Methylphenidate reduces spatial attentional bias by modulating fronto-striatal connectivity.

Spatial attention bias reflects tendency to direct attention to specific side in space. This bias reflects asymmetric dopamine (DA) signaling in the striatum. Administration of DA agonists reduces spatial bias, yet the underlying mechanism is not yet clear. To address this, the current study tested whether methylphenidate (MPH; an indirect DA agonist) reduces orienting bias by modulating fronto-striatal connectivity. 54 adults with consistent bias completed the greyscales task which detects subtle biases during fMRI scanning under MPH (20 mg) or placebo, in a double-blind design. As hypothesized, MPH reduced bias by increasing orienting towards non-preferred hemispace, regardless of whether the initial bias was left or right. MPH-induced increases were found in activation of the medial superior frontal gyrus (mSFG: F[1;53] = 4.632, cluster-defining threshold of P < 0.05, minimal cluster size = 0, p_FWE = 0.036, η2 = 0.08) and its functional connectivity with the caudate (left caudate: F[1;53] = 12.664, p_FWE = 0.001, η2 = 0.192; right caudate: F[1;53] = 11.069, p_FWE = 0.002, η2 = 0.172), when orienting towards the non-preferred hemispace. MPH also reduced mSFG activation and fronto-striatal connectivity for the preferred hemispace. Results suggest modulation of frontal excitability due to increased caudate-mSFG functional connectivity. This mechanism may underlie the positive effect of dopaminergic agonists on abnormal patterns of directing attention in space.

Graph analysis uncovers an opposing impact of methylphenidate on connectivity patterns within default mode network sub-divisions.

BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.

Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment.

Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3-14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition.

Dopamine asymmetries predict orienting bias in healthy individuals.

Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, resulting in orienting toward the contralateral, left, hemispace. Recent evidence suggests that healthy individuals differ from each other in both direction and magnitude of orienting bias, and moreover, the bias displayed by a person is consistent across time, suggesting that it may represent a trait of the individual. Animal studies reveal consistent orienting bias within an individual, which reflects asymmetry in dopaminergic brain systems. We measured basal D2-like receptor binding using positron emission tomography and the high-affinity ligand [F-18]fallypride, to test the hypothesis that asymmetry in dopaminergic neurotransmission in healthy humans modulates the orienting bias in humans. As predicted, we found that individual differences in the direction and magnitude of the orienting bias were strongly associated with the pattern of asymmetric binding of dopamine (DA) D2 receptors in the striatum, as well as clusters in the frontal and temporal cortex. These findings show for the first time that orienting bias reflects individual differences in the lateralization of DA systems in the healthy human brain.

PET evidence for a role for striatal dopamine in the attentional blink: functional implications.

Our outside world changes continuously, for example, when driving through traffic. An important question is how our brain deals with this constant barrage of rapidly changing sensory input and flexibly selects only newly goal-relevant information for further capacity-limited processing in working memory. The challenge our brain faces is experimentally captured by the attentional blink (AB): an impairment in detecting the second of two target stimuli presented in close temporal proximity among distracters. Many theories have been proposed to explain this deficit in processing goal-relevant information, with some attributing the AB to capacity limitations related to encoding of the first target and others assigning a critical role to on-line selection mechanisms that control access to working memory. The current study examined the role of striatal dopamine in the AB, given its known role in regulating the contents of working memory. Specifically, participants performed an AB task and their basal level of dopamine D2-like receptor binding was measured using PET and [F-18]fallypride. As predicted, individual differences analyses showed that greater D2-like receptor binding in the striatum was associated with a larger AB, implicating striatal dopamine and mechanisms that control access to working memory in the AB. Specifically, we propose that striatal dopamine may determine the AB by regulating the threshold for working memory updating, providing a testable physiological basis for this deficit in gating rapidly changing visual information. A challenge for current models of the AB lies in connecting more directly to these neurobiological data.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.

Methylphenidate reduces orienting bias in healthy individuals.

BACKGROUND: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. AIM: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. METHODS: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. RESULTS/OUTCOMES: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. CONCLUSIONS/INTERPRETATIONS: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

Individual sensitivity to pain expectancy is related to differential activation of the hippocampus and amygdala.

