Youngbin Kwak

Altered Resting State Cortico-Striatal Connectivity in Mild to Moderate Stage Parkinson's Disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinsons patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence.

Dopamine overdose hypothesis: Evidence and clinical implications

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinsons disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review, we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted‐U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor, as supported by multimodal neuroimaging studies. A patients individual genotype will determine the relative baseline position on this inverted‐U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable, inverted‐U dose‐response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities.

Effect of Dopaminergic Medications on the Time Course of Explicit Motor Sequence Learning in Parkinson's Disease

The capacity to learn new motor sequences is fundamental to adaptive motor behavior. The early phase of motor sequence learning relies on the ventral and anterior striatal circuitry, whereas the late phase relies on the dorsal and posterior striatal circuitry. Early Parkinsons disease (PD) is mainly characterized by dopaminergic denervation of the dorsal and posterior striatum while sparing anterior and ventral regions. Dopaminergic medication improves dorsal and posterior striatum function by compensating for the loss of dopamine. However, previous work has shown that dopaminergic medication interferes with the ventral and anterior striatum function by overdosing this relatively intact structure in early-state PD. Here we test whether these effects are also observed over the time course of motor sequence learning. Fourteen PD patients ON and OFF dopaminergic medications and 11 healthy age-matched control participants performed an explicit motor sequence learning task. When sequence learning was compared across different learning phases in patients ON and OFF medication, a significant impairment associated with medication was observed in the early relative to later phases of learning. The rate of learning in the early phase measured trial by trial in patients ON medication was significantly slower than that in controls and when patients were OFF medication. No significant impairment was found in the later learning phases. These results demonstrate that dopaminergic medications may selectively impair early-phase motor sequence learning. These results extend and generalize the dopamine overdose effects previously reported for (antero)ventral striatum-mediated cognitive tasks to motor sequence learning.

Disrupted cortico-cerebellar connectivity in older adults

Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age-related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performances indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior.

Differential relationships between transcallosal structural and functional connectivity in young and older adults

Numerous studies have identified age differences in brain structure and function that correlate with declines in motor performance. While these investigations have typically focused on activity in isolated regions of the brain, resting state functional connectivity magnetic resonance imaging (MRI) and diffusion tensor imaging allow for more integrative assessments of spatially disparate neural networks. The novel contribution of the current study is to combine both resting state functional connectivity and diffusion tensor imaging to examine motor corticocortical circuits in young and older adults. We find that relatively greater functional connectivity between the primary motor cortices was strongly associated with decreased structural connectivity and poorer motor performance solely in older adults. We suggest that greater functional connectivity in older adults may be reflective of a release from the normally predominantly inhibitory interhemispheric communication associated with the primary motor cortices.

l-DOPA changes ventral striatum recruitment during motor sequence learning in Parkinson's disease

We previously reported a differential effect of dopaminergic medication across the time course of motor sequence learning in early stage Parkinsons (PD) patients [1]. There was a medication-associated impairment specific to the early phase of learning. In the current study, we investigated the BOLD responses associated with this deleterious medication effect on motor sequence learning. We hypothesized that levodopa (l-DOPA) would negatively affect the recruitment of the ventral striatal circuitry during the early phase of learning. Seventeen early stage PD patients ON and OFF l-DOPA and 21 healthy control participants performed an explicit motor sequence learning task inside the MRI scanner. We observed sequence learning-specific activation during the early phase in the ventral putamen for controls and PD OFF but not for PD ON l-DOPA. A comparison of activation between PD OFF and PD ON showed that activation within the ventral putamen was decreased in PD ON compared to PD OFF. The extent of the l-DOPA associated activation decrease in the ventral putamen showed a small, positive correlation with the degree of sequence learning performance decrease in the early phase of learning (r=0.45-0.54 across measures, p<0.05, one-tailed). These findings provide evidence for the negative effects of l-DOPA in PD patients on the ventral putamen circuitry involved in early motor sequence learning, and provide support for a role of this structure in the sequence learning process.

