To investigate chemotherapy dosage-related cognitive impairment and its neural mechanisms in breast cancer (BC) patients. Twenty-eight breast cancer patients after each chemotherapy cycle and matched 29 healthy control subjects underwent structural magnetic resonance imaging. Voxel-based morphometry analysis was performed to compare group differences in the gray matter for the whole brain. Furthermore, mediation analysis was conducted to explore the role of brain structures in chemotherapy dosage-related cognitive impairment. Voxel-based morphometry analysis was performed in gray matter for the whole brain of BC patients after chemotherapy. The results revealed that the gray matter density in the left inferior frontal gyrus, right middle frontal gyrus, right fusiform area, and bilateral cerebellum was decreased in the BC patients compared to controls. The number of chemotherapy cycles was negatively associated with general cognitive capacity, verbal fluency and digit span performance in the BC patients. In addition, decreased gray matter density in the right middle frontal gyrus could mediate the chemotherapy dosage effects on verbal fluency performance. These findings indicate that the dose-response relationship between chemotherapy and cognitive impairment may depend on the decreases in gray matter density of the frontal cortical structures.
Tardive dyskinesia (TD) is a devastating motor disorder associated with the etiological process of schizophrenia or antipsychotic medication treatments. To examine whether cerebral morphological changes may manifest in TD, we used voxel-based morphometry to analyze high-resolution T1-weighted brain structural magnetic resonance images from 32 schizophrenics with TD (TD group), 31 schizophrenics without TD (non-TD group), and 32 healthy controls (HC group). We also assessed psychopathological symptoms with the Positive and Negative Syndrome Scale (PANSS), and TD severity with the Abnormal Involuntary Movement Scale (AIMS). We compared gray matter volumes (GMVs) among groups, and tested for correlations between GMV changes and psychopathological symptoms or TD severity. The results showed significant differences in GMV in the frontal and temporal cortices, insula and cerebellum among the three groups. Brainstem and inferior frontal and precentral gyri GMVs were significantly larger, whereas cuneus and lingual gyrus GMVs were significantly smaller in the TD group as compared to non-TD group. Further, the cuneus and lingual gyrus GMVs were positively correlated with AIMS scores in the TD group. The current results suggest that TD may be associated with the alterations in GMV that are different from that of schizophrenics without TD. Further studies are needed to confirm and to examine the functional significance of these structural findings.
Our previous work described the neural processes of motor response inhibition during a stop signal task (SST). Employing the race model, we computed the stop signal reaction time (SSRT) to index individuals' ability in inhibitory control. The pre-supplementary motor area (preSMA), which shows greater activity in individuals with short as compared to those with long SSRT, plays a role in mediating response inhibition. In contrast, the right inferior prefrontal cortex (rIFC) showed greater activity during stop success as compared to stop error. Here we further pursued this functional differentiation of preSMA and rIFC on the basis of an intra-subject approach. Of 65 subjects who participated in four sessions of the SST, we identified 30 individuals who showed a difference in SSRT but were identical in other aspects of stop signal performance between the first ("early") and last two ("late") sessions. By comparing regional brain activation between the two sessions, we confirmed greater preSMA but not rIFC activity during short as compared to long SSRT session within individuals. Furthermore, putamen, anterior cerebellum and middle/posterior cingulate cortex also showed greater activity in association with short SSRT. These results are consistent with a role of medial prefrontal cortex in controlled action and inferior frontal cortex in orienting attention. We discussed these findings with respect to the process of attentional monitoring and inhibitory motor control during stop signal inhibition.
Deficits in inhibitory control have been widely implicated in alcohol misuse. However, the literature does not readily distinguish the effects of drinking problems and chronic alcohol use. Here, we examined how years of drinking and the Alcohol Use Disorders Identification Test (AUDIT) score each influences the cerebral responses to inhibitory control in nondependent drinkers. Fifty-seven adult drinkers and 57 age- and gender-matched nondrinkers participated in one 40-minute functional magnetic resonance imaging scan of the stop signal task. Data were preprocessed and modeled using SPM8. In a regression model, we contrasted stop and go success trials for individuals and examined activities of response inhibition each in link with the AUDIT score and years of alcohol use in group analyses. We specified the effects of duration of use by contrasting regional activations of drinkers and age-related changes in nondrinkers. In mediation analyses, we investigated how regional activities mediate the relationship between drinking problems and response inhibition. Higher AUDIT score but not years of drinking was positively correlated with prolonged stop signal reaction time (SSRT) and diminished responses in the cerebellum, thalamus, frontal and parietal regions, independent of years of alcohol use. Further, activity of the thalamus, anterior cingulate cortex, and presupplementary motor area significantly mediates the association, bidirectionally, between the AUDIT score and SSRT. The duration of alcohol use was associated with decreased activation in the right inferior frontal gyrus extending to superior temporal gyrus, which was not observed for age-related changes in nondrinkers. The results distinguished the association of drinking problems and years of alcohol use to inhibitory control in young adult nondependent drinkers. These new findings extend the imaging literature of alcohol misuse and may have implications for treatment to prevent the escalation from social to dependent drinking. More research is needed to confirm age-independent neural correlates of years of alcohol use.
