What role for cognitive remediation in the treatment of depressive symptoms? A superiority and noninferiority meta-analysis for clinicians.

BACKGROUND: Cognitive remediation (CR) is a promising technique in the treatment of the cognitive dimension of depression. The present study evaluated the potential of CR in treating depressive symptoms and provides practical information about its usefulness in clinical settings. METHODS: We performed two meta-analyses of published randomized (and nonrandomized) clinical trials, comparing CR to control conditions in subjects with current depressive symptomatology. The superiority meta-analysis aimed to determine the superiority of CR when compared with placebo/waiting list interventions and its efficacy when used as an augmentation therapy. The noninferiority meta-analysis determined whether CR had noninferior efficacy compared with standard antidepressant interventions. RESULTS: CR was found to significantly improve depressive symptomatology in the superiority meta-analysis (CR: n = 466, control n = 478). Moreover, CR seemed to be noninferior to standard antidepressant interventions (CR: n = 230, control n = 235). CR was more effective when addressing hot (vs. cold) cognition, when involving younger patients (i.e., <30 years), and in the case of mild-moderate (vs. severe) depression. CONCLUSIONS: CR should be considered an augmentation treatment to improve treatment outcomes in depressed subjects, especially among young individuals. Interventions addressing hot cognition seem to be the most promising.

Anatomical and behavioral impact of a lentiviral tool tapping onto hippocampal serotonin reuptake in rats.

We aimed at the further characterization of rats in which SERT gene silencing was achieved by hippocampal injection of a lentiviral vector, carrying three si-RNA to block SERT mRNA at 66% of normal levels. Improved self-control and reduced restlessness were already demonstrated in these rats. Present further studies consisted of male adult rats, bilaterally inoculated within the hippocampus; control rats received lentivirus particles inactivated with heat. Both groups were maintained in isolation for 5 months, starting from inoculation. Neurochemical changes were studied by proton magnetic resonance spectroscopy (1H-MRS): we found increased hippocampal viability and bioenergetic potential; however, rats showed a behaviorally depressive pattern, also characterized by enhanced affiliation. Based on the extent of such effects, the whole lenti-SERT group was divided into two subgroups, termed intermediate- and extreme- phenotype profiles. While all rats had a widespread modification within dorsal/ventral striatum, amygdala, and hypothalamus, only the former subgroup showed an involvement of Raphé medialis, while, for the latter subgroup, an increase of SERT within hippocampus was unexpectedly caused. Within the less-affected "intermediate" rats, hippocampal 5-HT7 receptors were down-modulated, and also similarly within substantia nigra, septum, and neocortex. This picture demonstrates that additional rather than fewer neurobiological changes accompany a lower phenotypic expression. Overall, tapping hippocampal SERT affected the balance between habits versus strategies of coping by promoting morphogenetic processes indicative of a serotonergic fiber plasticity. Supplementary studies about serotonergic dynamics and neurogenesis within fronto-striatal circuits are needed.

Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats.

Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms.SIGNIFICANCE STATEMENT Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.

Variability in the "stereotyped" prey capture sequence of male cuttlefish (Sepia officinalis) could relate to personality differences.

Studies of animal personality have shown consistent between-individual variation in behaviour in many social and non-social contexts, but hunting behaviour has been overlooked. Prey capture sequences, especially in invertebrates, are supposed to be quite invariant. In cuttlefish, the attack includes three components: attention, positioning, and seizure. The previous studies indicated some variability in these components and we quantified it under the hypothesis that it could relate to personality differences. We, therefore, analysed predation sequences of adult cuttlefish to test their association with personality traits in different contexts. Nineteen subjects were first exposed to an "alert" and a "threat" test and then given a live prey, for 10 days. Predation sequences were scored for components of the attack, locomotor and postural elements, body patterns, and number of successful tentacle ejections (i.e. seizure). PCA analysis of predatory patterns identified three dimensions accounting for 53.1%, 15.9%, and 9.6% of the variance and discriminating individuals based on "speed in catching prey", "duration of attack behaviour", and "attention to prey". Predation rate, success rate, and hunting time were significantly correlated with the first, second, and third PCA factors, respectively. Significant correlations between capture patterns and responsiveness in the alert and threat tests were found, highlighting a consistency of prey capture patterns with measures of personality in other contexts. Personality may permeate even those behaviour patterns that appear relatively invariant.

The current clinical knowledge on the treatment of gambling disorder: A summary.

