Threat- and reward-related brain circuitry, perceived stress, and anxiety in adolescents during the COVID-19 pandemic: a longitudinal investigation.

The Coronavirus disease (COVID-19) pandemic led to heightened anxiety in adolescents. The basolateral amygdala (BLA) and the nucleus accumbens (NAcc) are implicated in response to stress and may contribute to anxiety. The role of threat- and reward-related circuitry in adolescent anxiety during the COVID-19 pandemic, however, is not clear. Ninety-nine adolescents underwent resting-state fMRI ∼1 year before the pandemic. Following shelter-in-place orders, adolescents reported their perceived stress and, 1 month later, their anxiety. Generalized multivariate analyses identified BLA and NAcc seed-based whole-brain functional connectivity maps with perceived stress. In the resulting significant clusters, we examined the association between seed-based connectivityand subsequent anxiety. Perceived stress was associated with bilateral BLA and NAcc connectivity across distributed clusters that included prefrontal, limbic, temporal, and cerebellar regions. Several NAcc connectivity clusters located in ventromedial prefrontal, parahippocampal, and temporal cortices were positively associated with anxiety; NAcc connectivity with the inferior frontal gyrus was negatively associated. BLA connectivity was not associated with anxiety. These results underscore the integrative role of the NAcc in responding to acute stressors and its relation to anxiety in adolescents. Elucidating the involvement of subcortical-cortical circuitry in adolescents' capacity to respond adaptively to environmental challenges can inform treatment for anxiety-related disorders.

Perception of social inclusion/exclusion and response inhibition in adolescents with past suicide attempt: a multidomain task-based fMRI study.

The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard clinical measures. Three groups of adolescents (N = 96; 78% females, age = 11.6-18.1) were included: patients with depressive disorders and previous suicide attempts (SA, n = 29); patient controls with depressive disorders but without any suicide attempt history (PC, n = 35); and healthy controls (HC, n = 32). We scanned participants with 3T-MRI during social inclusion/exclusion (Cyberball Game) and response inhibition (Go-NoGo) tasks. Neural activation was indexed by the blood-oxygenation-level dependent (BOLD) of the hemodynamic response during three conditions in the Cyberball Game ("Control condition", "Social Inclusion", and "Social Exclusion"), and two conditions in Go-NoGo task ("Go" and "NoGo" blocks). ANCOVA-style analysis identified group effects across three whole-brain contrasts: 1) NoGo vs. Go, 2) Social inclusion vs. control condition, 3) Social exclusion vs. control condition. We found that SA had lower activation in the left insula during social inclusion vs. control condition compared to PC and HC. Moreover, SA compared to PC had higher activity in the right middle prefrontal gyrus during social exclusion vs. control condition, and in bilateral precentral gyri during NoGo vs. Go conditions. Task-related behavioral and self-report measures (Self-reported emotional reactivity in the Cyberball Game, response times and number of errors in the Go-NoGo Task) did not discriminate groups. In conclusion, adolescent suicidal behaviors are likely associated with neural alterations related to the processing of social perception and response inhibition. Further research, involving prospective designs and diverse cohorts of patients, is necessary to explore the potential of neuroimaging as a tool in understanding the emergence and progression of suicidal behaviors.

Psychosocial interventions for the prevention of self-harm repetition: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Suicide is an important public health problem. Providing evidence-based psychosocial interventions to individuals presenting with self-harm is recognised as an important suicide prevention strategy. Therefore, it is crucial to understand which intervention is most effective in preventing self-harm repetition. We will evaluate the comparative efficacy of psychosocial interventions for the prevention of self-harm in adults. METHODS AND ANALYSIS: We will perform a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) testing psychosocial interventions for the prevention of self-harm repetition. We will include RCTs in adults (mean age: 18 years or more) who presented with self-harm in the 6 months preceding enrolment in the trial. Interventions will be categorised according to their similarities and underpinning theoretical approaches (eg, cognitive behavioural therapy, case management). A health sciences librarian will update and adapt the search strategy from the most recent Cochrane pairwise systematic review on this topic. The searches will be performed in MEDLINE (Ovid), Embase (Ovid), PsycInfo (Ovid), CINAHL (EBSCO), Cochrane Central (Wiley), Cochrane Protocols (Wiley), LILACS and PSYNDEX from 1 July 2020 (Cochrane review last search date) to 1 September 2023. The primary efficacy outcome will be self-harm repetition. Secondary outcomes will include suicide mortality, suicidal ideation and depressive symptoms. Retention in treatment (ie, drop-outs rates) will be analysed as the main acceptability outcome. Two reviewers will independently assess the study eligibility and risk of bias (using RoB-2). An NMA will be performed to synthesise all direct and indirect comparisons. Ranked forest plots and Vitruvian plots will be used to represent graphically the results of the NMA. Credibility of network estimates will be evaluated using Confidence in NMA (CINeMA). ETHICS AND DISSEMINATION: As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-review journals. TRIAL REGISTRATION NUMBER: CRD42021273057.

