Corticostriatal Connectivity Research Articles

Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder

BackgroundThe striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder. MethodsWe examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed–based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed–based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex. ResultsCortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed–based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder. ConclusionsThe current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders.

Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/−). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/− mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/− mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

Altered Cortico-Striatal Functional Connectivity During Resting State in Obsessive-Compulsive Disorder.

Background: Neuroimaging studies show that obsessive–compulsive disorder (OCD) is characterized by an alteration of the cortico–striato–thalamo–cortical (CSTC) system in terms of an imbalance of activity between the direct and the indirect loop of the CSTC. As resting-state functional connectivity (FC) studies investigated only specific parts of the CSTC in patients with OCD up to now, the present study aimed at exploring FC in the CSTC as a whole. Methods: We investigated potential alterations in resting-state FC within the CSTC system in 44 OCD patients and 40 healthy controls by taking into consideration all relevant nodes of the direct and indirect CSTC loop. Results: Compared to healthy controls, OCD patients showed an increased FC between the left subthalamic nucleus (STN) and the left external globus pallidus (GPe), as well as an increased FC between the left GPe and the left internal globus pallidus (GPi). Conclusion: These findings may contribute to a better understanding of the OCD pathophysiology by providing further information on the connectivity alterations within specific regions of the CSTC system. In particular, increased FC between the STN and the left GPe may play a major role in OCD pathology. This assumption is consistent with the fact that these regions are also the main target sites of therapeutic deep brain stimulation in OCD.

T175. The Effects of Lorazepam on Resting-State Functional Connectivity

Benzodiazepines, such as lorazepam, are commonly used to treat anxiety. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved during resting-state functional connectivity. The objective of this study is to investigate the effects of lorazepam administration (12 hours or less prior to rsMRI) compared to non-lorazepam during the resting state in patients with psychosis. We focused our analyses on the effects of lorazepam on corticostriatal connectivity, as we have previously demonstrated that a specific pattern of striatal connectivity, the striatal connectivity index (SCI; Sarpal et al., 2016), was related to antipsychotic drug response.

Synaptic Wiring of Corticostriatal Circuits in Basal Ganglia: Insights into the Pathogenesis of Neuropsychiatric Disorders.

The striatum is a key hub in the basal ganglia for processing neural information from the sensory, motor, and limbic cortices. The massive and diverse cortical inputs entering the striatum allow the basal ganglia to perform a repertoire of neurological functions ranging from basic level of motor control to high level of cognition. The heterogeneity of the corticostriatal circuits, however, also renders the system susceptible to a repertoire of neurological diseases. Clinical and animal model studies have indicated that defective development of the corticostriatal circuits is linked to various neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and schizophrenia. Importantly, many neuropsychiatric disease-risk genes have been found to form the molecular building blocks of the circuit wiring at the synaptic level. It is therefore imperative to understand how corticostriatal connectivity is established during development. Here, we review the construction during development of these corticostriatal circuits at the synaptic level, which should provide important insights into the pathogenesis of neuropsychiatric disorders related to the basal ganglia and help the development of appropriate therapies for these diseases.

Corticostriatal connectivity is associated with the reduction of intergroup bias and greater impartial giving in youth

Although prosocial behavior is preferentially directed toward the in-group across many species, prioritizing the outcomes of both the in- and out-group earlier in development can reduce intergroup biases. The current study examined the role of corticostriatal recruitment and connectivity in buffering the effect of intergroup bias on costly giving behavior during childhood and adolescence, a period when other-oriented preferences and associated brain functions undergo significant change. During functional magnetic resonance imaging, youth (n = 51; 8–16 years) made decisions that could potentially benefit in-group and out-group peers at a cost to themselves. Youth were more prosocial toward in-group relative to out-group peers, but were relatively more prosocial to out-group peers when there was a greater discrepancy between potential rewards for others over oneself (i.e., higher reward inequity). Although they showed no differences in corticostriatal activation, youth evinced greater connectivity between the ventral striatum (VS) and posterior superior temporal sulcus (pSTS) when considering more inequitable prosocial decisions that favored the outcomes of out-group peers, which attenuated intergroup biases in prosocial behavior. We found no age-related differences at the behavioral or neural level, suggesting that in-group preferences already bias prosocial behavior and its neurocognitive processes by late childhood and do not change across adolescence.

