Frontostriatal Circuits Alterations Associated with Cognitive Flexibility Deterioration in Huntington's Disease.

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have reported abnormal functional connectivity (FC) in the prefrontal cortex (PFC)-striatum circuit in patients with premanifest Huntington's disease (HD). However, there is a lack of evidence showing persistence of abnormal frontostriatal FC and its relation to cognitive flexibility performance in patients with clinically manifest HD. OBJECTIVE: The aim of this study was to evaluate the resting-state FC integrity of the frontostriatal circuit and its relation to cognitive flexibility in HD patients and healthy controls (HCs). METHOD: Eighteen patients with early clinical HD manifestation and 18 HCs matched for age, sex, and education participated in this study. Both groups performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional (IED) set-shift task, which measures cognitive flexibility. Resting-state functional magnetic resonance images were also acquired to examine the FC in specific frontostriatal circuits. Eight regions of interest were preselected based on regions previously associated with extradimensional (ED) shifting in patients with premanifest HD. RESULTS: Significant negative correlations between the number of attentional set-shifting errors and the ventral striatum-ventrolateral PFC FC were found in the HD group. This group also showed negative FC correlations between the total errors and the FC between right ventral striatum-right ventrolateral PFC, left ventral striatum-left ventrolateral PFC, and right ventral striatum-left ventrolateral PFC. Negative correlations between the ED errors and left ventral striatum-left ventrolateral PFC and right ventral striatum-right ventrolateral PFC FC were also found. Finally, a positive correlation between the number of stages completed and left ventral striatum-left ventrolateral PFC FC was found. CONCLUSIONS: Manifest HD patients show significant cognitive flexibility deficits in attentional set-shifting that are associated with FC alterations in the frontostriatal circuit. These results show that FC abnormalities found in the prodromal stage of the disease can also be associated with cognitive flexibility deficits at a later clinical stage, making them good candidates to be explored in longitudinal studies.

Reduced frontostriatal functional connectivity and associations with severity of Internet gaming disorder.

Cognitive, functional, and structural brain factors involving frontal executive and striatal reward networks have been implicated in Internet gaming disorder (IGD). However, frontostriatal network connectivity and its association with addiction severity are poorly understood in IGD. Resting-state fMRI data from 337 subjects (130 with IGD, 207 with recreational game use [RGU]) were collected. Striatal-cortical communications were measured with resting-state functional connectivity (FC) using coherent spontaneous fluctuations in the blood-oxygenation-level-dependent fMRI signal. Correlations were calculated between FC measures and IGD-related assessments (addiction severity and craving scores). Decreased FC was predominantly observed in IGD subjects, with IGD subjects showing decreased FC between the putamen and superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) and the ventral striatum and IFG, superior temporal gyrus, and MFG. Disorder severity and craving scores were negatively correlated with FC between striatal and frontal brain regions. Associations between diminished FC in corticostriatal circuitry and clinical features (IGD craving, severity) suggest potential therapeutic targets for neuromodulation treatments. The extent to which frontostriatal circuits involving executive control over reward processes may be altered to treat IGD warrants additional study.

Role of the dorsolateral prefrontal cortex in context-dependent motor performance.

Context-dependent motor performance is a phenomenon in which people perform better in the environmental context where they originally practised a task. Some animal and computer simulation studies have suggested that context-dependent performance may be associated with neural activation of the dorsolateral prefrontal cortex (DLPFC). This study aimed to determine the role of the DLPFC in context-dependent motor performance by perturbing the neural processing of the DLPFC with repetitive transcranial magnetic stimulation (rTMS) in healthy adults. Thirty healthy adults were recruited into the Control, rTMS DLPFC and rTMS Vertex groups. The participants practised three finger sequences associated with a specific incidental context (a coloured circle and a location on the computer screen). One day following practice, the rTMS groups received 1 Hz rTMS prior to the testing conditions in which the sequence-context associations remained the same as practice (SAME) or changed (SWITCH). All three groups improved significantly over practice on day 1. The second day testing results showed that the DLPFC group had a significantly lower decrease in motor performance under the SWITCH condition than the Control and Vertex groups. This finding suggests a specific role of the DLPFC in context-dependent motor performance.

White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: association with attention performance and symptoms.

The frontostriatal circuit has been postulated to account for the core symptoms such as inattention in attention deficit/hyperactivity disorder (ADHD). This study investigated the white matter integrity of frontostriatal fiber tracts using diffusion spectrum imaging (DSI) tractography and its correlations with measures of multi-dimensional aspects of inattention based on psychiatric interview and attention tasks in 25 children with ADHD and 25 matched typically developing (TD) children. All the subjects were assessed with comprehensive psychiatric interviews and the Conner's Continuous Performance Test (CCPT). DSI data were acquired on a 3-Tesla MRI system. The frontostriatal fiber pathways were reconstructed by deterministic tractography, and generalized fractional anisotropy values were measured along individual targeted tracts to investigate alterations in microstructure integrity. Children with ADHD performed worse than TD children in the dimensions of focused attention, sustained attention, impulsivity, and vigilance of the CCPT, and showed impaired integrity in four bilateral frontostriatal tracts, namely the dorsolateral-caudate, medial prefrontal-caudate, orbitofrontal-caudate, and ventrolateral-caudate tracts, and in global white matter as well. The integrity of the left orbitofronto-caudate tract was associated with the symptom of inattention in children with ADHD, compatible with the attention deficit and motivational dysfunction theories in ADHD. The integrity of the frontostriatal tracts was associated with the attention performance only in TD children, suggestive of possible recruitment of tracts other than the frontostriatal tracts implicated in attention deficits in children with ADHD. In conclusion, our results demonstrate the functional involvement of the frontostriatal circuit with respect to clinical symptoms and attention performance.