Gambling disorder (GD) is a topical problem in developed countries and may be present in 1-3% of the general population. The pathophysiology of this disorder is largely unknown but it shares similarities to other behavioral addictions. Multiple neurotransmitter systems, including dopaminergic, serotonergic, noradrenergic, glutamatergic, and opioidergic, have been implicated in GD. Based on available articles, only the opioid antagonist naltrexone has been documented to demonstrate clinical efficacy in multiple studies including double-blind studies. Nalmefene, another opioid antagonist, may be active as well but its dose-response effect remains unclear. Contrarily, current test results do not support the therapeutic use of any antidepressant drug. Some positive data has been made available supporting the use of N-acetylcystein, but more studies are needed to confirm this. No clear or definite information is currently available for other drugs.

Stimulation of 5-HT7 receptor during adolescence determines its persistent upregulation in adult rat forebrain areas.

Brain serotonin 7 (5-HT7) receptors play an important functional role in learning and memory, in regulation of mood and motivation, and for circadian rhythms. Recently, we have studied the modulatory effects of a developmental exposure (under subchronic regimen) in rats with LP-211, a brain-penetrant and selective 5-HT7 receptor agonist. We aimed at further deciphering long-term sequelae into adulthood. LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during the adolescent phase (postnatal days 43-45 to 47-49). When adult (postnatal days >70), forebrain areas were obtained for ex vivo immunohistochemistry, whose results prompted us to reconsider the brain connectivity maps presented in our previous study (Canese et al., Psycho-Pharmacol 2015;232:75-89.) Significant elevation in levels of 5-HT7 receptors were evidenced due to adolescent LP-211 exposure, in dorsal striatum (which also shows an increase of dopaminergic D2 auto-receptors) and-unexpectedly-in piriform cortex, with no changes in ventral striatum. We observed that functional connectivity from a seed on the right hippocampus was more extended than reported, also including the piriform cortex. As a whole, the cortical loop rearranged by adolescent LP-211 exposure consisted in a hippocampus receiving connections from piriform cortex and dorsal striatum, the latter both directly and through functional control over the 'extended amygdala'. Such results represent a starting point to explore neurophysiology of 5-HT7 receptors. Further investigation is warranted to develop therapies for sleep disorders, for impaired emotional and motivational regulation, for attentive and executive deficit. The 5-HT7 agonist LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during adolescence (postnatal days 43-45 to 47-49) in rats. When adult (postnatal days >70), a significant elevation in levels of 5-HT7 receptors were evidenced in dorsal striatum and-unexpectedly-in piriform cortex.

Hyperglycemia and cognitive impairments anticipate the onset of an overt type 2 diabetes-like phenotype in TALLYHO/JngJ mice.

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer's disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms.

Staying connected: An umbrella review of meta-analyses on the push-and-pull of social connection in depression.

BACKGROUND: Depression affects approximately 4 % of the global population and has huge social and economic implications. Social factors, including support, engagement, and stigma, play a crucial role in the development and severity of depression. METHODS: We provide a synthesis of the consistency and magnitude of the association between measures of social connection and depression. We searched PubMed, PsycINFO, Cochrane Library, and EMBASE and 47 meta-analyses were included in the umbrella review. The strength of the associations was extracted and compared among different populations. The quality/certainty of evidence was assessed using AMSTAR-2 and GRADE tool. RESULTS: Results indicate that social support serves as a protective factor against depression, particularly in peripartum populations, while its impact is weaker in clinical populations. No association was found between social support and depression in post-disaster populations. Stigma and discrimination favour the development and maintenance of depressive symptoms in clinical populations, but have a weaker effect in ethnic minorities. LIMITATIONS: The quality and certainty of evidence should be taken into account when interpreting our findings. Further research with more rigorous methodology and higher-quality evidence is needed to better understand the complex relationship between depression and social connection across various populations and contexts. CONCLUSIONS: Our findings confirm the role of social determinants in the emergence and severity of depression, particularly in the case of vulnerable populations. Efforts to counteract disconnection at the societal and individual levels and to reduce stigma should be central to an effective depression prevention agenda.

Using videos from social media to study the begging behaviour of peregrine falcon (Falco peregrinus) nestlings.

In 2013, two papers suggested behavioural biologists to use videos available on social media as a tool for investigating animal behaviour, a methodology referred to as video mining. Here, this approach was applied to the study of specific aspects of peregrine falcon (Falco peregrinus) nestlings' behaviour at critical developmental stages. Special attention was given to food begging behaviour and its development. The materials included 254 videos (from 31 nests and 51 different broods) that underwent strict selection procedures to ensure their reliability and quality. Following age estimation of the nestlings, videos were divided into four classes to study age-related differences in begging behaviour. No statistically significant differences emerged among age classes. Video mining may represent a valuable tool for qualitative analyses if wisely and rigorously applied in suitable species and for appropriate research questions. Besides, the video mining approach could also be applied in citizen-science-based studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12210-022-01129-x.

