Frontostriatal Function Research Articles

Cognitive phenotyping of GBA1-Parkinson's disease: A study on deep brain stimulation outcomes

BackgroundHeterozygous variants in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson's Disease (PD). GBA1-PD patients exhibit earlier disease onset, severe motor impairment, and heightened cognitive decline. Deep Brain Stimulation (DBS) offers motor improvement for PD patients, but its cognitive effects, particularly in GBA1-PD, are debated. MethodsThis study involved 96 PD patients who underwent subthalamic nucleus DBS at Hospital de la Santa Creu i Sant Pau between 2004 and 2023. Clinical and neuropsychological assessments were conducted pre- and post-surgery, focusing on Mattis Dementia Rating Scale (MDRS) and Frontal Systems Behavior Scale (FrSBe). Patients were categorized into GBA1-PD and non-GBA1-PD groups, with non-GBA1-PD further divided into cognitive fast-progressors and slow-progressors. ResultsGBA1 variants were present in 13.5 % of patients. GBA1-PD patients showed greater cognitive decline over time, particularly in attention, conceptualization, and memory, compared to non-GBA1-PD. Non-GBA1-PD fast-progressors exhibited significant cognitive deterioration in initiation and conceptualization within the first year post-DBS. Motor outcomes improved similarly across all groups, but slow-progressors showed a greater reduction in Levodopa Equivalent Daily Dose (LEDD). ConclusionsGBA1-PD patients experience more rapid cognitive decline, particularly in posterior-cortical and fronto-striatal functions. Additionally, a subset of non-GBA1-PD patients shows significant early cognitive decline post-DBS, especially in executive functions. Baseline MDRS scores do not predict cognitive outcomes, highlighting the need for further research to refine prognostic tools. Despite cognitive challenges, GBA1-PD patients benefit from DBS in terms of motor outcomes, underscoring the importance of individualized assessments for DBS suitability, regardless of genetic status.

HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits.

BackgroundHIV-associated neurocognitive disorder (HAND) is commonly observed in persons living with HIV (PWH) and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in animals.MethodsPPI was measured in male and female HIVtg rats and wild-type controls following acute, nonconcurrent treatment with the primary constituents of cannabis: Δ 9-tetrahydrocannabinol (THC; 1 and 3 mg/kg, s.c.) and cannabidiol (1, 10, and 30 mg/kg, i.p.).ResultsHIVtg rats exhibited a significant PPI deficit relative to wild-type controls. THC reduced PPI in controls but not HIVtg rats. Cannabidiol exerted only minor, genotype-independent effects on PPI.ConclusionsHIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use among PWH.

Baseline Function in Reward Circuitry in Adolescents With Anxiety Distinguishes Cognitive Behavioral Therapy Responders and Non-Responders

Function in frontostriatal reward circuitry is altered in youth with anxiety. While variability in this circuitry predicts treatment response in adolescent depression, it is unclear whether it contributes similarly to response in adolescent anxiety. We hypothesized that a more typical pattern of frontostriatal function—greater ventral striatum (VS) response, weaker prefrontal-VS connectivity—would characterize anxious adolescents who respond to psychosocial treatment.

Unraveling the Temporal Dynamics of Reward Signals in Music-Induced Pleasure with TMS.

Music's ability to induce feelings of pleasure has been the subject of intense neuroscientific research lately. Prior neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits related to the anticipation and receipt of biologically relevant rewards/incentives, but these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by applying transcranial magnetic stimulation (TMS) over the left dorsolateral PFC combined with fMRI in 17 male and female participants. Behaviorally, we found that, in accord with previous findings, excitation of fronto-striatal pathways enhanced subjective reports of music-induced pleasure and motivation, whereas inhibition of the same circuitry led to the reduction of both. fMRI activity patterns indicated that these behavioral changes were driven by bidirectional TMS-induced alteration of fronto-striatal function. Specifically, changes in activity in the NAcc predicted modulation of both hedonic and motivational responses, with a dissociation between pre-experiential versus experiential components of musical reward. In addition, TMS-induced changes in the fMRI functional connectivity between the NAcc and frontal and auditory cortices predicted the degree of modulation of hedonic responses. These results indicate that the engagement of cortico-striatal pathways and the NAcc, in particular, is indispensable to experience rewarding feelings from music.SIGNIFICANCE STATEMENT Neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits involved in the processing of biologically relevant rewards. Yet, these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by combining brain stimulation over the frontal cortex with functional imaging. Behaviorally, we found that excitation and inhibition of fronto-striatal pathways enhanced and disrupted, respectively, subjective reports of music-induced pleasure and motivation. These changes were associated with changes in NAcc activity and NAcc coupling with frontal and auditory cortices, dissociating between pre-experimental versus experiential components of musical reward. These results indicate that the engagement of cortico-striatal pathways, and the NAcc in particular, is indispensable to experience rewarding feeling from music.