<p>The effects of huntingtin-lowering: what do we know so far?</p>

Therapies targeting mutant huntingtin DNA, mRNA, and protein have a chance at becoming the first disease-modifying treatments for Huntington’s disease, a fatal inherited neurodegenerative disorder for which only symptom management treatments are available today. This review focuses on evidence addressing several key questions pertinent to huntingtin-lowering, ranging from the functions of wild-type huntingtin (wtHTT) that may be disrupted by huntingtin-lowering treatments through the various ways huntingtin can be lowered, the tolerability of wtHTT-lowering in mice and primates, what has been found in the Ionis Pharmaceutical safety trial of a huntingtin-lowering therapy, and to the question of how much mutant huntingtin may need to be lowered for a therapy to be clinically effective. We conclude that adverse consequences of lowering wtHTT in animals appear to be brain region-specific, and/or dependent upon the animal’s stage of development and the amount by which huntingtin is lowered. Therefore, safe approaches to huntingtin-lowering in patients may be to lower huntingtin only moderately, or lower huntingtin only in the most affected brain regions, or lower huntingtin allele-selectively, or all of the above. Many additional questions about huntingtin-lowering remain open, and will only be answered by upcoming clinical trials, such as whether the delivery approaches currently planned will be adequate to get the treatment to the necessary brain regions, and whether non-allele-selective huntingtin-lowering will be safe in the long run. Meantime, there is a role for preclinical research to address key knowledge gaps, including the effects of non-allele-selective huntingtin-lowering on protein trafficking and viability at the cellular level, the tolerability of wtHTT-lowering in the corticostriatal connections of the primate brain, and the effects of this lowering on the functioning of neurotransmitter systems and the transport of neurotrophic factors to the striatum.

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease.

Parkinson’s disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to striatal dopamine depletion. A partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion causes 40–60% dopamine depletion in the lesioned rat striatum, modeling the early stage of PD. In this study, we explored the connectivity between the brain regions in partially 6-OHDA lesioned male Wistar rats under urethane anesthesia using functional magnetic resonance imaging (fMRI) at 5 weeks after the 6-OHDA infusion. Under urethane anesthesia, the brain fluctuates between the two states, resembling rapid eye movement (REM) and non-REM sleep states. We observed clear urethane-induced sleep-like states in 8/19 lesioned animals and 8/18 control animals. 6-OHDA lesioned animals exhibited significantly lower functional connectivity between the brain regions. However, we observed these differences only during the REM-like sleep state, suggesting the involvement of the nigrostriatal dopaminergic pathway in REM sleep regulation. Corticocortical and corticostriatal connections were decreased in both hemispheres, reflecting the global effect of the lesion. Overall, this study describes a promising model to study PD-related sleep disorders in rats using fMRI.

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease.

BackgroundApathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited.ObjectivesTo disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease.MethodsForty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains.ResultsWe elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract.ConclusionsThe current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders.

Chronic psychosocial stressors are associated with alterations in salience processing and corticostriatal connectivity

Psychosocial stressors including childhood adversity, migration, and living in an urban environment, have been associated with several psychiatric disorders, including psychotic disorders. The neural and psychological mechanisms mediating this relationship remain unclear. In parallel, alterations in corticostriatal connectivity and abnormalities in the processing of salience, are seen in psychotic disorders. Aberrant functioning of these mechanisms secondary to chronic stress exposure, could help explain how common environmental exposures are associated with a diverse range of symptoms. In the current study, we recruited two groups of adults, one with a high degree of exposure to chronic psychosocial stressors (the exposed group, n = 20), and one with minimal exposure (the unexposed group, n = 22). All participants underwent a resting state MRI scan, completed the Aberrant Salience Inventory, and performed a behavioural task – the Salience Attribution Test (SAT). The exposed group showed reduced explicit adaptive salience scores (cohen's d = 0.69, p = 0.03) and increased aberrant salience inventory scores (d = 0.65, p = 0.04). The exposed group also showed increased corticostriatal connectivity between the ventral striatum and brain regions previously implicated in salience processing. Corticostriatal connectivity in these regions negatively correlated with SAT explicit adaptive salience (r = −0.48, p = 0.001), and positively correlated with aberrant salience inventory scores (r = 0.42, p = 0.006). Furthermore, in a mediation analysis there was tentative evidence that differences in striato-cortical connectivity mediated the group differences in salience scores.