A systematic review of preclinical studies exploring the role of insulin signalling in executive function and memory.

Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer's disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia - as a proxy of insulin-related metabolic dysfunctions - and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.

Automation at the service of the study of executive functions in preclinical models.

Cognitive flexibility involves the capability to switch between different perspectives and implement novel strategies upon changed circumstances. The Wisconsin Card Sorting Test (in humans) and the Attentional Set-Shifting Task (ASST, in rodents) evaluate individual capability to acquire a reward-associated rule and subsequently disregard it in favour of a new one. Both tasks entail consecutive stages wherein subjects discriminate between: two stimuli of a given category (simple discrimination, SD); the stimuli of SD confounded by an irrelevant stimulus of a different category (compound discrimination, CD); different stimuli belonging to the SD category (intradimensional shift, IDS); and two stimuli of the confounding category (extradimensional shift, EDS). The ASST is labour intensive, not sufficiently standardised, and prone to experimental error. Here, we tested the validity of a new, commercially available, automated version of ASST (OPERON) in two independent experiments conducted in: different mouse strains (C57BL/6 and CD1 mice) to confirm their differential cognitive capabilities (Experiment 1); and an experimental model of chronic stress (administration of corticosterone in the drinking water; Experiment 2). In both experiments, OPERON confirmed the findings obtained through the manual version. Just as in Experiment 1 both versions captured the deficit of C57BL/6 mice on the reversal of the CD (CDR), so also in Experiment 2 they provided analogous evidence that corticosterone treated mice have a remarkable impairment in the IDS. Thus, OPERON capitalises upon automated phenotyping to overcome the limitation of the manual version of the ASST while providing comparable results.

Choice with delayed or uncertain reinforcers in rats: influence of timeout duration and session length.

Interest is rising for animal modeling of impaired behavioral inhibition. Impulsivity and risk proneness, key symptoms of impulse-control disorders, are classically measured by Intolerance to Delay (ID) and Probabilistic Delivery (PD) tasks, requiring choice between a "Small & Soon" or "Sure" (SS) versus a "Large & Late" or "Luck-Linked" (LL or LLL, respectively) reinforcer. Several temporal parameters shall be set, which are not always explicit. Here, we focused on duration of timeout (TO; three groups: 15, 30, or 45 s; Exp. 1) and on session length (SL; three groups: 60, 90, or 120 min; Exp. 2) to determine whether these parameters may affect rats' performance in ID and PD tasks, respectively. In Exp. 1, rats' reaction to increasing experimental delays (absolute values 0-90 s, delay-equivalent odds 0 to 1.94 ± 0.11) was critically affected by TO duration: a steeper impulsivity curve was found in subjects tested with the longest TO, while random performance was elicited with too short TO. In Exp. 2, a specific "gambling" part was presented (LLL probability lower than 20%). Subjects tested with the shortest session length (60 min), who had a low number of gambling opportunities (performed trials = 84.33 ± 1.91), exhibited a profile of risk proneness, with sustained LLL preference despite high uncertainty and low payoff. Present data demonstrate that TO and SL crucially influence rats' performance in these operant tasks. Their methodological refinement is highly relevant to validate preclinical models for inhibitory-control impairments.

The presence of a potential competitor modulates risk preferences in rats.

Although both human and non-human animals, in everyday life, deal with risky decisions in a social environment, few studies investigated how social dimension influences risk preferences (i.e., if consequences on others feeds back over own choice). Here, we assessed whether the presence of a conspecific, acting as a potential competitor for the same food resource, influenced risky decision-making in male rats. Subjects received a series of choices between a safe option (always yielding a small yet optimal reward, solely to itself) and a risky option (yielding a larger but suboptimal reward, one third of times to itself and two third of times delivered to the other half cage); rats were tested twice, both alone and paired with a conspecific, recipient of own-lost food and hence acting as potential competitor. Results showed that focal subjects were more risk-prone when paired with a conspecific than when tested alone. However, rats exhibited also a higher motivational conflict with a competing bystander present than alone: data suggest that the primary drive was to increase "own" food rather than either a competitive or prosocial tendency. Overall, for rats tested in a risky-choice task, a competitive social context increased the salience and attractiveness of larger food outcomes, as observed in humans and great apes. This led to the economically irrational response of selecting the "binge-but-risky" option, notwithstanding uncertainty about the actual recipient of such food.

