Dopaminergic signals in primary motor cortex

Brainstem monoamine areas such as the ventral tegmental area (VTA) send dopaminergic projections to the cerebral cortex that are widely distributed across different cortical regions. Whereas the projection to prefrontal areas (PFC) has been studied in detail, little is known about dopaminergic projections to primary motor cortex (M1). These projections have been anatomically characterized in rat and primate M1. Primates have even denser dopaminergic projections to M1 than rats. The physiological role, the effects of dopaminergic input on the activity of M1 circuits, and the behavioral function of this projection are unknown. This review explores the existing anatomical, electrophysiological and behavioral evidence on dopaminergic projections to M1 and speculates about its functional role. The projection may explain basic features of motor learning and memory phenomena. It is of clinical interest because of its potential for augmenting motor recovery after a brain lesion as well as for understanding the symptomatology of patients with Parkinson's disease. Therefore, targeted investigations are necessary.     

Impaired mesial frontal and putamen activation in Parkinson's disease: a positron emission tomography study.

Selection of movement in normal subjects has been shown to involve the premotor, supplementary motor, anterior cingulate, posterior parietal, and dorsolateral prefrontal areas. In Parkinson's disease (PD), the primary pathological change is degeneration of the nigrostriatal dopaminergic projections, and this is associated with difficulty in initiating actions. We wished to investigate the effect of the nigral abnormality in PD on cortical activation during movement. Using C15O2 and positron emission tomography (PET), we studied regional cerebral blood flow in 6 patients with PD and 6 control subjects while they performed motor tasks. Subjects were scanned while at rest, while repeatedly moving a joystick forward, and while freely choosing which of four possible directions to move the joystick. Significant increases in regional cerebral blood flow were determined with covariance analysis. In normal subjects, compared to the rest condition, the free-choice task activated the left primary sensorimotor cortex, left premotor cortex, left putamen, right dorsolateral prefrontal cortex and supplementary motor area, anterior cingulate area, and parietal association areas bilaterally. In the patients with PD, for the free-choice task, compared with the rest condition, there was significant activation in the left sensorimotor and premotor cortices but there was impaired activation of the contralateral putamen, the anterior cingulate, supplementary motor area, and dorsolateral prefrontal cortex. Impaired activation of the medial frontal areas may account for the difficulties PD patients have in initiating movements.     

Alterations of dopaminergic and noradrenergic innervations in motor cortex in Parkinson's disease.

The motor areas of the cerebral cortex contain dense dopaminergic and noradrenergic innervation in humans. We looked for changes of these innervations in cases with Parkinson's disease (PD). The density of fibers immunolabeled with tyrosine hydroxylase or dopamine-beta-hydroxylase was evaluated in the primary motor, premotor, and prefrontal cortical regions in 6 cases with PD and 7 control cases. Reductions of both noradrenergic and dopaminergic cortical innervations were observed, with similar magnitudes of reduction found in the motor and prefrontal regions of the cortex. Depletion of noradrenergic innervation was diffuse, involving all cortical laminae. Depletion of dopaminergic innervation was laminar specific, with the most significant reductions in layers I and II; reductions in layers V and VI were either less marked (prefrontal cortex) or not detectable (primary motor). The results suggest the existence of two separate mesocortical dopaminergic systems in humans, with the one distributing to upper cortical layers being preferentially involved in PD.     

Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease

OBJECTIVES: Cognitive impairment is a common feature in Parkinson's disease (PD) and is an important predictor of quality of life. Past studies showed that some aspects of cognition, such as working memory, can be enhanced following dopaminergic therapy and transcranial magnetic stimulation. The aim of our study was to investigate whether another form of noninvasive brain stimulation, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability, is associated with a change in a working memory task performance in PD patients. METHODS: We studied 18 patients (12 men and 6 women) with idiopathic PD. The patients performed a three-back working memory task during active anodal tDCS of the left dorsolateral prefrontal cortex (LDLPFC), anodal tDCS of the primary motor cortex (M1) or sham tDCS. In addition, patients underwent two different types of stimulation with different intensities: 1 and 2 mA. RESULTS: The results of this study show a significant improvement in working memory as indexed by task accuracy, after active anodal tDCS of the LDLPFC with 2 mA. The other conditions of stimulation: sham tDCS, anodal tDCS of LDLPFC with 1 mA or anodal tDCS of M1 did not result in a significant task performance change. CONCLUSION: tDCS may exert a beneficial effect on working memory in PD patients that depends on the intensity and site of stimulation. This effect might be explained by the local increase in the excitability of the dorsolateral prefrontal cortex.     

Cognitive slowing in Parkinson's disease resolves after practice

OBJECTIVE: To assess the effect of dopaminergic repletion on working memory in Parkinson's disease. METHODS: The role of dopaminergic state on working memory in patients with Parkinson's disease was determined using the Sternberg item recognition paradigm, a continuous performance task that dissociates the motor and cognitive components of response time. Ten patients with Parkinson's disease were tested in an "on" state (on dopaminergic drug treatment) and a practical "off" state in two sessions held one week apart in counterbalanced order; 10 controls matched for age and education were studied at the same time points. RESULTS: Patients with Parkinson's disease showed impaired working memory, independent of motor slowing. During session 1, the performance of the patients was worse than the controls, regardless of dopaminergic state. The patients showed a significant improvement in the cognitive component of task performance during the second session, such that they no longer differed from the controls. The performance of the control subjects remained stable over the two sessions. CONCLUSIONS: Working memory performance of patients with Parkinson's disease did not change in association with dopaminergic state; rather, the performance improved over time. The pattern of improvement over time suggests a delay in proceduralising the task, similar to the deficits shown by such patients in procedural learning of other tasks.     

Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression.

BACKGROUND: A large number of studies suggest the presence of deficits in dorsolateral prefrontal cortex function during performance of working memory tasks in individuals with schizophrenia. However, working memory deficits may also present in other psychiatric disorders, such as major depression. It is not clear whether people with major depression also demonstrate impaired prefrontal activation during performance of working memory tasks. METHODS: We used functional magnetic resonance imaging to assess the patterns of cortical activation associated with the performance of a 2-back version of the N-Back task (working memory) in 38 individuals with schizophrenia and 14 with major depression. RESULTS: We found significant group differences in the activation of dorsolateral prefrontal cortex associated with working memory performance. Consistent with prior research, participants with schizophrenia failed to show activation of right dorsolateral prefrontal cortex in response to working memory tasks demands, whereas those with major depression showed clear activation of right and left dorsolateral prefrontal cortex as well as bilateral activation of inferior and superior frontal cortex. CONCLUSIONS: During performance of working memory tasks, deficits in prefrontal activation, including dorsolateral regions, are more severe in participants with schizophrenia (most of whom were recently released outpatients) than in unmedicated outpatients with acute nonpsychotic major depression.     

Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder

OBJECTIVE: Previous research has demonstrated that during task conditions requiring an increase in inhibitory function or working memory, children and adults with attention-deficit/hyperactivity disorder (ADHD) exhibit greater and more varied prefrontal cortical (PFC) activation compared to age-matched control participants. This pattern may reflect cortical inefficiency. We examined this hypothesis using a working memory task in a group of adolescent girls with and without ADHD. METHOD: Functional magnetic resonance imaging was used to investigate blood oxygenated level-dependent signal during a working memory task for 10 adolescents from each group, ages 11 to 17 years. We analyzed brain-behavior relationships with anatomically defined regions of interest in the PFC and primary motor cortex. RESULTS: The relationship between brain activity in the dorsolateral PFC and ventrolateral PFC and memory retrieval speed differed by group membership, whereby comparison girls had a more efficient brain-behavior relationship than girls with ADHD. There were no such group differences in brain-behavior relationships for primary motor cortex. CONCLUSIONS: These findings lend support to the idea that cognitive and behavioral deficits experienced by children and adolescents with ADHD may in part be related to relatively low efficiency of PFC function.     