Methylphenidate (MPH) influences catecholaminergic signaling. Extant work examined the effects of MPH on the neural circuits of attention and cognitive control, but few studies have investigated the effect of MPH on the brain's resting-state functional connectivity (rsFC). In this observational study, we compared rsFC of a group of 24 healthy adults who were administered an oral 45 mg dose of MPH with a group of 24 age and gender matched controls who did not receive MPH. We focused on three seed regions: basal nucleus of Meynert (BNM), locus coeruleus (LC), and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc), each providing cholinergic, noradrenergic and dopaminergic inputs to the cerebral cortex. Images were pre-processed and analyzed as in our recent work (Li et al., 2014; Zhang et al., 2015). We used one-sample t-test to characterize group-specific rsFC of each seed region and two-sample t-test to compare rsFC between groups. MPH reversed negative connectivity between BNM and precentral gyri. MPH reduced positive connectivity between LC and cerebellum, and induced positive connectivity between LC and right hippocampus. MPH decreased positive VTA/SNc connectivity to the cerebellum and putamen, and reduced negative connectivity to left middle occipital gyrus. MPH had distinct effects on the rsFC of BNM, LC, and VTA/SNc in healthy adults. These new findings may further our understanding of the role of catecholaminergic signaling in Attention Deficit Hyperactivity Disorder (ADHD) and Parkinson's disease and provide insights into the therapeutic mechanisms of MPH in the treatment of clinical conditions that implicate catecholaminergic dysfunction.
Our previous work characterized altered cerebral activations during cognitive control in individuals with alcohol dependence (AD). A hallmark of cognitive control is the ability to anticipate changes and adjust behavior accordingly. Here, we employed a Bayesian model to describe trial-by-trial anticipation of the stop signal and modeled fMRI signals of conflict anticipation in a stop signal task. Our goal is to characterize the neural correlates of conflict anticipation and its relationship to response inhibition and alcohol consumption in AD. Twenty-four AD and 70 age and gender matched healthy control individuals (HC) participated in the study. fMRI data were pre-processed and modeled with SPM8. We modeled fMRI signals at trial onset with individual events parametrically modulated by estimated probability of the stop signal, p(Stop), and compared regional responses to conflict anticipation between AD and HC. To address the link to response inhibition, we regressed whole-brain responses to conflict anticipation against the stop signal reaction time (SSRT). Compared to HC (54/70), fewer AD (11/24) showed a significant sequential effect - a correlation between p(Stop) and RT during go trials - and the magnitude of sequential effect is diminished, suggesting a deficit in proactive control. Parametric analyses showed decreased learning rate and over-estimated prior mean of the stop signal in AD. In fMRI, both HC and AD responded to p(Stop) in bilateral inferior parietal cortex and anterior pre-supplementary motor area, although the magnitude of response increased in AD. In contrast, HC but not AD showed deactivation of the perigenual anterior cingulate cortex (pgACC). Furthermore, deactivation of the pgACC to increasing p(Stop) is positively correlated with the SSRT in HC but not AD. Recent alcohol consumption is correlated with increased activation of the thalamus and cerebellum in AD during conflict anticipation. The current results highlight altered proactive control that may serve as an additional behavioral and neural marker of alcohol dependence.
Cognitive control is a critical executive function. Many studies have combined general linear modeling and the stop signal task (SST) to delineate the component processes of cognitive control. For instance, by contrasting stop success (SS) and stop error (SE) trials in the SST, investigators examined regional responses to stop signal inhibition. In contrast to this parameterized approach, independent component analysis (ICA) elucidates brain networks subserving cognitive control. In our earlier work of 59 adults performing the SST during fMRI, we characterized six independent components (ICs). However, none of these ICs correlated with stop signal performance, raising questions about their behavioral validity. Here, in a larger sample (n = 100), we identified and explored 23 ICs for correlation with the stop signal reaction time (SSRT), a measure of the efficiency of response inhibition. At a corrected threshold (P < 0.0005), a paracentral lobule-midcingulate network and a left inferior parietal-supplementary motor-somatomotor network showed a positive correlation between SE beta weight and SSRT. In contrast, a midline cerebellum-thalamus-pallidum network showed a negative correlation between SE beta weight and SSRT. These findings suggest that motor preparation and execution prolongs the SSRT, likely via an interaction between the go and stop processes as suggested by the race model. Behaviorally, consistent with this hypothesis, the difference in G and SE reaction times is positively correlated with SSRT across subjects. These new results highlight the importance of cognitive motor regions in response inhibition and support the utility of ICA in uncovering functional networks for cognitive control in the SST.
The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging.
