Childhood methylphenidate adherence as a predictor of antidepressants use during adolescence.

Methylphenidate (MPH) is a common and effective treatment for attention deficit hyperactivity disorder (ADHD), but little is known about the relationship between early childhood intake of MPH and onset of antidepressant treatment during adolescence. The study aimed to examine whether adherence to MPH during early childhood predicts the initiation of antidepressants during adolescence. This is a 12-year historical prospective nationwide cohort study of children enrolled in an integrated care system who were first prescribed MPH between the ages of 6 and 8 years (N = 6830). We tested for an association between their adherence to MPH during early childhood (as indicated by medication possession ratio from MPH onset through the age of twelve) and the likelihood of being prescribed any antidepressant during adolescence (age 13-18). As all country citizens are covered by mandatory health insurance, and full services are provided by one of the four integrated care systems, data regarding patients' diagnoses, prescriptions, and medical purchases are well documented. Logistic regression analysis indicated that those with higher adherence to MPH had a 50% higher risk (95% CI 1.16-1.93) of receiving antidepressants during adolescence when controlling for other comorbid psychiatric conditions and parental use of antidepressants. In this large-scale longitudinal study, MPH adherence during early childhood emerged as a predictor for antidepressant treatment during adolescence, which may reflect increased emotional and behavioral dysregulation in this group. The highly adherent patients are at higher risk and should be clinically monitored more closely, particularly into adolescence.

Cognitive Impairments in Abstinent Male Residents of a Therapeutic Community for Substance-Use Disorders: A Five-Year Retrospective Study.

BACKGROUND AND OBJECTIVES: Prior studies of residual cognitive deficits in abstinent substance-use disorder (SUD) patients, exhibited conflicting reports and a substantial patient selection bias. The aim of this study was to test the cognitive function of a sample of chronic abstinent SUD patients in a therapeutic-community. METHODS: The IntegNeuroTM cognitive test battery was used for a retrospective cross-sectional study of cognitive functioning of an unselected sample (n = 105) of abstinent male residents of a therapeutic-community. The results were compared to a large age-, gender-, and education-matched normative cohort. RESULTS: A significant negative deviance from the normal cohorts' mean was present in most of the cognitive test results and in all the cognitive domains that were tested. The most substantial deficit was found in the executive function domain (d = 1.02, 95%CI (±0.11)). Correct identification of facial emotions was significantly lower selectively in expressions of disgust and sadness. Substance-use starting at an early age (12.4 ± 0.8 years) was associated with lower performance in tests of sustained attention and impulsivity as well as with varied ability to identify correctly "negative" emotions in the emotion identification domain. CONCLUSIONS: This 5-year retrospective study demonstrates substantial cognitive impairments in an unselected sample of abstinent SUD patients. Impairment in multiple cognitive domains may lower the probability for remission and successful social integration. Early-age substance initiation may be associated with larger impairments in cognitive performance.

Mechanisms of firing patterns in fast-spiking cortical interneurons.

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+), delayed-rectifier K(+), and slowly inactivating d-type K(+) conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+) window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+) window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+) window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.

The association between cannabis use and suicidality among men and women: A population-based longitudinal study.

BACKGROUND: Evidence regarding the role of sex differences in the association between cannabis use and suicidality is lacking. We explored sex differences in the bidirectional association between cannabis use and suicidality in a 3-year longitudinal study. METHODS: Data were drawn from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Bidirectional analyses were conducted separately by sex, exploring incidence of suicidality among cannabis users (n=963 vs. 30,586 non-users) as well as initiation of cannabis use among suicidal individuals (n=1805 vs. 25,729 non-suicidal). Cannabis use was categorized based on frequency of use. Multivariate logistic regression analyses controlling for multiple covariates were conducted. RESULTS: Cannabis use was significantly associated with increased incidence of suicidality among men (Adjusted Odds Ratio [AOR] for any cannabis use =1.91[1.02-3.56]) but not among women (AOR=1.19[0.64-2.20]). Daily cannabis use was significantly associated with increased incidence of suicidality among men (AOR=4.28[1.32-13.82]) but not among women (AOR=0.75[0.28-2.05]). Conversely, baseline suicidality was associated with initiation of cannabis use among women (AOR=2.34[1.42-3.87]) but not among men (AOR=1.10[0.57-2.15]). Separate analyses of suicidal ideation and suicide attempts demonstrated a significant association between cannabis use and subsequent incidence of suicidal ideation in men, and a significant association between baseline suicidal ideation and subsequent initiation of cannabis use in women. No significant association was found for the bidirectional association between cannabis use and suicide attempts in either sex. LIMITATIONS: Suicidality was assessed only in individuals reporting depressed mood and/or anhedonia. CONCLUSIONS: Our findings support a longitudinal association between heavy cannabis use and the incidence of suicidality in men, but not in women. Conversely, baseline suicidality is longitudinally associated with the initiation of cannabis use in women, but not in men. This may have implications on clinical and social aspects of cannabis use and merit further research into the unique effects of sex differences on cannabis induced psychopathology.