Dopaminergic modulation of cognitive interference after pharmacological washout in Parkinson's disease

The dopaminergic modulation of prefrontal function in Parkinson's disease (PD) has been consistently demonstrated. There is evidence that the effects of pharmacological manipulations on cognitive performances are described by an "Inverted-U" shaped curve. Neuroimaging studies performed before and after an overnight withdrawal from therapy showed significant differences between drug states, but did not control for the relative impact of the long duration response to levodopa. Here we evaluate the brain response after a complete pharmacological washout by correlating dopaminergic-related changes of this response to changes in performance during cognitive interference. Twelve idiopathic PD patients were studied with functional MRI while performing a modified version of the Stroop task. Patients were scanned twice: (1) following a prolonged washout procedure ("OFF" state) and (2) 90-120 min after the administration of levodopa ("ON" state). Task-related changes of PD patients were compared to those of matched healthy controls. Healthy controls displayed prefrontal and parietal responses that were positively correlated with task accuracy. In the "OFF" state, PD patients showed significant responses in anterior cingulate and pre-supplementary motor area, which are hypothesized to operate at a higher level of basal dopaminergic modulation. Levodopa administration attenuated such responses and enhanced the response of prefrontal cortex (PFC), which was correlated with improved accuracy. Results demonstrate that the behavioral effects of pharmacological manipulations of the dopamine system are highly dependent on the baseline status of PFC. When a true hypodopaminergic state is induced in PD patients, cognitive interference might significantly benefit from the administration of levodopa via an enhanced PFC response.     

Functional mapping of dopaminergic transmission]

Patients with Parkinson's disease (PD) are impaired when performing cognitive tasks such as mental operations and working memory paradigms, which engage frontal lobe regions. These impairments may reflect degeneration of either nigrostriatal or mesocortical dopaminergic projections. D2 receptor antagonist 11C-raclopride (RAC) with positron emission tomography (PET) now provides an in vivo approach for investigating dopaminergic transmission by monitoring changes in synaptic dopamine levels during task performance, Our RAC PET study suggests that the capacity to release dopamine during a working memory task is impaired in the striatum but relatively preserved in the medial prefrontal cortex in patients with PD. This pattern of dopamine release is in accordance with our previous H2(15)O PET findings showing hypoactivity of the striatum during a mental operation task in PD. These PET findings support a view that degeneration of nigrostriatal dopaminergic projection causing disruption of the cortico-basal ganglia circuit contributes to the cognitive impairments observed in PD. The findings also implicates that mesocortical dopaminergic function may be preserved in PD. Since excessive stimulation of dopamine receptors in the frontal cortex can rather deteriorate its function, the benefit in the striatum and the risk in the frontal cortex should be properly evaluated for dopamine replacement therapy.     

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts

Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinson's disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement-related activation of frontal cortical areas in 4 PD patients using H2 15O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F-dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinson's Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F-dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD.     

Organization of working memory within the human prefrontal cortex: a PET study of self-ordered object working memory

The prefrontal cortex plays a critical role in working memory, the active maintenance of information for brief periods of time for guiding future motor and cognitive processes. Two competing models have emerged to account for the growing human and non-human primate literature examining the functional neuroanatomy of working memory. One theory holds that the lateral frontal cortex plays a domain-specific role in working memory with the dorsolateral and ventrolateral cortical regions supporting working memory for spatial and non-spatial material, respectively. Alternatively, the lateral frontal cortex may play a process-specific role with the more dorsal regions becoming recruited whenever active manipulation or monitoring of information in working memory becomes necessary. Many working memory tasks do not allow for direct tests of these competing models. The present study used a novel self-ordered working memory task and positron emission tomography to identify whether dorsal or ventral lateral cortical areas are recruited during a working memory task that required extensive monitoring of non-spatial information held within working memory. We observed increased blood flow in the right dorsolateral, but not ventrolateral, prefrontal cortex. Increases in blood flow in the dorsolateral region correlated strongly with task performance. Thus, the results support the process-specific hypothesis.     