The basal ganglia nuclei are critical for a variety of cognitive and motor functions. Much work has shown age-related structural changes of the basal ganglia. Yet less is known about how the functional interactions of these regions with the cerebral cortex and the cerebellum change throughout the lifespan. Here, we took advantage of a convenient sample and examined resting state functional magnetic resonance imaging data from 250 adults 18 to 49 years of age, focusing specifically on the caudate nucleus, pallidum, putamen, and ventral tegmental area/substantia nigra (VTA/SN). There are a few main findings to report. First, with age, caudate head connectivity increased with a large region of ventromedial prefrontal/medial orbitofrontal cortex. Second, across all subjects, pallidum and putamen showed negative connectivity with default mode network (DMN) regions such as the ventromedial prefrontal cortex and posterior cingulate cortex, in support of anti-correlation of the "task-positive" network (TPN) and DMN. This negative connectivity was reduced with age. Furthermore, pallidum, posterior putamen and VTA/SN connectivity to other TPN regions, such as somatomotor cortex, decreased with age. These results highlight a distinct effect of age on cerebral functional connectivity of the dorsal striatum and VTA/SN from young to middle adulthood and may help research investigating the etiologies or monitoring outcomes of neuropsychiatric conditions that implicate dopaminergic dysfunction.
Magnetic resonance imaging has provided a wealth of information on altered brain activations and structures in individuals addicted to cocaine. However, few studies have considered the influence of age and alcohol use on these changes. We examined gray matter volume with voxel based morphometry (VBM) and low frequency fluctuation (LFF) of BOLD signals as a measure of cerebral activity of 84 cocaine dependent (CD) and 86 healthy control (HC) subjects. We performed a covariance analysis to account for the effects of age and years of alcohol use. Compared to HC, CD individuals showed decreased gray matter (GM) volumes in frontal and temporal cortices, middle/posterior cingulate cortex, and the cerebellum, at p<0.05, corrected for multiple comparisons. The GM volume of the bilateral superior frontal gyri (SFG) and cingulate cortices were negatively correlated with years of cocaine use, with women showing a steeper loss in the right SFG in association with duration of use. In contrast, the right ventral putamen showed increased GM volume in CD as compared to HC individuals. Compared to HC, CD individuals showed increased fractional amplitude of LFF (fALFF) in the thalamus, with no significant overlap with regions showing GM volume loss. These results suggested that chronic cocaine use is associated with distinct changes in cerebral structure and activity that can be captured by GM volume and fALFF of BOLD signals.
Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral, data-driven approach to the analysis of connectivity is vital. We analyzed resting-state functional connectivity data collected at 3T in 27 OCD patients and 66 matched control subjects with a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain. We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within regions of interest in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD. These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD.
Error detection and behavioral adjustment are core components of cognitive control. Numerous studies have focused on the anterior cingulate cortex (ACC) as a critical locus of this executive function. Our previous work showed greater activation in the dorsal ACC and subcortical structures during error detection, and activation in the ventrolateral prefrontal cortex (VLPFC) during post-error slowing (PES) in a stop signal task (SST). However, the extent of error-related cortical or subcortical activation across subjects was not correlated with VLPFC activity during PES. So then, what causes VLPFC activation during PES? To address this question, we employed Granger causality mapping (GCM) and identified regions that Granger caused VLPFC activation in 54 adults performing the SST during fMRI. These brain regions, including the supplementary motor area (SMA), cerebellum, a pontine region, and medial thalamus, represent potential targets responding to errors in a way that could influence VLPFC activation. In confirmation of this hypothesis, the error-related activity of these regions correlated with VLPFC activation during PES, with the cerebellum showing the strongest association. The finding that cerebellar activation Granger causes prefrontal activity during behavioral adjustment supports a cerebellar function in cognitive control. Furthermore, multivariate GCA described the "flow of information" across these brain regions. Through connectivity with the thalamus and SMA, the cerebellum mediates error and post-error processing in accord with known anatomical projections. Taken together, these new findings highlight the role of the cerebello-thalamo-cortical pathway in an executive function that has heretofore largely been ascribed to the anterior cingulate-prefrontal cortical circuit.
Functional connectivities of the amygdala support emotional and cognitive processing. Life-span development of resting-state functional connectivities (rsFC) of the amygdala may underlie age-related differences in emotion regulatory mechanisms. To date, age-related changes in amygdala rsFC have been reported through adolescence but not as thoroughly for adulthood. This study investigated age-related differences in amygdala rsFC in 132 young and middle-aged adults (19-55 years). Data processing followed published routines. Overall, amygdala showed positive rsFC with the temporal, sensorimotor and ventromedial prefrontal cortex (vmPFC), insula and lentiform nucleus, and negative rsFC with visual, frontoparietal, and posterior cingulate cortex and caudate head. Amygdala rsFC with the cerebellum was positively correlated with age, and rsFCs with the dorsal medial prefrontal cortex (dmPFC) and somatomotor cortex were negatively correlated with age, at voxel < 0.001 in combination with cluster < 0.05 FWE. These age-dependent changes in connectivity appeared to manifest to a greater extent in men than in women, although the sex difference was only evident for the cerebellum in a slope test of age regressions ( = 0.0053). Previous studies showed amygdala interaction with the anterior cingulate cortex (ACC) and vmPFC during emotion regulation. In region of interest analysis, amygdala rsFC with the ACC and vmPFC did not show age-related changes. These findings suggest that intrinsic connectivity of the amygdala evolved from young to middle adulthood in selective brain regions, and may inform future studies of age-related emotion regulation and maladaptive development of the amygdala circuits as an etiological marker of emotional disorders.