Neural systems underlying reward cue processing in early adolescence: The role of puberty and pubertal hormones

Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10–13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence.

Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity

Cannabis is the most commonly used illicit drug and is known to alter state of consciousness and impair neurocognitive function. However, the mechanisms underlying these effects have yet to be fully elucidated. Rodent studies suggest that Δ9-tetrahydrocannabinol (THC) activates dopaminergic neurons in the limbic system, subsequently enhancing dopamine, which is implicated in the rewarding effects of cannabis. Additional evidence suggests that THC may act indirectly on dopamine firing by modulating GABA and glutamate release. This double-blind, placebo-controlled study assessed the acute influence of two doses of THC on brain kinetics of glutamate, GABA, and dopamine, in relation to behavioral outcomes, by using magnetic resonance spectroscopy and functional magnetic resonance imaging. Twenty occasional cannabis users received acute doses of cannabis (300 µg/kg THC) and placebo, in one of two dose regimes (full dose and divided dose), during two separate testing days. Administration of THC increased striatal glutamate concentrations, and dopamine as indicated by a reduction in functional connectivity (FC) between the nucleus accumbens (NAc) and cortical areas. Alterations in glutamate and FC were dose dependent and evident in the full dose group where THC serum concentrations exceeded 2 ng/ml at T-max. Average glutamate changes correlated strongly with FC alterations. Additionally, THC induced changes in FC correlated with feelings of subjective high and decreased performance on an attention task. Taken together, this suggests that THC elicits subjective and cognitive alterations via increased striatal dopaminergic activity and loss of corticostriatal connectivity, which is associated with an increase in striatal glutamate.

Functional MRI connectivity of children with autism and low verbal and cognitive performance

BackgroundFunctional neuroimaging research in autism spectrum disorder has reported patterns of decreased long-range, within-network, and interhemispheric connectivity. Research has also reported increased corticostriatal connectivity and between-network connectivity for default and attentional networks. Past studies have excluded individuals with autism and low verbal and cognitive performance (LVCP), so connectivity in individuals more significantly affected with autism has not yet been studied. This represents a critical gap in our understanding of brain function across the autism spectrum.MethodsUsing behavioral support procedures adapted from Nordahl, et al. (J Neurodev Disord 8:20–20, 2016), we completed non-sedated structural and functional MRI scans of 56 children ages 7–17, including LVCP children (n = 17, mean IQ = 54), children with autism and higher performance (HVCP, n = 20, mean IQ = 106), and neurotypical children (NT, n = 19, mean IQ = 111). Preparation included detailed intake questionnaires, video modeling, behavioral and anxiety reduction techniques, active noise-canceling headphones, and in-scan presentation of the Inscapes movie paradigm from Vanderwal et al. (Neuroimage 122:222–32, 2015). A high temporal resolution multiband echoplanar fMRI protocol analyzed motion-free time series data, extracted from concatenated volumes to mitigate the influence of motion artifact. All participants had > 200 volumes of motion-free fMRI scanning. Analyses were corrected for multiple comparisons.ResultsLVCP showed decreased within-network connectivity in default, salience, auditory, and frontoparietal networks (LVCP < HVCP) and decreased interhemispheric connectivity (LVCP < HVCP=NT). Between-network connectivity was higher for LVCP than NT between default and dorsal attention and frontoparietal networks. Lower IQ was associated with decreased connectivity within the default network and increased connectivity between default and dorsal attention networks.ConclusionsThis study demonstrates that with moderate levels of support, including readily available techniques, information about brain similarities and differences in LVCP individuals can be further studied. This initial study suggested decreased network segmentation and integration in LVCP individuals. Further imaging studies of LVCP individuals with larger samples will add to understanding of origins and effects of autism on brain function and behavior.

Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA–BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

Multi-echo fMRI, resting-state connectivity, and high psychometric schizotypy.