Neocortical system abnormalities in autism: an fMRI study of spatial working memory

OBJECTIVE: To test the hypothesis that deficits in spatial working memory in autism are due to abnormalities in prefrontal circuitry. METHODS: Functional MRI (fMRI) at 3 T was performed in 11 rigorously diagnosed non-mentally retarded autistic and six healthy volunteers while they performed an oculomotor spatial working memory task and a visually guided saccade task. RESULTS: Autistic subjects demonstrated significantly less task-related activation in dorsolateral prefrontal cortex (Brodmann area [BA] 9/46) and posterior cingulate cortex (BA 23) in comparison with healthy subjects during a spatial working memory task. In contrast, activation of autistic individuals was not reduced in other regions comprising the neural circuitry for spatial working memory including the cortical eye fields, anterior cingulate cortex, insula, basal ganglia, thalamus, and lateral cerebellum. Autistic subjects also did not demonstrate reduced activation in any brain regions while performing visually guided saccades. CONCLUSION: Impairments in executive cognitive processes in autism may be subserved by abnormalities in neocortical circuitry as evidenced by decreased activation in prefrontal and posterior cingulate circuitry during a spatial working memory task.     

A large-scale neurocomputational model of task-oriented behavior selection and working memory in prefrontal cortex

The prefrontal cortex (PFC) is crucially involved in the executive component of working memory, representation of task state, and behavior selection. This article presents a large-scale computational model of the PFC and associated brain regions designed to investigate the mechanisms by which working memory and task state interact to select adaptive behaviors from a behavioral repertoire. The model consists of multiple brain regions containing neuronal populations with realistic physiological and anatomical properties, including extrastriate visual cortical regions, the inferotemporal cortex, the PFC, the striatum, and midbrain dopamine (DA) neurons. The onset of a delayed match-to-sample or delayed nonmatch-to-sample task triggers tonic DA release in the PFC causing a switch into a persistent, stimulus-insensitive dynamic state that promotes the maintenance of stimulus representations within prefrontal networks. Other modeled prefrontal and striatal units select cognitive acceptance or rejection behaviors according to which task is active and whether prefrontal working memory representations match the current stimulus. Working memory task performance and memory fields of prefrontal delay units are degraded by extreme elevation or depletion of tonic DA levels. Analyses of cellular and synaptic activity suggest that hyponormal DA levels result in increased prefrontal activation, whereas hypernormal DA levels lead to decreased activation. Our simulation results suggest a range of predictions for behavioral, single-cell, and neuroimaging response data under the proposed task set and under manipulations of DA concentration.     

Functional magnetic resonance imaging studies of eye movements in first episode schizophrenia: smooth pursuit, visually guided saccades and the oculomotor delayed response task

Schizophrenia patients show eye movement abnormalities that suggest dysfunction in neocortical control of the oculomotor system. Fifteen never-medicated, first episode schizophrenia patients and 24 matched healthy individuals performed eye movement tasks during functional magnetic resonance imaging studies. For both visually guided saccade and smooth pursuit paradigms, schizophrenia patients demonstrated reduced activation in sensorimotor areas supporting eye movement control, including the frontal eye fields, supplementary eye fields, and parietal and cingulate cortex. The same findings were observed for an oculomotor delayed response paradigm used to assess spatial working memory, during which schizophrenia patients also had reduced activity in dorsolateral prefrontal cortex. In contrast, only minimal group differences in activation were found during a manual motor task. These results suggest a system-level dysfunction of cortical sensorimotor regions supporting oculomotor function, as well as in areas of dorsolateral prefrontal cortex that support spatial working memory. These findings indicate that a generalized rather than localized pattern of neocortical dysfunction is present early in the course of schizophrenia and is related to deficits in the sensorimotor and cognitive control of eye movement activity.     