Anxiety arising during pain expectancy can modulate the subjective experience of pain. However, individuals differ in their sensitivity to pain expectancy. The amygdale and hippocampus were proposed to mediate the behavioral response to aversive stimuli. However, their differential role in mediating anxiety-related individual differences is not clear. Using fMRI, we investigated brain activity during expectancy to cued or uncued thermal pain applied to the wrist. Following each stimulation participants rated the intensity of the painful experience. Activations in the amygdala and hippocampus were examined with respect to individual differences in harm avoidance (HA) personality trait, and individual sensitivity to expectancy, (i.e. response to cued vs. uncued painful stimuli). Only half of the subjects reported on cued pain as being more painful than uncued pain. In addition, we found a different activation profile for the amygdala and hippocampus during pain expectancy and experience. The amygdala was more active during expectancy and this activity was correlated with HA scores. The hippocampal activity was equally increased during both pain expectancy and experience, and correlated with the individual's sensitivity to expectancy. Our findings suggest that the amygdala supports an innate tendency to approach or avoid pain as reflected in HA trait, whereas the hippocampus mediates the effect of context possibly via appraisal of the stimulus value.

Attentional bias as trait: correlations with novelty seeking.

Pseudoneglect is traditionally viewed as reflecting right hemisphere specialization for processing spatial information, which brings about relatively greater activation of the right hemisphere and orienting towards the contralateral space. Such interpretation implies that the leftward attentional bias is a population trait. Animal studies, however, suggest that orienting bias is a trait of the individual and individual differences in the direction and magnitude of this orienting bias reflect individual differences in asymmetry in dopaminergic brain systems, which are also reflected in other behavioral differences. The present study was designed to test the hypothesis that healthy individuals show consistent attentional bias, the direction and magnitude of which varies among individuals and is associated with the degree of novelty seeking, a temperament trait associated with dopamine asymmetry. Forty-nine right-handed participants performed the greyscales task on two separate occasions and completed the Tridimensional Personality Questionnaire. Although on average some degree of leftward attentional bias was observed on both occasions, both the direction and the magnitude of the bias differed greatly, with some individuals showing a strong leftward bias whereas others showed a strong rightward bias. A highly significant correlation was found between degree and magnitude of this bias on the two testing sessions, supporting the hypothesis that it may reflect an individual trait. As predicted, higher scores on novelty seeking were associated with rightward attentional bias, suggesting that this bias may reflect asymmetries in dopaminergic circuits in healthy individuals.

Incentive motivation is associated with striatal dopamine asymmetry.

Dopamine plays an important role in modulating incentive motivation, expressed behaviorally as approach behavior. EEG studies report association between approach behavior and asymmetric pattern of activation in anterior cortical regions (as measured by the inverse of EEG alpha power). Therefore, individual differences in incentive motivation may reflect asymmetries in dopaminergic systems. We examined this hypothesis by studying the relationship between self-reported degree of incentive motivation, and asymmetry of D2 receptor availability in healthy volunteers. Nineteen healthy participants were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors in left and right striatum. Incentive motivation was assessed by the Achievement scale of the Multidimensional Personality Questionnaire. The Achievement score was negatively correlated with the Asymmetry Index ([R-L]/[R+L]) of D2 receptor availability (r=-.721, p=.001), suggesting that greater positive incentive motivation is associated with higher receptor availability in the left relative to the right hemisphere.

Dopamine asymmetry interacts with medication to affect cognition in Parkinson's disease.

Contradictory evidence exists regarding the nature and degree of impaired cognitive flexibility in PD. Dopaminergic medication may be expected to ameliorate such cognitive deficits, yet both medicated and unmedicated patients have been reported to perform more poorly than control subjects on tasks of cognitive flexibility, suggesting that such deficits may also be affected by other disease-related variables. The present study examined whether asymmetric dopamine deficiency (revealed by unilateral symptom onset) is related to the performance of spontaneous and reactive flexibility in PD, and the possible interaction of dopaminergic medication with such asymmetry. Thirty-five PD patients with mild motor symptoms and unilateral onset of PD (left-onset=14; right-onset=21) performed the Alternate Uses (AU) and intradimensional/extradimensional shift (IED) tasks. Interaction between side of onset and medication was observed for the number of errors in the AU task and number of reversal errors in the IED task. Significantly more AU errors were made by medicated patients with left-onset, as compared to all other participants. Conversely, medicated patients with right-onset made the most reversal errors. These results suggest that relatively early in the disease process when dopamine deficit in the less-affected hemisphere is mild, optimal dopaminergic medication (with respect to motor function) may involve over-medication of the less-affected hemisphere. Thus, AU errors may be the consequence of hyperdopaminergic state leading to impaired functioning of the left hemisphere, whereas increased reversal errors in right-onset PD patients receiving dopaminergic medication is related to impaired dopamine function in the right hemisphere.

Spatial attention and neural asymmetry in obsessive-compulsive disorder.

Patterns of lateralized dysfunction in obsessive-compulsive disorder (OCD) were examined using the Posner spatial attention paradigm. While controls responded faster to left visual field targets than to right, patients lacked this asymmetry. The difference in asymmetry patterns was significant for the invalid cue condition, but not for the valid cue condition. Reversal of normal asymmetry was correlated with obsession severity. Findings support aberrant hemispheric balance in OCD.