Correlates and predictors of the severity of suicidal ideation in adolescence: an examination of brain connectomics and psychosocial characteristics.

BACKGROUND: Suicidal ideation (SI) typically emerges during adolescence but is challenging to predict. Given the potentially lethal consequences of SI, it is important to identify neurobiological and psychosocial variables explaining the severity of SI in adolescents. METHODS: In 106 participants (59 female) recruited from the community, we assessed psychosocial characteristics and obtained resting-state fMRI data in early adolescence (baseline: aged 9-13 years). Across 250 brain regions, we assessed local graph theory-based properties of interconnectedness: local efficiency, eigenvector centrality, nodal degree, within-module z-score, and participation coefficient. Four years later (follow-up: ages 13-19 years), participants self-reported their SI severity. We used least absolute shrinkage and selection operator (LASSO) regressions to identify a linear combination of psychosocial and brain-based variables that best explain the severity of SI symptoms at follow-up. Nested-cross-validation yielded model performance statistics for all LASSO models. RESULTS: A combination of psychosocial and brain-based variables explained subsequent severity of SI (R2 = .55); the strongest was internalizing and externalizing symptom severity at follow-up. Follow-up LASSO regressions of psychosocial-only and brain-based-only variables indicated that psychosocial-only variables explained 55% of the variance in SI severity; in contrast, brain-based-only variables performed worse than the null model. CONCLUSIONS: A linear combination of baseline and follow-up psychosocial variables best explained the severity of SI. Follow-up analyses indicated that graph theory resting-state metrics did not increase the prediction of the severity of SI in adolescents. Attending to internalizing and externalizing symptoms is important in early adolescence; resting-state connectivity properties other than local graph theory metrics might yield a stronger prediction of the severity of SI.

Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of the role of puberty.

Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.

Heart rate variability moderates the effects of COVID-19-related stress and family adversity on emotional problems in adolescents: Testing models of differential susceptibility and diathesis stress.

The COVID-19 pandemic is a unique period of stress, uncertainty, and adversity that will have significant implications for adolescent mental health. Nevertheless, stress and adversity related to COVID-19 may be more consequential for some adolescents' mental health than for others. We examined whether heart rate variability (HRV) indicated differential susceptibility to mental health difficulties associated with COVID-19 stress and COVID-19 family adversity. Approximately 4 years prior to the pandemic, we assessed resting HRV and HRV reactivity to a well-validated stress paradigm in 87 adolescents. During the pandemic, these adolescents (ages 13-19) reported on their health-related stress and concerns about COVID-19, family adversity related to COVID-19, and their recent emotional problems. The association between COVID-19 stress and emotional problems was significantly stronger for adolescents who previously exhibited higher resting HRV or higher HRV reactivity. For adolescents who exhibited lower resting HRV or HRV augmentation, COVID-19 stress was not associated with emotional problems. Conversely, lower resting HRV indicated vulnerability to the effect of COVID-19 family adversity on emotional problems. Different patterns of parasympathetic functioning may reflect differential susceptibility to the effects of COVID-19 stress versus vulnerability to the effects of COVID-19 family adversity on mental health during the pandemic.

Brain cortical and subcortical morphology in adolescents with depression and a history of suicide attempt.

Background: Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. Methods: We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from T1-weighted anatomic MRI scans acquired at 3 T. Results: We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei (pFDR ≤ 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Limitations: Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Conclusion: Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour.