From discourse to pathology: Automatic identification of Parkinson's disease patients via morphological measures across three languages

Embodied cognition research on Parkinson's disease (PD) points to disruptions of frontostriatal language functions as sensitive targets for clinical assessment. However, no existing approach has been tested for crosslinguistic validity, let alone by combining naturalistic tasks with machine-learning tools. To address these issues, we conducted the first classifier-based examination of morphological processing (a core frontostriatal function) in spontaneous monologues from PD patients across three typologically different languages. The study comprised 330 participants, encompassing speakers of Spanish (61 patients, 57 matched controls), German (88 patients, 88 matched controls), and Czech (20 patients, 16 matched controls). All subjects described the activities they perform during a regular day, and their monologues were automatically coded via morphological tagging, a computerized method that labels each word with a part-of-speech tag (e.g., noun, verb) and specific morphological tags (e.g., person, gender, number, tense). The ensuing data were subjected to machine-learning analyses to assess whether differential morphological patterns could classify between patients and controls and reflect the former's degree of motor impairment. Results showed robust classification rates, with over 80% of patients being discriminated from controls in each language separately. Moreover, the most discriminative morphological features were associated with the patients' motor compromise (as indicated by Pearson r correlations between predicted and collected motor impairment scores that ranged from moderate to moderate-to-strong across languages). Taken together, our results suggest that morphological patterning, an embodied frontostriatal domain, may be distinctively affected in PD across languages and even under ecological testing conditions.

Acetylcholine Muscarinic M4 Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents

BackgroundAlcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function. MethodsWe performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate–putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target. ResultsWe found that G protein–coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M4 muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M4 mAChR, specifically on dopamine D1 receptor–expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M4 mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking. ConclusionsCollectively, these results identify the M4 mAChR as a potential therapeutic target for the treatment of AUD and the D1 receptor–positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M4 mAChR in relation to alcohol consumption and seeking.

Efavirenz is associated with altered fronto-striatal function in HIV+ adolescents.

Neurotoxicity associated with the antiretroviral efavirenz (EFV) has been documented in HIV-infected adults, but there are no data on the impact of EFV on brain function in adolescents. We investigated potential alterations in fronto-striatal function associated with EFV use in adolescents. A total of 86 adolescents underwent a Stop Signal Anticipation Task (SSAT) during functional MRI (fMRI), 39 HIV+ adolescents receiving EFV, 27 HIV+ adolescents on antiretroviral therapy without EFV (matched on age, gender, education, CD4 cell count and HIV viral load) and 20 HIV- matched controls (matched on age and gender). The task required participants to give timed GO responses with occasional STOP signals at fixed probabilities. Reactive inhibition was modelled as a correct STOP response and proactive inhibition was modelled after response slowing as the STOP probability increases. A priori mask-based regions associated with reactive and proactive inhibition were entered into two respective multivariate ANOVAs. The EFV treatment group showed significantly blunted proactive inhibitory behavioural responses compared to HIV+ adolescents not receiving EFV. There was no difference in reactive inhibition between treatment groups. We also demonstrated a significant effect of EFV treatment on BOLD signal in proactive inhibition regions. There was no difference in regions involved in reactive inhibition. We found no differences between adolescents not receiving EFV and HIV- controls, showing that functional and behavioural differences were unique to the EFV group. Here, we demonstrate for the first time a potential adverse impact of EFV on higher cortical function in young HIV+ adolescents.

Deficient Functioning of Frontostriatal Circuits Duringthe Resolution of Cognitive Conflict in Cannabis-Using Youth.