Neurocognitive Mechanisms of Error-Based Motor Learning

One mechanism for acquiring new motor skills is minimization of errors from one practice trial to the next. A substantial body of literature supports a role for cerebellar pathways in such adaptive motor error minimization processes. A region in the medial prefrontal cortex, including the anterior cingulate cortex, has been linked to performance monitoring and error detection processes for cognitive tasks. Recent findings support the notion that this region is also sensitive to the commission of motor errors. Furthermore, the basal ganglia nuclei also exhibit neural activity which varies with both errors and rewards. Here, we review the literature supporting a potential role for each of these networks in error-based motor learning, focusing on both feedback and feedforward control processes. We also speculate about the relative independence versus interactivity of their respective functions.

Altered cerebellar connectivity in Parkinson's patients ON and OFF L-DOPA medication.

Although nigrostriatal changes are most commonly affiliated with Parkinsons disease, the role of the cerebellum in Parkinsons has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinsons patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinsons patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinsons patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinsons patients, further demonstrating cerebellar changes associated with Parkinsons disease and the moderating effects of medication.

Association of COMT val158met and DRD2 G>T genetic polymorphisms with individual differences in motor learning and performance in female young adults

Individuals learn new skills at different rates. Given the involvement of corticostriatal pathways in some types of learning, variations in dopaminergic transmission may contribute to these individual differences. Genetic polymorphisms of the catechol-O-methyltransferase (COMT) enzyme and dopamine receptor D2 (DRD2) genes partially determine cortical and striatal dopamine availability, respectively. Individuals who are homozygous for the COMT methionine (met) allele show reduced cortical COMT enzymatic activity, resulting in increased dopamine levels in the prefrontal cortex as opposed to individuals who are carriers of the valine (val) allele. DRD2 G-allele homozygotes benefit from a higher striatal dopamine level compared with T-allele carriers. We hypothesized that individuals who are homozygous for COMT met and DRD2 G alleles would show higher rates of motor learning. Seventy-two young healthy females (20 ± 1.9 yr) performed a sensorimotor adaptation task and a motor sequence learning task. A nonparametric mixed model ANOVA revealed that the COMT val-val group demonstrated poorer performance in the sequence learning task compared with the met-met group and showed a learning deficit in the visuomotor adaptation task compared with both met-met and val-met groups. The DRD2 TT group showed poorer performance in the sequence learning task compared with the GT group, but there was no difference between DRD2 genotype groups in adaptation rate. Although these results did not entirely come out as one might predict based on the known contribution of corticostriatal pathways to motor sequence learning, they support the role of genetic polymorphisms of COMT val158met (rs4680) and DRD2 G>T (rs 1076560) in explaining individual differences in motor performance and motor learning, dependent on task type.

The Pattern of Striatal Dopaminergic Denervation Explains Sensorimotor Synchronization Accuracy in Parkinson’s Disease

The basal ganglia are thought to play a critical role in duration perception and production. However, experimental evidence for impaired temporal processing in Parkinsons disease (PD) patients is mixed. This study examined the association between striatal dopaminergic denervation in PD patients and sensorimotor synchronization. Twenty-eight mild-to-moderate stage PD patients synchronized finger taps to tone sequences of either 500 ms, 1000 ms or 1500 ms time intervals while ON levodopa (l-DOPA) or placebo pill (on separate test days) with the index finger of their more and less affected hands. We measured the accuracy and variability of synchronization. In a separate session, patients underwent (11)C-dihydrotetrabenazine ((11)C-DTBZ) PET scanning to measure in vivo striatal dopaminergic denervation. Patients were less accurate synchronizing to the 500 ms target time interval, compared to the 1000 ms and 1500 ms time intervals, but neither medication state nor hand affected accuracy; medication state, hand nor the target time interval affected synchronization variability. Regression analyses revealed no strong relationships between synchronization accuracy or variability and striatal dopaminergic denervation. We performed a cluster analysis on the degree of dopaminergic denervation to determine whether patient subgroup differences underlie our results. Three patient subgroups showed behavioral differences in synchronization accuracy, but not variability, paralleling their pattern of denervation. These findings provide further evidence for the role of the basal ganglia and dopamine in duration production and suggest that the degree of striatal dopaminergic denervation may explain the heterogeneity of performance between PD patients on the sensorimotor synchronization task.