Non-invasive brain stimulation targets and approaches to modulate gambling-related decisions: A systematic review.

INTRODUCTION: Despite intense neuroscience research on the neurobiological underpinnings of Gambling Disorder (GD) and gambling-related decision-making, effective treatments targeting these dysfunctions are still lacking. Non Invasive Brain Stimulation (NIBS) techniques, such as transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS), selectively modulate activity of brain circuits and have the potential to reverse alterations sustaining GD symptoms. Therefore, the aim of this systematic review was to determine the impact of different NIBS interventions on gambling-related decision processes. METHODS: We conducted a comprehensive and translational search in three online databases (MEDLINE via PubMed, Scopus, Web of Science), in accordance with the PRISMA guidelines. We included studies applying neuromodulation (TMS, tDCS) techniques in GD patients or assessing gambling-related decision-making in healthy subjects. In addition, we explored the potential impact of NIBS in drug-induced GD (e.g., Parkinson's Disease). RESULTS: Twenty-seven studies have been included. We summarized results to detect the impact of different targets and stimulation/inhibition protocols in terms of gambling-related decision-making. The majority of both tDCS and TMS studies targeted the dorsolateral prefrontal cortex. Although heterogeneous in protocols and parameters, results from tDCS and TMS studies converge in indicating that the stimulation (instead of inhibition) of prefrontal regions could be beneficial to contrast dysfunctional gambling-related decision processes. CONCLUSION: NIBS interventions show promise to be further tested in controlled clinical settings for the treatment of behavioral addictions. Further studies are also necessary to investigate connectivity changes and laterality issues (unilateral versus bilateral; left versus right) of NIBS application in GD.

The transition time to gambling disorder: The roles that age, gambling preference and personality traits play.

BACKGROUND AND AIMS: Gambling Disorder (GD) is considered a heterogeneous, multidimensional pathology with high personal and social consequences. The transition time (TT) between problematic gaming and pathological gambling, which varies significantly across patients, may predict the disorder's severity. As only limited studies have investigated the factors implicated in the TT, the current study set out to identify its predictors and their relationships with GD severity. METHODS: Correlation were performed in 725 male GD patients to identify factors associated to TT and GD severity, including: age of onset of gambling behaviors, alcohol/drug use, personality traits and gambling preferences (i.e., strategic, non-strategic, and mixed). Then a regression analysis was performed to identify predictors of TT to GD. RESULTS: Longer TT correlated with higher GD severity, early age of onset of problematic gambling, substance use and a non-strategic gambling preference. Personality traits including low self-directedness, high novelty seeking, and low cooperativeness were also related with longer TT. The strongest associations with GD severity were substance use, and some of the personality traits (i.e., low self-directedness and cooperativeness, high harm avoidance and self-transcendence). Factors significantly predicting longer transition to GD were older ages, low self-directedness, and non-strategic gambling. CONCLUSIONS: A clinical profile characterized by a longer TT and more severe GD symptoms pertains to older patients with low self-directedness, and preference for non-strategic gambling. Other relevant factors associated with this profile of patients included early age of onset problematic gambling, substance consumption, high novelty seeking and low cooperativeness.

Exploring dopaminergic transmission in gambling addiction: A systematic translational review.

Dopamine has a crucial and well-documented role in the development and maintenance of Gambling Disorder (GD). This systematic review adopts a translational approach aimed at providing a comprehensive synthesis of current clinical and preclinical knowledge on dopaminergic function in GD at a neurobiological level. To this end, we present and discuss converging dopaminergic alterations and phenotypes. Preclinical and clinical review protocols were registered on the PROSPERO database (CRD42019124404, CRD42019124405). The literature search was conducted in accordance with PRISMA guidelines using three databases (PubMed, Web of Science, Scopus). We identified 67 preclinical studies using pharmacological and non-pharmacological manipulations of the gambling-like phenotype and 33 human studies investigating either genetic polymorphisms or functional brain imaging data. Dopamine transporter and D2, D3, D4 receptor alterations showed strongest translational concordance. Though no postsynaptic dopaminergic alterations were observed, several studies point at dysfunctions in presynaptic dopamine trafficking in GD, suggestive of hyperdopaminergic states. Developing meaningful translational models is essential to working towards the development of an integrated conceptual framework for GD and neurobiologically-based treatment interventions.

Striatal dynamics as determinants of reduced gambling vulnerability in the NHE rat model of ADHD.