Disturbances in self-regulatory control are involved in the initiation and maintenance of addiction, including cannabis use disorder. In adults, long-term cannabis use is associated with disturbances in frontostriatal circuits during tasks that require the engagement of self-regulatory control, including the resolution of cognitive conflict. Understudied are the behavioral and neural correlates of these processes earlier in the course of cannabis use disentangled from effects of long-term use. The present study investigated the functioning of frontostriatal circuits during the resolution of cognitive conflict in cannabis-using youth. Functional magnetic resonance imaging data were acquired from 28 cannabis-using youth and 32 age-matched healthy participants during the performance of a Simon task. General linear modeling was used to compare patterns of brain activation during correct responses to conflict stimuli across groups. Psychophysiologic interaction analyses were used to examine conflict-related frontostriatal connectivity across groups. Associations of frontostriatal activation and connectivity with cannabis use measures were explored. Decreased conflict-related activity was detected in cannabis-using versus healthy control youth in frontostriatal regions, including the ventromedial prefrontal cortex, striatum, pallidum, and thalamus. Frontostriatal connectivity did not differ across groups, but negative connectivity between the ventromedial prefrontal cortex and striatum was detected in the 2 groups. These findings are consistent with previous reports of cannabis-associated disturbances in frontostriatal circuits in adults and point to the specific influence of cannabis on neurodevelopmental changes in youth. Future studies should examine whether frontostriatal functioning is a reliable marker of cannabis use disorder severity and a potential target for circuit-based interventions.

Modulating musical reward sensitivity up and down with transcranial magnetic stimulation.

Humans have the unique capacity to experience pleasure from aesthetic stimuli, such as art and music. Recent neuroimaging findings with music have led to a model in which mesolimbic striatal circuits interact with cortical systems to generate expectancies leading to pleasure 1,2 . However, neuroimaging approaches are correlational. Here, we provide causal evidence for the model by combining transcranial magnetic stimulation over the left dorsolateral prefrontal cortex to directly modulate fronto-striatal function 3 bidirectionally together with measures of pleasure and motivation during music listening. Our results show that perceived pleasure, psychophysiological measures of emotional arousal, and the monetary value assigned to music, are all significantly increased by exciting fronto-striatal pathways, whereas inhibition of this system leads to decreases in all of these variables compared with sham stimulation. These findings support the hypothesis that fronto-striatal function causally mediates both the affective responses and motivational aspects of music-induced reward, and provide insights into how aesthetic responses emerge in the human brain.

The effects of low dose MK-801 administration on NMDAR dependent executive functions in pigeons

An avian analogue of human fronto-executive dysfunction was used to study the long-term effects of a repeated low dose of MK-801. MK-801 is known to selectively antagonize the excitatory N-methyl-d-aspartate receptors (NMDAR) and indirectly impair inhibitory related processes (GABA-AR). First, eight pigeons were divided into two groups, receiving either 0.15mg/kg MK-801 or saline (i.p.) 1-hour prior to each session. Thirty 90-min sessions of a Differential Reinforcement of Low Rate of Response (DRL-10s) schedule were run over 3-months. Both overall number of responses and efficiency were unaffected by treatment, establishing a sub-threshold motoric dose. Then, another eight pigeons, treated identically, were given an operant visual discrimination task. Results demonstrated impairment of the fronto-striatal function of both excitatory and inhibitory processes in the MK-801 group during the entire 3-months. A 30-session treatment cross-over showed that the Saline-to-MK-801 group was unaffected, whereas the MK-801-to-Saline group exhibited rapid recovery of inhibitory control, however excitatory control did not fully recover. Together, these results suggested that the NMDAR system is involved in the acquisition of excitatory learning, but only in the expression of inhibitory learning. Our findings were discussed in terms of the value of avian models in translational research. Furthermore, our results were examined within the context of the NIH Research Domain of Criteria initiative and the role of NMDAR disruption, which underlie executive dysfunction in various neuropsychiatric disorders. Finally, our findings suggested that the potential long-term effects of the clinical and recreational use of NMDAR antagonists require further study.

COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes.

BackgroundCompulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto-striatal functioning, which may be related to altered glutamatergic signalling. Genetic factors are also thought to play an important role in the aetiology of compulsivity-related disorders.MethodsThe COMPULS study is a multi-center study designed to investigate the relationship between the traits compulsivity, impulsivity, and, to a lesser extent, addictive behaviour within and across the neurodevelopmental disorders ADHD, ASD, and OCD. This will be done at the phenotypic, cognitive, neural, and genetic level. In total, 240 participants will take part in COMPULS across four different sites in Europe. Data collection will include diagnostic interviews, behavioural questionnaires, cognitive measures, structural, functional and spectral neuroimaging, and genome-wide genetic information.DiscussionThe COMPULS study will offer the unique opportunity to investigate several key aspects of compulsivity across a large cohort of ADHD, ASD and OCD patients.

Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal-Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity

BackgroundA recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity. MethodsMultiecho resting-state acquisition, combined with micromovement correction by blood oxygen level–dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal-directed performance (planning of sequential response sequences) by means of well-validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal-directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived. ResultsReduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects. ConclusionsThese data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms.

Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

BackgroundSchizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits.MethodsWe recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design.ResultsAfter placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals.ConclusionsThese results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

Diminishing striatal activation across adolescent development during reward anticipation in offspring of schizophrenia patients

Schizophrenia is a severe psychiatric disorder associated with impaired fronto-striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto-striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10–19years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia.

Dopamine modulation of spatial navigation memory in Parkinson's disease

Striatal dopamine depletion is a key pathophysiological feature of Parkinson's disease (PD) causing motor and nonmotor symptoms. Research on nonmotor symptoms has mainly focused on frontostriatal functions. However, dopamine pathways ascending from the ventral tegmental area also innervate hippocampal structures and modulate hippocampal-dependent functions, such as spatial memory. Using a virtual spatial navigation task, we investigated dopaminergic modulation of spatial memory in PD patients in a crossover medication ON/OFF design. We examined medication effects on striatal- and hippocampal-dependent spatial memory by either replacing a location cue in the environment or enlarging its spatial boundary. Key results indicate that in contrast to prior evidence for younger adults, PD patients, like their age-matched controls, rely more on striatal cue-based than hippocampal spatial learning. Medication facilitated striatal-dependent cue-location learning, whereas medication benefit in hippocampal boundary-related spatial memory depended on prior experience with the task. Medication effects on spatial memory were comparable to and independent of benefits on motor symptoms. These findings shed new light on dopaminergic modulation of hippocampal-striatal functions in PD.

The nature of working memory gating in Parkinson's disease: A multi-domain signal detection examination.

Distractions are ubiquitous; our brains are inundated with task-irrelevant information. Thus, to remember successfully, one must actively maintain relevant information and prevent distraction from entering working memory. Researchers suggest the basal ganglia-prefrontal pathways are vital to this process by acting as a working memory gate. Using Parkinson's disease as a model of frontostriatal functioning and with signal detection analyses, the present study aims to better characterize the contribution of frontostriatal pathways of this gating process and to determine how it operates across multiple domains. To achieve this, Parkinson's disease patients and healthy controls completed verbal and spatial working memory tasks consisting of three conditions: low-load without distraction; low-load with distraction; and high-load without distraction. Patients were tested both ON and OFF dopaminergic medication, allowing for assessment of the contribution of dorsal and ventral frontostriatal pathways. The results demonstrate that when medication is withheld, Parkinson's patients have a response bias to answer "NO" across all conditions and domains, supporting our hypothesis that the basal ganglia-prefrontal pathways allow or prevent updates of working memory. Contrastingly, medication status affects d' in the distraction condition but not in the high- or low-load conditions. We attribute this to stimulus valuation processes that were impaired by dopaminergic medication overdosing the ventral pathway. These findings are both consistent with the hypothesis that the working memory gate filters spatial and verbal information before it enters into the working memory system, adding support for the gate being a domain-general mechanism of the central executive.

Forgetting the best when predicting the worst: Preliminary observations on neural circuit function in adolescent social anxiety

Social anxiety disorder typically begins in adolescence, a sensitive period for brain development, when increased complexity and salience of peer relationships requires novel forms of social learning. Disordered social learning in adolescence may explain how brain dysfunction promotes social anxiety. Socially anxious adolescents (n = 15) and adults (n = 19) and non-anxious adolescents (n = 24) and adults (n = 32) predicted, then received, social feedback from high and low-value peers while undergoing functional magnetic resonance imaging (fMRI). A surprise recall task assessed memory biases for feedback. Neural correlates of social evaluation prediction errors (PEs) were assessed by comparing engagement to expected and unexpected positive and negative feedback. For socially anxious adolescents, but not adults or healthy participants of either age group, PEs elicited heightened striatal activity and negative fronto-striatal functional connectivity. This occurred selectively to unexpected positive feedback from high-value peers and corresponded with impaired memory for social feedback. While impaired memory also occurred in socially-anxious adults, this impairment was unrelated to brain-based PE activity. Thus, social anxiety in adolescence may relate to altered neural correlates of PEs that contribute to impaired learning about social feedback. Small samples necessitate replication. Nevertheless, results suggest that the relationship between learning and fronto-striatal function may attenuate as development progresses.

