Erratum: Resting state functional connectivity of the rat claustrum.

[This corrects the article DOI: 10.3389/fnana.2019.00022.].

Examining putamen resting-state connectivity markers of suicide attempt history in depressed adolescents.

Introduction: Suicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt. Methods: We examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male). Results: Only the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p<.001, cluster-wise p<.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted. Discussion: The results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome.

An Autopsy Case of Dextromethorphan Poisoning.

A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 µg/ml at admission and 1.61 µg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.

Predictors associated with the rate of progression of nigrostriatal degeneration in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. METHODS: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. RESULTS: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. DISCUSSION: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.

Localization of stuttering based on causal brain lesions.

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.

Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking.

The dorsal striatum is composed of the caudate nucleus and the putamen in human and non-human primates. These two regions receive different cortical projections and are functionally distinct. The caudate is involved in the control of goal-directed behaviors, while the putamen is implicated in habit learning and formation. Previous reports indicate that ethanol differentially influences neurotransmission in these two regions. Because neurotransmitters primarily signal through G protein-coupled receptors (GPCRs) to modulate neuronal activity, the present study aimed to determine whether ethanol had a region-dependent impact on the expression of proteins that are involved in the trafficking and function of GPCRs, including G protein subunits and their effectors, protein kinases, and elements of the cytoskeleton. Western blotting was performed to examine protein levels in the caudate and the putamen of male cynomolgus macaques that self-administered ethanol for 1 year under free access conditions, along with control animals that self-administered an isocaloric sweetened solution under identical operant conditions. Among the 18 proteins studied, we found that the levels of one protein (PKCß) were increased, and 13 proteins (Gαi1/3, Gαi2, Gαo, Gß1γ, PKCα, PKCε, CaMKII, GSK3ß, ß-actin, cofilin, α-tubulin, and tubulin polymerization promoting protein) were reduced in the caudate of alcohol-drinking macaques. However, ethanol did not alter the expression of any proteins examined in the putamen. These observations underscore the unique vulnerability of the caudate nucleus to changes in protein expression induced by chronic ethanol exposure. Whether these alterations are associated with ethanol-induced dysregulation of GPCR function and neurotransmission warrants future investigation.

The well-worn route revisited: Striatal and hippocampal system contributions to familiar route navigation.

Classic research has shown a division in the neuroanatomical structures that support flexible (e.g., short-cutting) and habitual (e.g., familiar route following) navigational behavior, with hippocampal-caudate systems associated with the former and putamen systems with the latter. There is, however, disagreement about whether the neural structures involved in navigation process particular forms of spatial information, such as associations between constellations of cues forming a cognitive map, versus single landmark-action associations, or alternatively, perform particular reinforcement learning algorithms that allow the use of different spatial strategies, so-called model-based (flexible) or model-free (habitual) forms of learning. We sought to test these theories by asking participants (N = 24) to navigate within a virtual environment through a previously learned, 9-junction route with distinctive landmarks at each junction while undergoing functional magnetic resonance imaging (fMRI). In a series of probe trials, we distinguished knowledge of individual landmark-action associations along the route versus knowledge of the correct sequence of landmark-action associations, either by having absent landmarks, or "out-of-sequence" landmarks. Under a map-based perspective, sequence knowledge would not require hippocampal systems, because there are no constellations of cues available for cognitive map formation. Within a learning-based model, however, responding based on knowledge of sequence would require hippocampal systems because prior context has to be utilized. We found that hippocampal-caudate systems were more active in probes requiring sequence knowledge, supporting the learning-based model. However, we also found greater putamen activation in probes where navigation based purely on sequence memory could be planned, supporting models of putamen function that emphasize its role in action sequencing.

Parkinson's disease and Parkinsonism syndromes: Evaluating iron deposition in the putamen using magnetic susceptibility MRI techniques - A systematic review and literature analysis.

Magnetic resonance imaging (MRI) techniques, such as quantitative susceptibility mapping (QSM) and susceptibility-weighted imaging (SWI), can detect iron deposition in the brain. Iron accumulation in the putamen (PUT) can contribute to the pathogenesis of Parkinson's disease (PD) and atypical Parkinsonian disorders. This systematic review aimed to synthesize evidence on iron deposition in the PUT assessed by MRI susceptibility techniques in PD and Parkinsonism syndromes. The PubMed and Scopus databases were searched for relevant studies. Thirty-four studies from January 2007 to October 2023 that used QSM, SWI, or other MRI susceptibility methods to measure putaminal iron in PD, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and healthy controls (HCs) were included. Most studies have found increased putaminal iron levels in PD patients versus HCs based on higher quantitative susceptibility. Putaminal iron accumulation correlates with worse motor scores and cognitive decline in patients with PD. Evidence regarding differences in susceptibility between PD and atypical Parkinsonism is emerging, with several studies showing greater putaminal iron deposition in PSP and MSA than in PD patients. Alterations in putaminal iron levels help to distinguish these disorders from PD. Increased putaminal iron levels appear to be associated with increased disease severity and progression. Thus, magnetic susceptibility MRI techniques can detect abnormal iron accumulation in the PUT of patients with Parkinsonism. Moreover, quantifying putaminal susceptibility may serve as an MRI biomarker to monitor motor and cognitive changes in PD and aid in the differential diagnosis of Parkinsonian disorders.