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction.

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

Prenatal environmental tobacco smoke exposure alters children's cognitive control circuitry: A preliminary study.

BACKGROUND AND OBJECTIVES: Prenatal exposure to environmental tobacco smoke (ETS) is associated with increased attention problems in children, however, the effects of such exposure on children's brain structure and function have not been studied. Herein, we probed effects of prenatal ETS on children's cognitive control circuitry and behavior. METHODS: Forty-one children (7-9 years) recruited from a prospective longitudinal birth cohort of non-smoking mothers completed structural and task-functional magnetic resonance imaging to evaluate effects of maternal ETS exposure, measured by maternal prenatal urinary cotinine. Attention problems and externalizing behaviors were measured by parent report on the Child Behavior Checklist. RESULTS: Compared to non-exposed children, exposed children had smaller left and right thalamic and inferior frontal gyrus (IFG) volumes, with large effect sizes (p-FDR < .05, Cohen's D range from 0.79 to 1.07), and increased activation in IFG during the resolution of cognitive conflict measured with the Simon Spatial Incompatibility Task (38 voxels; peak t(25) = 5.25, p-FWE = .005). Reduced thalamic volume was associated with increased IFG activation and attention problems, reflecting poor cognitive control. Mediation analyses showed a trend toward left thalamic volume mediating the association between exposure and attention problems (p = .05). CONCLUSIONS: Our findings suggest that maternal ETS exposure during pregnancy has deleterious effects on the structure and function of cognitive control circuitry which in turn affects attentional capacity in school-age children. These findings are consistent with prior findings documenting the effects of active maternal smoking on chidlren's neurodevleoment, pointing to the neurotixicity of nicotine regardless of exposure pathway.

Higher Trait Impulsivity and Altered Frontostriatal Connectivity in Betel-Quid Dependent Individuals.

Objective: Betel quid dependency (BQD) is characterized by functional and structural brain alterations. Trait impulsivity may influence substance dependence by impacting its neurobiological underpinnings in the frontostriatal circuit. However, little is known about the trait impulsivity and its neural correlates in individuals with BQD. Methods: Forty-eight participants with BQD and 22 normal controls (NCs) were recruited and scanned on a 3T MRI scanner. Barratt impulsiveness scale (BIS) was used to measure trait impulsivity: motor, attention, and no plan impulsivity. We used voxel-based morphometry (VBM) to assess the relationship between trait impulsivity and gray matter volumes. The relevant clusters identified were served as regions of interest (ROI) seeds. The whole-volume psycho-physiological interactions (PPI) analysis was used to investigate the changes of functional connectivity related to ROI seeds in the cue-reactivity task condition (BQ and control images). Results: Behaviorally, the BQD group showed significantly higher trait impulsivity including motor and no plan impulsivity than the NCs group. VBM analyses showed that motor impulsivity was negatively associated with gray matter volume of right caudate in the whole sample. No difference in gray matter volume between the two groups was observed. PPI analyses showed that there was a significantly decreased functional connectivity between the right caudate and right dorsolateral prefrontal cortex (DLPFC) when watching BQ related images than control images in individuals with BQD. Furthermore, functional connectivity between the right caudate and right DLPFC was negatively correlated with BQ dependency scores. Conclusions: Our study demonstrated the structural basis of trait impulsivity in the caudate and provided evidence for abnormal interactions within frontostriatal circuitsin individuals with BQD, which may provide insight into the selection of potential novel therapeutic targets for the treatment of BQ dependency.

Linking personality and brain anatomy: a structural MRI approach to Reinforcement Sensitivity Theory.

Reinforcement Sensitivity Theory (RST) proposes a widely used taxonomy of human personality linked to individual differences at both behavioral and neuropsychological levels that describe a predisposition to psychopathology. However, the body of RST research was based on animal findings, and little is known about their anatomical correspondence in humans. Here we set out to investigate MRI structural correlates (i.e. voxel-based morphometry) of the main personality dimensions proposed by the RST in a group of 400 healthy young adults who completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ). Sensitivity to punishment scores correlated positively with the gray matter volume in the amygdala, whereas sensitivity to reward scores correlated negatively with the volume in the left lateral and medial prefrontal cortex. Moreover, a negative relationship was found between the striatal volume and the reward sensitivity trait, but only for male participants. The present results support the neuropsychological basis of the RST by linking punishment and reward sensitivity to anatomical differences in limbic and frontostriatal regions, respectively. These results are interpreted based on previous literature related to externalizing and internalizing disorders, and they highlight the possible role of SPSRQ as a measure of proneness to these disorders.

White matter integrity in the fronto-striatal accumbofrontal tract predicts impulsivity.

Frontostriatal projections have been shown to mediate impulsivity. Recent findings have demonstrated that the projection from the prefrontal cortex to the nucleus accumbens (the accumbofrontal tract) can be isolated by using probabilistic tractography on human brain MRI data, specifically, diffusion tensor images (DTI). Using DTI tractography, we isolated the tract and tested its association with the impulsivity. DTI data from 143 individuals obtained from Nathan Kline Institute-Rockland Sample was used along with the impulsivity measure assessed by the UPPS (urgency, premeditation, perseverance, and sensation seeking) impulsive behavior total score. Probabilistic tractography was first performed between the prefrontal cortex and nucleus accumbens, then, as a measure of white matter integrity in the tract, fractional anisotropy was calculated for each individual's tract. In the multiple regression, accumbofrontal FA showed significant positive association with the impulsivity, suggesting that the accumbofrontal tract integrity may contribute to individual differences in impulsivity. This study bridges the literature in rodents, in which this glutamatergic projection has been shown to mediate impulsive behavior, and the findings in humans which allow the in-vivo isolation of the tract and comparison with behavior.