Natural history of dementia associated with lacunar infarctions.

BACKGROUND: Lacunar stroke (VaD-L) is the most common stroke subtype associated with vascular dementia (VaD). OBJECTIVE: To evaluate the rate of cognitive and behavioral changes in patients with probable VaD-L. METHODS: We measured rates of change on the Mini-Mental State Examination (MMSE), Digit Span, Logical Memory, Controlled Oral Word Association Test, CERAD battery and the Neuropsychiatric Inventory (NPI) of 77 [age at entry 65.9+/-8.1 (mean+/-standard deviation) years] patients with probable VaD, periventricular white matter and basal ganglia lacunae, longitudinally studied for 25.7+/-11 months. RESULTS: Mean number of follow-up visits was 2.6. Overall annual vascular event rate was 0.25. VaD-L in mildly and moderately impaired patients is characterized by progressive cognitive and behavioral decline. The rate of cognitive and behavioral progression depends on the occurrence of vascular episodes (VE) during the course of the illness [(-1.1) MMSE and (+4.0) NPI points annually without VE vs. (-2.0) and (+10.3) points following VE]. The rates of progression are a function of the severity of the cognitive and behavioral impairment. Impaired cognition is associated with impaired behavior. A subgroup of VaD-L patients runs a progressively deteriorating course despite the absence of clinically apparent new vascular episodes. CONCLUSION: VaD-L is characterized by cognitive and behavioral decline in 83% of the patients. The rate of decline is determined mainly by the severity of the cognitive and behavioral impairment at baseline and by the occurrence of new vascular episodes.

Asymmetric dopamine loss differentially affects effort to maximize gain or minimize loss.

BACKGROUND: Dopamine (DA) plays an important role in regulating effort expenditure for reward, but whether it is also involved in modulating effort to avoid punishment is not clear. Preference for approach towards rewarding stimuli or away from aversive stimuli is associated with asymmetric activation in anterior brain regions. Asymmetric DA signaling in subcortical-frontal circuits may therefore contribute to differentially energizing behavior towards approach or avoidance behavior. We tested this hypothesis in patients with Parkinson's disease (PD), characterized by asymmetric DA loss. METHODS: Patients with greater DA deficit in the left (n = 20) or right (n = 19) hemisphere, performed a task that measures separately effort to approach (maximize gains) versus effort to avoid (minimize loss), on and off DA replacement therapy. RESULTS: When tested off medication, patients with relatively greater DA deficit in the left hemisphere showed greater approach deficit (less effort to increase gain than to avoid loss) whereas the opposite pattern of effort expenditure was demonstrated by patients with greater DA deficit in the right hemisphere. Performing the same task when medicated revealed increased willingness to expend effort, such that increased effort to maximize gain was associated left hemisphere improved DA function (reflected by reduced symptoms), while increased effort to avoid loss was related to right hemisphere improvement. CONCLUSIONS: These results suggest that asymmetry of DA levels modulates the differential exertion of effort toward attaining rewards versus avoiding aversive consequences, providing new insights into understanding the underlying pathophysiology of behavioral syndromes such as apathy and impulsive-compulsive disorders.

Dopamine system genes are associated with orienting bias among healthy individuals.

Healthy individuals display subtle orienting bias, manifested as a tendency to direct greater attention toward one hemispace, and evidence suggests that this bias reflects an individual trait, which may be modulated by asymmetric dopamine signaling in striatal and frontal regions. The current study examined the hypothesis that functional genetic variants within dopaminergic genes (DAT1 3' VNTR, dopamine D2 receptor Taq1A (rs1800497) and COMT Val158Met (rs4680)) contribute to individual differences in orienting bias, as measured by the greyscales paradigm, in a sample of 197 young healthy Israeli Jewish participants. For the Taq1A variant, homozygous carriers of the A2 allele displayed significantly increased leftward orienting bias compared to the carriers of the A1 allele. Additionally, and as previously reported by others, we found that bias towards leftward orienting of attention was significantly greater among carriers of the 9-repeat allele of the DAT1 3' VNTR as compared to the individuals who were homozygous for the 10-repeat allele. No significant effect of the COMT Val158Met on orienting bias was found. Taken together, our findings support the potential influence of genetic variants on inter-individual differences in orienting bias, a phenotype relevant to both normal and impaired cognitive processes.

Effects of asymmetric dopamine depletion on sensitivity to rewarding and aversive stimuli in Parkinson's disease.