An fMRI study of behavioral response inhibition in adolescents with and without histories of heavy prenatal alcohol exposure

Heavy prenatal alcohol exposure results in a range of deficits, including both volumetric and functional changes in brain regions involved in response inhibition such as the prefrontal cortex and striatum. The current study examined blood oxygen level-dependent (BOLD) response during a stop signal task in adolescents (ages 13–16y) with histories of heavy prenatal alcohol exposure (AE, n=21) and controls (CON, n=21). Task performance was measured using percent correct inhibits during three difficulty conditions: easy, medium, and hard. Group differences in BOLD response relative to baseline motor responding were examined across all inhibition trials and for each difficulty condition separately. The contrast between hard and easy trials was analyzed to determine whether increasing task difficulty affected BOLD response. Groups had similar task performance and demographic characteristics, except for full scale IQ scores (AE<CON). The AE group demonstrated greater BOLD response in frontal, sensorimotor, striatal, and cingulate regions relative to controls, especially as task difficulty increased. When contrasting hard vs. easy inhibition trials, the AE group showed greater medial/superior frontal and cuneus BOLD response than controls. Results were unchanged after demographics and FAS diagnosis were statistically controlled. This was the first fMRI study to utilize a stop signal task, isolating fronto-striatal functioning, to assess response inhibition and the effects task difficulty in adolescents with prenatal alcohol exposure. Results suggest that heavy prenatal alcohol exposure disrupts neural function of this circuitry, resulting in immature cognitive processing and motor-association learning and neural compensation during response inhibition.

SY38-3 * SIMILARITIES AND DIFFERENCES IN REWARD AND AVOIDANCE LEARNING IN OCD AND PROBLEM GAMBLERS

Learning to approach rewards (i.e., reward learning; RL) and to avoid punishers (i.e., avoidance learning; AL) is required to promote optimal responses and ensure our survival. For instance, AL is required in the face of basic threats (e.g., predators, rotten food), and when coupled with certain personality traits and decision-making patterns, also promotes optimal responses to more abstract threats in social (e.g., antagonists, competitors) and economic (e.g., risky investments) domains. However, difficulties or maladaptive patterns of AL and RL have been linked different forms of psychopathology. Indeed, AL is typically exaggerated in obsessive-compulsive disorder and reduced in substance and behavioural addictions (e.g., gambling), leading to differences in the anticipation and avoidance of aversive outcomes. In this talk, I will discuss the behavioural aspects of AL and RL (e.g., individual differences and temporal dynamics in learning from reward and punishment and prediction error) across OCD and problem gamblers using a newly developed task. I will then discuss how these individual differences are associated with the severity of the disorder, impulsive and compulsive personality tendencies, as well as fronto-striatal function.

The caudate: a key node in the neuronal network imbalance of insomnia?

Insomnia is prevalent, severe and partially heritable. Unfortunately, its neuronal correlates remain enigmatic, hampering the development of mechanistic models and rational treatments. Consistently reported impairments concern fragmented sleep, hyper-arousal and executive dysfunction. Because fronto-striatal networks could well play a role in sleep, arousal regulation and executive functioning, the present series of studies used an executive task to evaluate fronto-striatal functioning in disturbed sleep. Patients with insomnia showed reduced recruitment of the head of the left caudate nucleus during executive functioning, which was not secondary to altered performance or baseline perfusion. Individual differences in caudate recruitment were associated with hyper-arousal severity. Seed-based functional connectivity analysis suggested that attenuated input from a projecting orbitofrontal area with reduced grey matter density contributes to altered caudate recruitment in patients with insomnia. Attenuated caudate recruitment persisted after successful treatment of insomnia, warranting evaluation as a potential vulnerability trait. A similar selective reduction in caudate recruitment could be elicited in participants without sleep complaints by slow-wave sleep fragmentation, providing a model to facilitate investigation of the causes and consequences of insomnia.