Default mode and salience network alterations in suicidal and non-suicidal self-injurious thoughts and behaviors in adolescents with depression.

Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide deaths in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents-49 adolescents with depression and 21 healthy controls-to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (all ps < 0.043, uncorrected). Depressed adolescents with NSSI had lower coherence in the anterior DMN and in insula-SN (all ps < 0.030, uncorrected), and higher CEN-DMN connectivity compared to those without NSSI and healthy controls (all ps < 0.030, uncorrected). Lower network coherence in all DMN subnetworks and insula-SN were associated with higher past-month SI and NSSI (all ps < 0.001, uncorrected). Thus, in our sample, both SI and NSSI are related to brain networks associated with difficulties in self-referential processing and future planning, while NSSI specifically is related to brain networks associated with disruptions in interoceptive awareness.

Decision-making and cognitive control in adolescent suicidal behaviors: a qualitative systematic review of the literature.

Suicide and suicidal behaviors represent a leading cause of morbidity and mortality during adolescence. While several lines of evidence suggest that suicidal behaviors are associated with risky decisions and deficient cognitive control in laboratory tasks in adults, comparatively less is known about adolescents. Here, we systematically reviewed the literature on the association between these neurocognitive variables and adolescent suicidal behaviors. The online search strategy identified 17 neurocognitive studies examining either cognitive control or decision-making processes in adolescents with past suicidal behaviors. Several studies have reported that adolescents with a history of suicidal behaviors present neuropsychological differences in the cognitive control (using Go/NoGo, suicide Stroop Test, continuous performance test, suicide/death Implicit Association Test), and decision-making (Iowa Gambling Task, Cambridge Gambling Task, cost computation, delay discounting, loss aversion tasks) domains. Due to a lack of replication or conflicting findings, our systematic review suggests that no firm conclusion can be drawn as to whether altered decision-making or poor cognitive control contribute to adolescent suicidal behaviors. However, these results collectively suggest that further research is warranted. Limitations included scarcity of longitudinal studies and a lack of homogeneity in study designs, which precluded quantitative analysis. We propose remediating ways to continue neuropsychological investigations of suicide risk in adolescence, which could lead to the identification of novel therapeutic targets and predictive markers, enabling early intervention in suicidal youth.

Testing a Developmental Model of Positive Parenting, Amygdala-Subgenual Anterior Cingulate Cortex Connectivity, and Depressive Symptoms in Adolescents Before and During the COVID-19 Pandemic.

Background: Neurobiological measures may inform our understanding of individual differences in adolescents' general risk for and resilience to depressive symptoms, including during the COVID-19 pandemic. We tested a developmental model linking variation in amygdala-subgenual anterior cingulate cortex (sgACC) resting-state connectivity to perceived parenting experiences earlier in adolescence, to concurrent depressive symptoms before the pandemic, and to subsequent depressive symptoms during the pandemic. Methods: We used data from a longitudinal study that included three waves (N = 214 adolescents; ages 9-15 years at time 1 [T1], 11-17 years at T2, and 12-19 years during the pandemic at T3). We assessed positive parenting (warm and supportive) (T1), depressive symptoms (T1 to T3), and functional connectivity between the sgACC and basolateral (BLA) and centromedial amygdala (T1 and T2). We modeled associations among earlier positive parenting, amygdala-sgACC connectivity, and depressive symptoms before and during the pandemic. Results: Less positive parenting at T1 was associated prospectively with stronger BLA-sgACC connectivity at T2 (ß = -0.22) over and above the effect of BLA-sgACC connectivity at T1. Stronger BLA-sgACC connectivity, in turn, was associated with heightened depressive symptoms, both before the pandemic (r = 0.21) and during the pandemic (ß = 0.19; independent of the effect of pre-pandemic symptoms). Conclusions: Adolescents who experience less positive parenting may develop a pattern of BLA-sgACC connectivity that increases their risk for mental health problems. BLA-sgACC connectivity may be associated with depressive symptoms in general, including during periods of heightened risk for adolescents, such as the pandemic.

Early Life Stress Predicts Depressive Symptoms in Adolescents During the COVID-19 Pandemic: The Mediating Role of Perceived Stress.