Maturation of brain function associated with response inhibition

OBJECTIVE: To investigate the developmental trajectory of response inhibition and, more specifically, whether there is a dissociation of function in the prefrontal cortex over the course of development of executive function and associated response inhibition abilities. METHOD: Nineteen typically developing subjects, ranging in age from 8 to 20, performed a Go/NoGo task while behavioral and functional magnetic resonance imaging (fMRI) data were collected. RESULTS: All subjects performed the task with few errors of omission and commission. No relationship between accuracy and age emerged, but the ability to inhibit responses significantly improved with age. Analyses of fMRI data revealed a positive correlation between activation and age in the left inferior frontal gyrus/insula/orbitofrontal gyrus, and a negative correlation between activation and age in the left middle/superior frontal gyri. CONCLUSION: These data provide the first evidence of dissociable processes occurring in the prefrontal cortex during development of executive functions associated with response inhibition: (1) Younger subjects activate more extensively than older subjects in discrete regions of the prefrontal cortex, presumably due to increased demands and inefficient recruitment of brain regions subserving executive functions including working memory. (2) Older subjects show increasingly focal activation in specific regions thought to play a more critical role in response inhibition.     

Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: an fMRI study

Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits. Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing. Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included. Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto-parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus. The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding.     

Cortical dysfunction in patients with Huntington's disease during working memory performance

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy-related activation confounds. Voxel-based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso- and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM-related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy.     

Chemistry of the mind: neurochemical modulation of prefrontal cortical function

The neurochemical modulation of prefrontal cortical function is reviewed with special reference to the ascending dopaminergic and serotoninergic projections. Evidence is surveyed from studies of rats, nonhuman primates, and humans to suggest that prefrontal dopamine has specific functions in attentional control and working memory, mediated mainly through the D1 receptor, whereas manipulations of serotonin are shown by contrast to affect reversal learning in monkeys and human volunteers and measures of impulsivity in rats. These findings are discussed in the context of these as well as other neurotransmitter systems (including noradrenaline and acetylcholine) having distinct roles in the neuromodulation of prefrontal cortical function. The capacity of the prefrontal cortex itself to exert top-down regulation of these ascending neurochemical systems is also discussed.     

Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia

CONTEXT: It remains unclear whether altered regional brain physiological activity in patients with schizophrenia during working memory tasks relates to maintenance-related processes, manipulation-related (ie, executive) processes, or both. OBJECTIVE: To examine regional functional activations of the brain during maintenance- and manipulation-related working memory processing in patients with schizophrenia and in healthy comparison subjects. DESIGN: Functional images of the brain were acquired in 11 schizophrenic patients and 12 healthy control subjects (matched for age, sex, handedness, and parental education) during 2 spatial working memory paradigms, one contrasting maintenance-only processing with maintenance and manipulation processing and the other contrasting parametrically varying maintenance demands. RESULTS: Patients and controls showed activation of a large, spatially distributed network of cortical and subcortical regions during spatial working memory processing. When task demands required explicit manipulation of information held in memory, controls recruited right dorsolateral prefrontal cortex (Brodmann areas 45 and 46) to a significantly greater extent than patients. A similar effect was observed for the larger memory set sizes of the memory set size task. No other brain regions showed activation differences between groups for either task. These differences persisted when comparing activation maps for memory set sizes in which the 2 groups were equivalent in behavioral accuracy and when comparing subgroups of patients and controls matched for behavioral accuracy on either task. CONCLUSIONS: Physiological disturbances in the dorsolateral prefrontal cortex contribute differentially to patients' difficulties with maintaining spatial information across a brief delay, as well as with manipulating the maintained representation. These differences persisted when comparing conditions in which the 2 groups were equivalent in behavioral accuracy.     

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

OBJECTIVE: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. METHOD: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic ((1)H-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [(15)O]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with (1)H-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). RESULTS: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships. CONCLUSIONS: These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder.