Edited by: Joshua Oon Soo Goh, National Taiwan University, Taiwan
Reviewed by: Wei Gao, Cedars-Sinai Medical Center, USA; Mingrui Xia, Beijing Normal University, China
*Correspondence: Chiang-Shan R. Li
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We seek to characterize the effects of methylphenidate (MPH) on resting state functional connectivity (rsFC) in humans. This study expands upon a previous work, which focused on the dorsal striatum and thalamus (Farr et al.,
Low frequency, “spontaneous” blood oxygenation level dependent (BOLD) signals are spatially organized and provide valuable insights to the functional architecture of the brain (Fair et al.,
The current study focuses on subcortical nuclei that mediate cholinergic and catecholaminergic signaling as these circuits are of great importance to both basic and clinical neuroscience. For instance, although MPH has been used to treat ADHD and other clinical conditions since the 1950s (Lange et al.,
The BNM provides cholinergic inputs to the hippocampus, olfactory bulb, amygdala, and all of the neo-cortex (Pearson et al.,
40% to 76% of BNM neurons are lost (Tagliavini and Pilleri,
The interaction of catecholaminergic and cholinergic systems is also evident in other animal studies (Janowsky et al.,
LC is the largest source of NA neurons in the central nervous system (CNS) (Moore and Bloom,
MPH ameliorates impulsivity both in humans and non-human primates (Rajala et al.,
The VTA/SNc projects to the striatum and neocortex and receives heavy glutamatergic projections from the ventromedial prefrontal cortex (vmPFC), OFC, dorsal ACC (dACC), as well as the hippocampus and amygdala (Haber and Knutson,
The DA pathway is a major component of the reward system, a network of brain regions that predict and encode value during reward-based processing and learning (Schultz et al.,
MPH elicited increase in BOLD activity in the SN of rats (Easton et al.,
Participants, study procedures, and imaging pre-processing were described in detail in our recent work (Farr et al.,
Twenty-four healthy adults (16 females; age 25 ± 6 years) participated in the study. All were without medical, neurological, or psychiatric conditions, denied history of head injury and current use of prescription medications or illicit substances, and showed negative urinalysis on the day of fMRI. These 24 participants received a single 45 mg oral dose of MPH before fMRI and comprised the methylphenidate (MPH) group. Data of a cohort of 24 matched healthy participants (16 females; age 24 ± 4 years) scanned under identical imaging protocols except without being given MPH were used for comparison—the no-MPH group. Compared to baseline, MPH increased heart rate, systolic blood pressure, and anxiety rating, as we reported recently (Farr et al.,
Conventional T1-weighted spin-echo sagittal anatomical images were acquired for slice localization using a 3T scanner (Siemens Trio). Anatomical images of the functional slice locations were next obtained with spin-echo imaging in the axial plane parallel to the AC-PC line with TR = 300 ms, TE = 2.5 ms, bandwidth = 300 Hz/pixel, flip angle = 60°, field of view = 220 × 220 mm, matrix = 256 × 256, 32 slices with slice thickness = 4 mm and no gap. Functional, BOLD signals were then acquired with a single-shot gradient echo echo-planar imaging (EPI) sequence. Thirty-two axial slices parallel to the AC-PC line covering the whole brain were acquired with repetition time = 2000 ms, echo time = 25 ms, bandwidth = 2004 Hz/pixel, flip angle = 85°, field of view = 220 × 220 mm, matrix = 64 × 64, 32 slices with slice thickness = 4 mm and no gap. Three hundred images were acquired in the resting state during which participants were instructed to close their eyes but stay awake for a period of 10 min (Farr et al.,
Brain imaging data were pre-processed using the same routine as described in our previous work (Zhang et al.,
Additional pre-processing was applied to reduce spurious BOLD variances that were unlikely to reflect neuronal activity (Rombouts et al.,
As extensively investigated by Van Dijk et al. (
We used the same seed regions as in our earlier work (Li et al.,
A mask of the BNM was created based on a stereotaxic probabilistic map of magnocellular cell groups in the basal forebrain (Zaborszky et al.,
We used a probabilistic template of the LC derived by Keren et al. (
The BOLD time courses were averaged spatially across all voxels each for the three seed regions. We computed the correlation coefficient between the averaged time course of each mask and the time courses of individual voxels of the brain for individual subjects. To assess and compare the resting state “correlograms,” we converted these image maps, which were not normally distributed, to z score maps by Fisher's z transform (Jenkins and Watts,
The main results of the differences in rsFC between the two groups are summarized in Figure
6507 | 4.20 | −36 | −28 | 70 | L Precentral gyrus |
4.10 | −51 | −22 | 58 | ||
4.09 | −24 | −31 | 76 | ||
7992 | 4.14 | 30 | −31 | 70 | R Precentral gyrus |
3.85 | 48 | −16 | 64 | ||
3.78 | 51 | −16 | 43 | ||
None | |||||
2484 | 4.71 | 27 | −16 | −17 | R Hippocampal gyrus |
3.44 | 15 | −10 | −23 | ||
3.43 | 36 | −31 | −5 | ||
5373 | 4.70 | 12 | −43 | −50 | R Cerebellum |
3.90 | 9 | −52 | −50 | ||
3.67 | −15 | −46 | −47 | L Cerebellum | |
3537 | 4.40 | −30 | −82 | −14 | L Middle occipital gyrus |
4.22 | −48 | −79 | −5 | ||
3.36 | −18 | −88 | −11 | ||
24,975 | 4.55 | 15 | −52 | −35 | R Cerebellum |
4.46 | 3 | −73 | −17 | ||
4.42 | 12 | −82 | −32 | ||
4104 | 4.24 | −21 | −1 | 13 | L Putamen/Pallidum |
3.76 | −9 | −13 | 13 |
MPH reversed negative connectivity between the BNM and bilateral precentral gyri, including regions of the primary motor and premotor cortex (Figures
Both groups showed positive connectivity of LC with the bilateral cerebellum, with the MPH group showing significantly less positive connectivity. While the no-MPH group showed no significant connectivity of LC with the right hippocampus, the MPH group showed significant positive connectivity (Figures