BACKGROUND: Exposure to early life stress (ELS) is alarmingly prevalent and has been linked to the high rates of depression documented in adolescence. Researchers have theorized that ELS may increase adolescents' vulnerability or reactivity to the effects of subsequent stressors, placing them at higher risk for developing symptoms of depression. METHODS: We tested this formulation in a longitudinal study by assessing levels of stress and depression during the COVID-19 pandemic in a sample of adolescents from the San Francisco Bay Area (N = 109; 43 male; ages 13-20 years) who had been characterized 3-7 years earlier (M = 5.06, SD = 0.86 years) with respect to exposure to ELS and symptoms of depression. RESULTS: As expected, severity of ELS predicted levels of depressive symptoms during the pandemic [r(107) = 0.26, p = 0.006], which were higher in females than in males [t(107) = -3.56, p < 0.001]. Importantly, the association between ELS and depression was mediated by adolescents' reported levels of stress, even after controlling for demographic variables. CONCLUSIONS: These findings underscore the importance of monitoring the mental health of vulnerable children and adolescents during this pandemic and targeting perceived stress in high-risk youth.

Reduced dorsal striatal gray matter volume predicts implicit suicidal ideation in adolescents.

Suicidal ideation (SI), a potent risk factor for suicide attempts, increases in adolescence. While alterations in dopaminergic functioning have been implicated in suicidal acts-particularly in adults-we do not know whether morphological alterations in dopamine-rich regions of the brain, such as the striatum, are vulnerability factors for the emergence of SI in adolescents. At baseline, a community sample of 152 adolescents (89 female; mean age: 11.41 ± 1.01 years) completed a magnetic resonance imaging (MRI) scan that was used to estimate gray matter volumes (GMVs) of three striatal structures: caudate, nucleus accumbens and putamen. At a 24 month follow-up session, participants completed a self-report measure of SI frequency [Suicidal Ideation Questionnaire (SIQ)] and the death version of the Implicit Association Test (IAT). Robust linear regression models were conducted to predict SIQ and IAT scores from striatal GMV. Bilateral putamen and left caudate GMV significantly predicted IAT scores (all Ps < 0.03). No other associations were significant (all Ps > 0.05). Our finding of reduced dorsal striatal GMV predicting implicit SI may indicate that downstream dopaminergic dysfunction is implicated in the development of overt suicidal behaviors. Self-reported SI was not associated with striatal GMV, suggesting that biological correlates of suicide risk may correlate specifically with objective measurements of SI in adolescents.

Corpus callosum volumes in bipolar disorders and suicidal vulnerability.

Reduced size of the corpus callosum (CC) has been associated with bipolar disorders and suicidality. Here, we aimed at investigating the relative independence of these associations in a large sample of patients. Two samples of males and females totaling 209 euthymic participants were recruited, including 72 patients with a major depressive disorder, 64 with bipolar disorders and 73 healthy controls. Among patients, 61 had a lifetime history of suicide attempt and 75 had none. Structural scans were acquired with 1.5T magnetic resonance imaging. Surface-based morphometry (Freesurfer) analysis was used to compute the volumes of the CC. In the whole sample, there was a significant reduction in the volume of mid-anterior, central, and mid-posterior (all p<0.008) CC in bipolar patients independently from suicidality, with medium effect sizes between unipolar and bipolar patients (Cohen's d between 0.46 and 0.62). In contrast, suicide attempters did not differ from non-attempters. This significant association between CC volumes and bipolar disorders was mainly found in the male sample, while a trend was found in the female sample. Within each patient group, medication had no major effect. Our study adds to the growing body of evidence linking corpus callosum alterations and bipolar disorders.

Neural mapping of guilt: a quantitative meta-analysis of functional imaging studies.

