception as well as with information–processing models that emphasize the importance of temporal coding in a variety of working-memory phenomena.

Dysfunctional action monitoring hyperactivates frontal–striatal circuits in obsessive–compulsive disorder: an event-related fMRI study

Converging evidence suggests that hyperactivity in frontal-striatal circuits and in action-monitoring processes characterizes obsessive-compulsive disorder (OCD). It remains unclear, however, just how these abnormalities in brain function translate into the cognitive, affective, and behavioral manifestations of OCD. One possibility is that exaggerated or false error signals generated by the anterior cingulate (ACC) underlie compulsive behaviors by triggering the feeling that things are "not just right" even when no actual error has been made. Since recurrent compulsive behavior typically follows correct completion of a behavioral task (e.g., hand washing), ACC hyperactivity should be observed during correctly completed, high-conflict trials as well as during error trials. Frontal-striatal regions would also be expected to be activated during both trial types, as these regions are robustly associated with OCD across multiple neuroimaging paradigms. To test this hypothesis, 14 OCD patients and 14 matched controls completed a speeded reaction time task during functional magnetic resonance imaging (fMRI). Only correctly rejected, high-conflict trials produced excessive activation in both action monitoring (rostral and caudal ACC, LPFC) and frontal striatal regions (lateral orbitofrontal cortex (OFC), caudate, and thalamus) among OCD patients when compared to healthy controls. Portions of the posterior cingulate were also hyperactive among OCD patients. These results suggest that correctly rejected, high-conflict trials that require response inhibition may provide a better model than error trials of compulsive behaviors in OCD.

Selective cognitive deficits in obsessive‐compulsive disorder compared to panic disorder with agoraphobia

Visual-spatial and executive functions deficits have been reported in obsessive-compulsive disorder (OCD). We investigated their specificity comparing cognitive function in OCD, panic disorder with agoraphobia (PD/A) and controls by a comprehensive neuropsychological battery. Fifty-five subjects (25 OCD, 15 PD/A, 15 controls) without current depressive episode underwent structured clinical interview for DSM-IV, Yale-Brown Obsessive Compulsive Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale. Neuropsychological battery assessed: executive functions, visual discrimination, spatial memory and learning, verbal memory, general intellectual functioning. OCD showed controlled fluency, visual-spatial construction, learning and memory deficits; PD/A spatial learning impairment. OCD was discriminated from PD/A and controls by three tests scores, predicting group membership for 76.4% of the cases. Visual-constructive and controlled fluency deficits seem specific in OCD, while the spatial learning deficit, shared with PD patients, may not be disorder-specific, but anxiety-related. Results support the proposed ventral frontal-striatal circuit involvement in OCD.

The Neurobiology of Category Learning

Many recent studies have examined the neural basis of category learning. Behavioral neuroscience results suggest that both the prefrontal cortex and the basal ganglia play important category-learning roles; neurons that develop category-specific firing properties are found in both regions, and lesions to both areas cause category-learning deficits. Similar studies indicate that the inferotemporal cortex does not mediate the learning of new categories. The cognitive neuroscience literature on category learning appears contradictory until the results are partitioned according to the type of category-learning task that was used. Three major tasks can be identified: rule based, information-integration, and prototype-distortion. Recent results are consistent with the hypotheses that (a) learning in rule-based tasks requires working memory and executive attention and is mediated by frontal-striatal circuits, (b) learning in information-integration tasks requires procedural memory and is mediated primarily within the basal ganglia, and (c) learning in prototype-distortion tasks depends on multiple memory systems, including the perceptual representation system.

ERRATUM

The following is a correction for an error that occurred in the Journal of the International Neuropsychological Society, Vol. 9, No. 1. The Critical Review titled “Frontal-striatal Circuit Functions: Context, Sequence, and Consequence” by Jean A. Saint-Cyr had two lines of copy accidentally omitted at the bottom of the second column on page 103.

Frontal-striatal circuit functions: Context, sequence, and consequence

The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinson's disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms.

Frontal-Striatal Circuits in Cognitive Aging: Evidence for Caudate Involvement

Changes in cognition with aging have been claimed to be due in large part to a decline in frontal lobe function. However, at our present state of knowledge, the emphasis on the frontal lobes to the exclusion of the rest of the frontal-striatal circuits of which they are a part is unwarranted. To argue this point, I consider another anatomical candidate within these circuits, the caudate. Evidence is presented that the caudate decreases in size with age as much as the frontal lobes and that damage to either the frontal lobes or the caudate is accompanied by declines in inhibitory processes, executive control, and cognitive speed similar to those seen in normal aging. Separating the unique contributions of the frontal lobes and the caudate to these circuits is difficult but should be the focus of future studies of the biological basis of cognitive aging.