Putamen iron quantification in diseases with neurodegeneration: a meta-analysis of the quantitative susceptibility mapping technique.

Quantitative susceptibility mapping (QSM) is an MRI technique that accurately measures iron concentration in brain tissues. This meta-analysis synthesized evidence from 30 studies that used QSM to quantify the iron levels in the putamen. The PRISMA statement was adhered to when conducting the systematic reviews and meta-analyses. We conducted a meta-analysis using a random-effects model, as well as subgroup analyses (disease type, geographic region, field strength, coil, disease type, age, and sex) and sensitivity analysis. A total of 1247 patients and 1035 controls were included in the study. Pooled results showed a standardized mean difference (SMD) of 0.41 (95% CI 0.19 to 0.64), with the strongest effect seen in Alzheimer's disease (AD) at 1.01 (95% CI 0.50 to 1.52). Relapsing-remitting multiple sclerosis (RRMS) also showed increased putaminal iron at 0.37 (95% CI 0.177 to 0.58). No significant differences were observed in Parkinson's disease (PD). No significant differences were found between subgroups based on geographic region, field strength, coil, disease type, age, and sex. The studies revealed significant heterogeneity, with field strength as the primary source, while other factors, such as disease type, location, age, sex, and coil type, may have contributed. The sensitivity analysis showed that these factors did not have a significant influence on the overall results. In summary, this meta-analysis supports abnormalities in putaminal iron content across different diseases with neurodegeneration, especially AD and RRMS, as measured by QSM. This highlights the potential of QSM as an imaging biomarker to better understand disease mechanisms involving disturbances in brain iron homeostasis.

Revealing the spatiotemporal brain dynamics of covert speech compared with overt speech: A simultaneous EEG-fMRI study.

Covert speech (CS) refers to speaking internally to oneself without producing any sound or movement. CS is involved in multiple cognitive functions and disorders. Reconstructing CS content by brain-computer interface (BCI) is also an emerging technique. However, it is still controversial whether CS is a truncated neural process of overt speech (OS) or involves independent patterns. Here, we performed a word-speaking experiment with simultaneous EEG-fMRI. It involved 32 participants, who generated words both overtly and covertly. By integrating spatial constraints from fMRI into EEG source localization, we precisely estimated the spatiotemporal dynamics of neural activity. During CS, EEG source activity was localized in three regions: the left precentral gyrus, the left supplementary motor area, and the left putamen. Although OS involved more brain regions with stronger activations, CS was characterized by an earlier event-locked activation in the left putamen (peak at 262 ms versus 1170 ms). The left putamen was also identified as the only hub node within the functional connectivity (FC) networks of both OS and CS, while showing weaker FC strength towards speech-related regions in the dominant hemisphere during CS. Path analysis revealed significant multivariate associations, indicating an indirect association between the earlier activation in the left putamen and CS, which was mediated by reduced FC towards speech-related regions. These findings revealed the specific spatiotemporal dynamics of CS, offering insights into CS mechanisms that are potentially relevant for future treatment of self-regulation deficits, speech disorders, and development of BCI speech applications.

Larger putamen in individuals at risk and with manifest bipolar disorder.

BACKGROUND: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. METHODS: In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. RESULTS: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. CONCLUSIONS: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

Grey matter alterations in generalized anxiety disorder: A voxel-wise meta-analysis of voxel-based morphometry studies.

OBJECTIVE: Grey matter, a crucial component of the brain, has been found altered in generalized anxiety disorder (GAD) of several voxel-based morphometry studies. The conclusive and consistent grey matter alterations in GAD have not been confirmed. METHOD: Eleven voxel-based morphometry studies of GAD patients were included in the current systematic review and meta-analysis. The linear model of anxiety severity scores was applied to explore the relationship of grey matter alterations and anxiety severity. The subgroup analysis of adult GAD and adolescent GAD was also performed. RESULTS: Significantly modest grey matter alterations in the left superior temporal gyrus of patients with GAD were found. The anxiety severity score was significantly correlated with grey matter alterations in the right insula, lenticular nucleus, putamen and striatum. The subgroup analysis of adult GAD and adolescent GAD all failed to show significant grey matter alterations. However, in the adult GAD subgroup, anxiety severity score was significantly correlated with grey matter alterations in the right insula. CONCLUSION: GAD might have the modest grey matter alterations in the left superior temporal gyrus. Anxiety severity might be related to the grey matter alterations in the limbic regions, such as the right insula, lenticular nucleus, putamen and striatum. This kind of correlation might be related to the effects of adult GAD. Future studies with adequate sample sizes and sophisticated GAD categories will be needed.

Differential Cortical and Subcortical Activations during Different Stages of Muscle Control: A Functional Magnetic Resonance Imaging Study.

Movement and muscle control are crucial for the survival of all free-living organisms. This study aimed to explore differential patterns of cortical and subcortical activation across different stages of muscle control using functional magnetic resonance imaging (fMRI). An event-related design was employed. In each trial, participants (n = 10) were instructed to gently press a button with their right index finger, hold it naturally for several seconds, and then relax the finger. Neural activation in these temporally separated stages was analyzed using a General Linear Model. Our findings revealed that a widely distributed cortical network, including the supplementary motor area and insula, was implicated not only in the pressing stage, but also in the relaxation stage, while only parts of the network were involved in the steady holding stage. Moreover, supporting the direct/indirect pathway model of the subcortical basal ganglia, their substructures played distinct roles in different stages of muscle control. The caudate nucleus exhibited greater involvement in muscle contraction, whereas the putamen demonstrated a stronger association with muscle relaxation; both structures were implicated in the pressing stage. Furthermore, the subthalamic nucleus was exclusively engaged during the muscle relaxation stage. We conclude that even the control of simple muscle movements involves intricate automatic higher sensory-motor integration at a neural level, particularly when coordinating relative muscle movements, including both muscle contraction and muscle relaxation; the cortical and subcortical regions assume distinct yet coordinated roles across different stages of muscle control.

A dynamic computational model of the parallel circuit on the basal ganglia-cortex associated with Parkinson's disease dementia.

The cognitive impairment will gradually appear over time in Parkinson's patients, which is closely related to the basal ganglia-cortex network. This network contains two parallel circuits mediated by putamen and caudate nucleus, respectively. Based on the biophysical mean-field model, we construct a dynamic computational model of the parallel circuit in the basal ganglia-cortex network associated with Parkinson's disease dementia. The simulated results show that the decrease of power ratio in the prefrontal cortex is mainly caused by dopamine depletion in the caudate nucleus and is less related to that in the putamen, which indicates Parkinson's disease dementia may be caused by a lesion of the caudate nucleus rather than putamen. Furthermore, the underlying dynamic mechanism behind the decrease of power ratio is investigated by bifurcation analysis, which demonstrates that the decrease of power ratio is due to the change of brain discharge pattern from the limit cycle mode to the point attractor mode. More importantly, the spatiotemporal course of dopamine depletion in Parkinson's disease patients is well simulated, which states that with the loss of dopaminergic neurons projecting to the striatum, motor dysfunction of Parkinson's disease is first observed, whereas cognitive impairment occurs after a period of onset of motor dysfunction. These results are helpful to understand the pathogenesis of cognitive impairment and provide insights into the treatment of Parkinson's disease dementia.

The longitudinal volumetric and shape changes of subcortical nuclei in Parkinson's disease.

Brain structural changes in Parkinson's disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson's Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.

Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy. Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS. Methods: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis. Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes. Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.

Hyperglycemia-Induced Complete Left-Sided Hemiballismus Due to Uncontrolled Diabetes in a 70-Year-Old Female: A Case Report.

This report details the presentation of a 72-year-old female with left-sided continuous non-rhythmic involuntary movements persisting for two months. The movements affected the left side of her face, arm, and leg. The patient had a history of multiple hyperglycemic episodes and diabetic ketoacidosis. This report investigates the basal ganglia's involvement in hemiballismus, a movement disorder possibly linked to the patient's hyperglycemia. It discusses the complex management of hyperglycemia-induced hemiballismus and the need for more research to understand the underlying mechanism and optimal treatment strategies.

Brain structural correlates of subjective sleepiness and insomnia symptoms in shift workers.

Background: Studies on the brain structures of shift workers are limited; thus, this cross-sectional study aimed to compare the brain structures and the brain structural correlates of subjective sleepiness and insomnia symptoms between shift workers and non-shift workers. Methods: Shift workers (n = 63) and non-shift workers (n = 58) completed questionnaires assessing subjective sleepiness and insomnia symptoms. Cortical thickness, cortical surface area, and subcortical volumes were measured by magnetic resonance imaging. The brain morphometric measures were compared between the groups, and interaction analyses using the brain morphometric measures as the dependent variable were performed to test the interactions between the study group and measures of sleep disturbance (i.e., subjective sleepiness and insomnia symptoms). Results: No differences in cortical thickness, cortical surface area, or subcortical volumes were detected between shift workers and non-shift workers. A single cluster in the left motor cortex showed a significant interaction between the study group and subjective sleepiness in the cortical surface area. The correlation between the left motor cortex surface area and the subjective sleepiness level was negative in shift workers and positive in non-shift workers. Significant interaction between the study group and insomnia symptoms was present for the left/right putamen volumes. The correlation between the left/right putamen volumes and insomnia symptom levels was positive in shift workers and negative in non-shift workers. Conclusion: Left motor cortex surface area and bilateral putamen volumes were unique structural correlates of subjective sleepiness and insomnia symptoms in shift workers, respectively.

Comparative Roles of the Caudate and Putamen in the Serial Order of Behavior: Effects of Striatal Glutamate Receptor Blockade on Variable versus Fixed Spatial Self-Ordered Sequencing in Marmosets.

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.