Guilt is a self-conscious emotion associated with the negative appraisal of one's behavior. In recent years, several neuroimaging studies have investigated the neural correlates of guilt, but no meta-analyses have yet identified the most robust activation patterns. A systematic review of literature found 16 functional magnetic resonance imaging studies with whole-brain analyses meeting the inclusion criteria, for a total of 325 participants and 135 foci of activation. A meta-analysis was then conducted using activation likelihood estimation. Additionally, Meta-Analytic Connectivity Modeling (MACM) analysis was conducted to investigate the functional connectivity of significant clusters. The analysis revealed 12 significant clusters of brain activation (voxel-based FDR-corrected p < 0.05) located in the prefrontal, temporal and parietal regions, mainly in the left hemisphere. Only the left dorsal cingulate cluster survived stringent FWE correction (voxel-based p < 0.05). Secondary analyses (voxel-based FDR-corrected p < 0.05) on the 7 studies contrasting guilt with another emotional condition showed an association with clusters in the left precuneus, the anterior cingulate, the left medial frontal gyrus, the right superior frontal gyrus and the left superior temporal gyrus. MACM demonstrated that regions associated with guilt are highly interconnected. Our analysis identified a distributed neural network of left-lateralized regions associated with guilt. While voxel-based FDR-corrected results should be considered exploratory, the dorsal cingulate was robustly associated with guilt. We speculate that this network integrates cognitive and emotional processes involved in the experience of guilt, including self-representation, theory of mind, conflict monitoring and moral values. Limitations of our meta-analyses comprise the small sample size and the heterogeneity of included studies, and concerns about naturalistic validity.

Subcortical nuclei volumes in suicidal behavior: nucleus accumbens may modulate the lethality of acts.

Previously, studies have demonstrated cortical impairments in those who complete or attempt suicide. Subcortical nuclei have less often been implicated in the suicidal vulnerability. In the present study, we investigated, with a specific design in a large population, variations in the volume of subcortical structures in patients with mood disorders who have attempted suicide. We recruited 253 participants: 73 suicide attempters with a past history of both mood disorders and suicidal act, 89 patient controls with a past history of mood disorders but no history of suicidal act, and 91 healthy controls. We collected 1.5 T magnetic resonance imaging data from the caudate, pallidum, putamen, nucleus accumbens, hippocampus, amygdala, ventral diencephalon, and thalamus. Surface-based morphometry (Freesurfer) analysis was used to comprehensively evaluate gray matter volumes. In comparison to controls, suicide attempters showed no difference in subcortical volumes when controlled for intracranial volume. However, within attempters negative correlations between the left (r = -0.35, p = 0.002), and right (r = -0.41, p < 0.0005) nucleus accumbens volumes and the lethality of the last suicidal act were found. Our study found no differences in the volume of eight subcortical nuclei between suicide attempters and controls, suggesting a lack of association between these regions and suicidal behavior in general. However, individual variations in nucleus accumbens structure and functioning may modulate the lethality of suicidal acts during a suicidal crisis. The known role of nucleus accumbens in action selection toward goals determined by the prefrontal cortex, decision-making or mental pain processing are hypothesized to be potential explanations.

dcc Haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking.

Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence.

Lesions of the lateral habenula dissociate the reward-enhancing and locomotor-stimulant effects of amphetamine.

Midbrain dopamine neurons play a key role in goal-directed behaviour as well as in some psychiatric disorders. Recent studies have provided electrophysiological, anatomical and biochemical evidence that the lateral habenula (LHb) exerts strong inhibitory control over midbrain dopamine neurons. However, the behavioural relevance of this inhibitory input is poorly understood. Our aim was to examine the contribution of the LHb to dopamine-sensitive behaviour. Here, we characterized the locomotor-stimulant and reward-enhancing properties of amphetamine in rats with and without neurotoxic lesions of the LHb. Amphetamine-induced forward locomotion and reward were respectively measured in automated activity cages and with intracranial self-stimulation. Adult, male Sprague-Dawley rats were bilaterally infused with ibotenic acid in the LHb and allowed 7-10 days post-operative recovery. The locomotor-stimulant and reward-enhancing properties of amphetamine (0, 0.5 and 1.0 mg/kg, ip) were then tested in different groups of lesioned and sham-lesioned rats. Neurotoxic lesions of the LHb caused a significant enhancement of the locomotor-stimulant effect of amphetamine, an effect not seen following lesions of the medial habenula. Conversely, the reward-enhancing properties of amphetamine did not differ between lesioned and sham-lesioned rats responding for rewarding electrical stimulation of the posterior mesencephalon or the medial forebrain bundle. The dissociation between the locomotor-stimulant and reward-enhancing effects of amphetamine following LHb lesions suggests the contribution of two distinct substrates that are functionally dissociable and differentially sensitive to LHb modulation.