The Naples High-Excitability (NHE) is a validated rat strain to model for a mesocortical variant of Attention Deficit Hyperactivity Disorder (ADHD). NHE rats' brains have a tuned-down cortical and a potentiated limbic loop (Zoratto et al., 2017). ADHD and comorbid pathological gambling (PG) involve similar deficits of prefrontal-striatal dialogue. This work aimed to understand if NHE rats (compared to normal random-bred rats, NRB) can be a useful model for gambling vulnerability in ADHD. Experiment 1 evaluated gambling proneness in NHE rats, namely attraction/avoidance in nose-poking for a "Large & Luck-Linked" (LLL) reward (versus a "Small & Sure" one, SS), when the probability of LLL delivery was progressively reduced. Experiment 2 assessed (by phMRI) differential responsivity of ventral (vStr) versus dorsal (dStr) striatum following a methylphenidate (MPH, 4 mg/kg I.P.) challenge. In NHE rats, reduced attraction by secondary cues (associated with uncertain, rarefying LLL delivery) comes along with little or no activation of dStr and enhanced activation of vStr by MPH. Together, such evidences from NHE rats indicate distinctive roles of ventral (enhanced value given to actual primary reward) and dorsal (lower encoding of repeated stimulus-reward associations into a habit) striatum. In conclusion, the dynamics of reward systems could link an attention deficit with a decreased vulnerability to pathological gambling.

Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies.

Repetitive transcranial magnetic stimulation (rTMS) has gained growing interest for the treatment of major depression (MDD) and treatment-resistant depression (TRD). Most knowledge on rTMS comes from human studies as preclinical application has been problematic. However, recent optimization of rTMS in animal models has laid the foundations for improved translational studies. Preclinical studies have the potential to help identify optimal stimulation protocols and shed light on new neurobiological-based rationales for rTMS use. To assess existing evidence regarding rTMS effects on depressive-like symptoms in rodent models, we conducted a comprehensive literature search in accordance with PRISMA guidelines (PROSPERO registration number: CRD42019157549). In addition, we conducted a meta-analysis to determine rTMS efficacy, performing subgroup analyses to examine the impact of different experimental models and neuromodulation parameters. Assessment of the depressive-like phenotype was quite homogeneous whilst rTMS parameters among the 23 included studies varied considerably. Most studies used a stress-induced model. Overall, results show a largely beneficial effect of active rTMS compared to sham stimulation, as reflected in the statistically significant recovery of both helplessness (SDM 1.34 [1.02;1.66]) and anhedonic (SDM 1.87 [1.02;2.72]) profiles. Improvement of the depressive-like phenotype was obtained in all included models and independently of rTMS frequency. Nonetheless, these results have limited predictive value for TRD patients as only antidepressant-sensitive models were used. Extending rTMS studies to other MDD models, corresponding to distinct endophenotypes, and to TRD models is therefore crucial to test rTMS efficacy and to develop cost-effective protocols, with the potential of yielding faster clinical responses in MDD and TRD.

Methylphenidate administration promotes sociability and reduces aggression in a mouse model of callousness.

RATIONALE: Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. OBJECTIVES: Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. METHODS: Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). RESULTS: Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. CONCLUSIONS: Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.

Anhedonia across borders: Transdiagnostic relevance of reward dysfunction for noninvasive brain stimulation endophenotypes.

INTRODUCTION: Anhedonia is a transdiagnostic psychopathological dimension, consisting in the impaired ability to experience pleasure. In order to further our understanding of its neural correlates and to explore its potential relevance as a predictor of treatment response, in this article we systematically reviewed studies involving anhedonia and neuromodulation interventions, across different disorders. METHODS: We included seven studies fulfilling inclusion/exclusion criteria and involving different measures of anticipatory and consummatory anhedonia, as well as different noninvasive brain stimulation interventions (transcranial magnetic stimulation and transcranial direct current stimulation). Studies not exploring hedonic measures or not involving neuromodulation intervention were excluded. RESULTS: All the included studies entailed the use of rTMS protocols in one of the diverse prefrontal targets. The limited amount of studies and the heterogeneity of stimulation protocols did not allow to draw any conclusion with regard to the efficacy of rTMS in the treatment of transnosographic anhedonia. A potential for anhedonia in dissecting possible endophenotypes of different psychopathological conditions preliminarily emerged. CONCLUSIONS: Anhedonia is an underexplored condition in neuromodulation trials. It may represent a valuable transdiagnostic dimension that requires further examination in order to discover new clinical predictors for treatment response.