The onset and progression of Parkinson's disease (PD) motor symptoms is generally asymmetric, reflecting differential extent of nigral pathology and resulting dopamine depletion in each of the hemispheres. Given the role of dopamine in processing rewarding and aversive events, and considering findings associating asymmetric neural activity with differential sensitivity to positive and negative stimuli, the current study examined the possibility that dopamine asymmetry in PD is related to differential approach and avoidance tendencies. An original task assessing and comparing sensitivity to positive and negative probabilistic feedback was administered to 29 right-handed participants with idiopathic PD, 16 with predominant right-side and 13 with predominant left-side motor symptoms, to compare the two groups. As dopamine replacement therapy (DRT) has shown different effects on reward and punishment processing, all participants were assessed in both off- and on-medication states. As predicted, when off medication, participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while those with a greater right hemisphere deficit showed a trend toward the opposite pattern. Medication reversed the relationship between gain and loss sensitivity in the left-hemisphere PD group, but not in the right-hemisphere group. Particularly in the left-hemisphere PD group, findings support the possibility that subcortical dopaminergic asymmetry is reflected in behaviorally-expressed approach and avoidance tendencies. Furthermore, the effects of DRT on approach and avoidance appear to interact with asymmetry, shedding light on previous conclusions regarding the role of dopamine in reinforcement processing.

Eye-blink rate predicts individual differences in pseudoneglect.

Most healthy individuals display a subtle spatial attentional bias, exhibiting relative inattention for stimuli on one side of the visual field, a phenomenon known as pseudoneglect. Prior work in animals and patients has implicated dopamine in spatial attention asymmetries. The current study therefore examined - in healthy individuals - the relationship between the attentional bias and spontaneous eye-blink rate (EBR), a putative measure of central dopaminergic function. We found that those individuals, who blinked more often under resting conditions, displayed greater preference for the right side of the visual display in a subsequent attention task. This finding may support the idea that the observed attentional bias in healthy individuals reflects asymmetries in dopaminergic circuits, and corroborates previous findings implicating dopamine in spatial attention.

Dissociation between spontaneous and reactive flexibility in early Parkinson's disease.

OBJECTIVE: This study was designed to examine the relations between the severity of motor symptoms and impaired cognitive flexibility in Parkinson's disease. BACKGROUND: Studies that examine cognitive flexibility in Parkinson's disease report conflicting results. We hypothesized that such inconsistency may reflect a differential pattern of impairment on tasks that measure spontaneous versus reactive flexibility. METHODS: The performance of tasks requiring either spontaneous (Alternate Uses) or reactive (Wisconsin Card Sorting Test) cognitive flexibility was examined in newly diagnosed unmedicated patients with idiopathic Parkinson's disease, as compared with age- and education-matched controls. The correlation between the degree of deficit and severity of motor symptoms was also examined. RESULTS: Patients were significantly worse than controls in performing both types of tasks. The patients' performance on tasks of spontaneous reactivity was not correlated with the presence or severity of the motor signs and symptoms. However, only patients showing signs of bradykinesia were impaired on a measure of reactive cognitive flexibility and the degree of impairment was significantly correlated with the severity of bradykinesia. CONCLUSIONS: These findings suggest that the dissociation between the two types of cognitive flexibility may reflect the differential involvement of the mesocortical and striatonigral dopaminergic circuits in the mediation of these tasks.

Progression of dementia associated with lacunar infarctions.

BACKGROUND: Lacunar stroke (L) is the most common stroke subtype associated with vascular dementia (VaD-L). OBJECTIVE: To evaluate the cognitive and behavioral course in patients with probable VaD-L. METHODS: We longitudinally measured rates of change on MMSE, digit span, logical memory, Controlled Oral Word Association, CERAD battery and neuropsychiatric inventory (NPI) in 77 patients (age at entry 69 +/- 8.1 years) with probable VaD-L for 25.75 +/- 11 months. RESULTS: The mean number of follow-up visits was 2.6 +/- 0.67 (range 2-4). Time interval between any two consecutive visits was at least 5 months (range 5-41). MMSE deteriorated by 1.44+/- 1.8 points annually and NPI increased by 6.01 +/- 13.7 points annually (p < 0.0001). The rates of cognitive and behavioral decline were predominantly influenced by the cognitive state at entry into the study and the occurrence of new vascular episodes during follow-up [(-0.95 +/- 1.7) MMSE and (+2.02 +/- 14.1) NPI points annually without vascular episodes vs. (-2.09 +/- 1.6) and (+11.3 +/- 11.4) points following vascular episodes (p < 0.0001)]. Impaired cognition was associated with impaired behavior (p < 0.001). VaD-L patients without additional vascular episodes at follow-up have a progressively deteriorating course as well (p < 0.0001). CONCLUSION: VaD-L is characterized by cognitive and behavioral decline. The rate of decline is determined mainly by the severity of the cognitive and behavioral impairment at baseline and by the occurrence of new vascular episodes.