Disrupted striatal functional connectivity is proposed to play a critical role in the development of psychotic symptoms. Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies typically reported disrupted striatal connectivity in patients with psychosis and in individuals at clinical and genetic high risk of the disorder relative to healthy controls. This has not been widely studied in healthy individuals with subclinical psychotic-like experiences (schizotypy). Here we applied the emerging technology of multi-echo rs-fMRI to examine corticostriatal connectivity in this group, which is thought to drastically maximize physiological noise removal and increase BOLD contrast-to-noise ratio. Multi-echo rs-fMRI data (echo times, 12, 28, 44, 60 ms) were acquired from healthy individuals with low (LS, n = 20) and high (HS, n = 19) positive schizotypy as determined with the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). After preprocessing to ensure optimal contrast and removal of non-BOLD signal components, whole-brain functional connectivity from six striatal seeds was compared between the HS and LS groups. Effects were considered significant at cluster-level p < .05 family-wise error correction. Compared to LS, HS subjects showed lower rs-fMRI connectivity between ventromedial prefrontal regions and ventral striatal regions. Lower connectivity was also observed between the dorsal putamen and the hippocampus, occipital regions, as well as the cerebellum. These results demonstrate that subclinical positive psychotic-like experiences in healthy individuals are associated with striatal hypoconnectivity as detected using multi-echo rs-fMRI. Further application of this approach may aid in characterizing functional connectivity abnormalities across the extended psychosis phenotype.

Biomarkers of Parkinson's disease: Striatal sub-regional structural morphometry and diffusion MRI.

Parkinson's disease (PD) is a progressive neurological disorder that has no reliable biomarkers. The aim of this study was to explore the potential of semi-automated sub-regional analysis of the striatum with magnetic resonance imaging (MRI) to distinguish PD patients from controls (i.e., as a diagnostic biomarker) and to compare PD patients at different stages of disease.With 3 Tesla MRI, diffusion- and T1-weighted scans were obtained on two occasions in 24 PD patients and 18 age-matched, healthy controls. PD patients completed one session on and the other session off dopaminergic medication. The striatum was parcellated into seven functionally disparate sub-regions. The segmentation was guided by reciprocal connections to distinct cortical regions. Volume, surface-based morphometry, and integrity of white matter connections were calculated for each striatal sub-region.Test-retest reliability of our volume, morphometry, and white matter integrity measures across scans was high, with correlations ranging from r = 0.452, p < 0.05 and r = 0.985, p < 0.001. Global measures of striatum such as total striatum, nucleus accumbens, caudate nuclei, and putamen were not significantly different between PD patients and controls, indicating poor sensitivity of these measures, which average across sub-regions that are functionally heterogeneous and differentially affected by PD, to act as diagnostic biomarkers. Further, these measures did not correlate significantly with disease severity, challenging their potential to serve as progression biomarkers. In contrast, a) decreased volume and b) inward surface displacement of caudal-motor striatum—the region first and most dopamine depleted in PD—distinguished PD patients from controls. Integrity of white matter cortico-striatal connections in caudal-motor and adjacent striatal sub-regions (i.e., executive and temporal striatum) was reduced for PD patients relative to controls. Finally, volume of limbic striatum, the only striatal sub-region innervated by the later-degenerating ventral tegmental area in PD, was reduced in later-stage compared to early stage PD patients a potential progression biomarker.Segmenting striatum based on distinct cortical connectivity provided highly sensitive MRI measures for diagnosing and staging PD.

P35. Cortico-striatal functional connectivity in Huntington’s disease measured with high-field functional MRI: A biomarker for disease progression?