While the no-MPH group showed negative VTA/SNc connectivity with the left middle occipital gyrus (MOG), the MPH group showed no significant connectivity. Both groups showed positive VTA/SNc connectivity with bilateral cerebellum, with the MPH group showing lower connectivity than the no-MPH group. While the no-MPH group showed positive connectivity with bilateral putamen the MPH group showed no significant connectivity (Figures
We re-analyzed the data without using global signal regression in pre-processing. The findings showed that changes in functional connectivity were slightly diminished in significance but were otherwise similar. To confirm the findings, we extracted the effect size of connectivity (in data without global signal regression) of the ROIs as identified from the original analysis for comparison between the MPH and no-MPH groups (Figure
Anatomically, VTA/SNc projects directly to the BNM (Gaykema and Zaborszky,
MPH's effects on the motor systems are well-documented. MPH increased frontal activation in both healthy and ADHD children (Vaidya et al.,
MPH elicited reversal of the sign of BNM—motor cortical connectivity may have treatment implications for PD. Combined with levodopa (L-Dopa), MPH improves hand tapping speed but worsens dyskinesia symptoms as compared to L-Dopa alone (Camicioli et al.,
MPH significantly reduced positive LC connectivity with specific regions of the cerebellar cortex, likely lobules IV, V, and X (Schmahmann et al.,
It has been suggested that long-term potentiation (LTP) in the hippocampus is mediated by NA activity (Ramos and Arnsten,
Indeed, MPH improved 1-week retention of both casually and intentionally learned information when administered 12 h after learning (Izquierdo et al.,
Thus, MPH diminishes negative connectivity between VTA/SNc and left MOG. While the prefrontal cortex receives both direct NE and DA projections, the occipital cortex receives scarce DA projections in the rat (Descarries et al.,
It is plausible that MPH diminishes negative connectivity between VTA/SNc and the MOG as a result of complex interaction of NA and DA systems. Further, DA projections to cortex are more abundant in primates including humans than in rats (Björklund and Dunnett,
Many studies have implicated the MOG in ADHD. In diffusion tensor imaging (DTI), ADHD patients show reductions in trace (a measure of diffusion magnitude) in the left MOG (Alexander et al.,
MPH reduced positive connectivity between VTA/SNc and multiple areas of the dorsomedial cerebellum including the vermis, culmen, and medial hemispheres. The cerebellum is important to cognition and motor control, with distinct areal connections to motor and prefrontal cortices (Middleton and Strick,
Acute stimulation of the VTA/SNc increases cFOS immunoreactivity, an indirect measure of brain activity, in the dorsal cerebellum, and chronic DA antagonism decreased cFOS in the dorsal vermis while increasing it in the dorsal cerebellar hemisphere (Herrera-Meza et al.,
Cerebellum has been implicated in catecholaminergic dysfunction. Mice generated with decreased levels of monoamine oxidase A (MAO-A), an enzyme integral to maintaining normal catecholamine levels, exhibit smaller cerebellums, decreased Purkinje cell count and dendritic density, and vermal hypoplasia (Alzghoul et al.,
The link between catecholaminergic function and the cerebellum may lead to new insights in treating motor disorders like PD. DA signaling from the striatum, as well as input from the cerebellum, influences the plasticity of the PMC during motor learning, a process known to be abnormal in PD (Kishore et al.,
MPH increases cerebellar activity in both ADHD adults and children (Epstein et al.,
Several issues should be considered. First, this observational study is based on a between-subjects design and did not involve a placebo control; thus, the placebo effect may confound the results. Further, we did not control for individual differences such as personality traits and pharmacokinetics, which may underlie variability of the effects of MPH. Thus, although the MPH and no-MPH groups are also individually matched in age and gender, the current results should be considered as preliminary and require replication in future work with a within-subject design. Second, the LC seed is very small. Although our recent study examined and negated the influence of physiological signals on BOLD activity and functional connectivity of the LC (Zhang et al.,
In summary, MPH had varying effects on the functional connectivity of BNM, LC, and VTA/SN. MPH reversed negative BNM connectivity with bilateral precentral gyrus, in accord with its effects on motor control and learning in ADHD and PD. MPH decreased positive connectivity between LC and cerebellum, which may underlie priming for cognitive over motor processing. MPH increased connectivity between LC and hippocampus, a change that may underlie reported improvements in memory. MPH eliminated or nearly eliminated connectivity of VTA/SNc with the cerebellum, putamen and left MOG, suggesting a DA mechanism of its effects on cognitive motor processing and visual attention. However, the current findings are obtained in healthy individuals and may not readily generalize to neuropsychiatric populations.
All authors made substantial contributions to the conception or design of the work, data acquisition and analysis, interpretation of data; and drafting or revising the work for publication. All authors approved the final version and agreed to be accountable for the whole contents of the work.
This study is supported by NIH grants DA026990, DA023248, AA021449, NS23945 (LZ), T32 NS07224 (OMF), and K25DA040032 (SZ) as well as the Peter McManus Trust, and conducted partly as a senior thesis project (RK) in the Department of Psychology at Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Drug Abuse or the National Institutes of Health.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.