Background Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by CAG expansion in the Huntingtin gene. HD manifests by involuntary movements, cognitive and behavioral changes. The approximate time-to-onset can be predicted from the length of CAG repeat in HD subjects, which allows for the identification of subjects in the pre-manifest stage of HD, who do not have symptoms or structural brain changes (atrophy). Disease modifying treatment may have special value if it is initiated in the premanifest stage of HD, before structural brain changes occur. Aim Cortico-striatal functional connectivity may be altered in HD many years before symptoms onset. Thus cortico-striatal functional connectivity as assess by functional Magnetic Resonance Imaging (fMRI) may be a promising biomarker to be used for trials of disease modifying treatment. In particular, fMRI may of special interest to assess disease progression in HD subjects in the pre-manifest stage who do not have symptoms clinically. Question Is cortico-striatal functional connectivity in HD as assessed by fMRI at 7 T a biomarker for disease progression? Method We assessed 24 pre-manifest HD subjects, 12 manifest HD subjects as well as 16 healthy controls at baseline. 13 HD subjects (9 in the pre-manifest stage of HD) and 8 healthy controls participated in a one year follow-up study. The functional connectivity between the striatum and several cortical areas were analysis. Two tailed t-test was applied. ANOVA was used for the analysis of the one year follow-up data with group as between-subjects factor and time as within-subjects factor. Results Functional connectivity between striatum and supplementary motor area was impaired comparing manifest HD subjects with controls (p = 0.01) and premanifest HD subjects with controls (p = 0.03) at baseline. At the one year follow-up, functional connectivity between striatum and premotor area was impaired comparing manifest HD subjects with controls (group p = 0.002, time p = 0.04, group by time p = 0.02). Likewise, premanifest HD subjects showed decline compared to control subjects over time (group p Conclusion These data indicate progressive impairment of functional connectivity between striatum and premotor area in HD subjects. Assessment of cortico-striatal functional connectivity by fMRI is a promising biomarker to assess disease progression including the premanifest stage of HD, when subjects do not have symptoms.

Novelty modulates human striatal activation and prefrontal\u2013striatal effective connectivity during working memory encoding

The functional role of the basal ganglia (BG) in the gating of suitable motor responses to the cortex is well established. Growing evidence supports an analogous role of the BG during working memory encoding, a task phase in which the “input-gating” of relevant materials (or filtering of irrelevant information) is an important mechanism supporting cognitive capacity and the updating of working memory buffers. One important aspect of stimulus relevance is the novelty of working memory items, a quality that is understudied with respect to its effects on corticostriatal function and connectivity. To this end, we used functional magnetic resonance imaging (fMRI) in 74 healthy volunteers performing an established Sternberg working memory task with different task phases (encoding vs. retrieval) and degrees of stimulus familiarity (novel vs. previously trained). Activation analyses demonstrated a highly significant engagement of the anterior striatum, in particular during the encoding of novel working memory items. Dynamic causal modeling (DCM) of corticostriatal circuit connectivity identified a selective positive modulatory influence of novelty encoding on the connection from the dorsolateral prefrontal cortex (DLPFC) to the anterior striatum. These data extend prior research by further underscoring the relevance of the BG for human cognitive function and provide a mechanistic account of the DLPFC as a plausible top-down regulatory element of striatal function that may facilitate the “input-gating” of novel working memory materials.

Corticostriatal Connectivity in Antisocial Personality Disorder by MAO-A Genotype and Its Relationship to Aggressive Behavior.

BackgroundThe influence of genetic variation on resting-state neural networks represents a burgeoning line of inquiry in psychiatric research. Monoamine oxidase A, an X-linked gene, is one example of a molecular target linked to brain activity in psychiatric illness. Monoamine oxidase A genetic variants, including the high and low variable nucleotide tandem repeat polymorphisms, have been shown to differentially affect brain functional connectivity in healthy humans. However, it is currently unknown whether these same polymorphisms influence resting-state brain activity in clinical conditions. Given its high burden on society and strong connection to violent behavior, antisocial personality disorder is a logical condition to study, since in vivo markers of monoamine oxidase A brain enzyme are reduced in key affect-modulating regions, and striatal levels of monoamine oxidase A show a relation with the functional connectivity of this same region.MethodsWe utilized monoamine oxidase A genotyping and seed-to-voxel-based functional connectivity to investigate the relationship between genotype and corticostriatal connectivity in 21 male participants with severe antisocial personality disorder and 19 male healthy controls.ResultsDorsal striatal connectivity to the frontal pole and anterior cingulate gyrus differentiated antisocial personality disorder subjects and healthy controls by monoamine oxidase A genotype. Furthermore, the linear relationship of proactive aggression to superior ventral striatal-angular gyrus functional connectivity differed by monoamine oxidase A genotype in the antisocial personality disorder groups.ConclusionsThese results suggest that monoamine oxidase A genotype may affect corticostriatal connectivity in antisocial personality disorder and that these functional connections may also underlie use of proactive aggression in a genotype-specific manner.

Nicotine normalizes cortico-striatal connectivity in non-smoking individuals with major depressive disorder.

Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc-rACC and a trend for enhanced DS-DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine's effects on NAc-rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine's ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine's influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.