Characteristics of Synthetic Cannabinoid and Cannabis Users Admitted to a Psychiatric Hospital: A Comparative Study.

BACKGROUND: Psychotic and affective exacerbations associated with synthetic cannabinoid (SC) use are becoming an emerging concern in psychiatric hospitals. However, data are lacking regarding whether clinical manifestations of SC use differ from those associated with cannabis use. OBJECTIVE: Our aim was to explore the unique profile of SC users admitted to a mental health center in terms of demographic, clinical, and physiologic variables in comparison to cannabis users. METHODS: We retrieved retrospective data of patients admitted to a mental health center between October 2007 and May 2014 who self-reported recent use of SC (n = 60) and patients who were cannabis users (positive carboxy-tetrahydrocannabinol urine test at admission) without a history of SC use (n = 163). Clinical measures included hospitalization length, number of previous hospitalizations, Positive and Negative Syndrome Scale (PANSS) scores, psychiatric status at admission, and relevant physiologic and laboratory parameters. RESULTS: Hospitalized SC users were younger than hospitalized cannabis users (n = 163) (30.46 ± 7.83 years versus 34.67 ± 10.07 years, U223 = 3,781.5, P = .009, respectively). SC patients had longer hospitalizations compared to cannabis users (43.45 ± 54.02 days versus 22.91 ± 31.36 days, U219 = 5,701.5, P = .005, respectively), had more previous hospitalizations (3.73 ± 5.05 versus 1.98 ± 5.12, U223 = 6,284, P < .001, respectively), and were more likely to be hospitalized by criminal court order (36.7% [n = 22] versus 19.9% [n = 32], χ²2 = 7.136, P = .028, respectively). SC patients presented with a more severe clinical picture manifested by higher total PANSS scores (82.53 ± 23.05 versus 69.98 ± 19.94, t91 = -2.696, P = .008) in a subset of patients with PANSS scores assessed within a week from admission (n = 30 in the SC group and n = 63 in the cannabis group). No differences were found in physiologic or laboratory measures on admission between the SC and cannabis groups. CONCLUSIONS: Patients admitted following use of SC are generally younger males who have higher severity of psychotic symptoms at admission, are more likely to be admitted by criminal court order, and require longer hospitalization periods in comparison to cannabis users.

Emerging issues in the relationship between adolescent substance use and suicidal behavior.

Adolescent suicidal behavior poses a major global public health concern as it is highly prevalent and associated with mortality and morbidity worldwide. Substanceuse disorders are also an issue of increasing concern among adolescents and have been shown to increase the risk for suicidal behaviors. In this review we address emerging issues in the relationship between adolescent substance use disorders and suicidal behaviors. We focus on common hazardous patterns of substance abuse such as binge drinking and poly-substance abuse and point out developing patterns of substance preferences as evidenced by the contemporary widespread use of synthetic cannabinoids. We address these issues in the context of vulnerable populations such as sexual-minority adolescents and youth with co-occurring mental-disorder diagnoses. Finally, we relate to the present and future challenges presented by these issues to implement effective anti-suicidal treatment and prevention strategies in adolescents with substance use disorders.

Spatiotemporal alterations of cortical network activity by selective loss of NOS-expressing interneurons.

Deciphering the role of GABAergic neurons in large neuronal networks such as the neocortex forms a particularly complex task as they comprise a highly diverse population. The neuronal isoform of the enzyme nitric oxide synthase (nNOS) is expressed in the neocortex by specific subsets of GABAergic neurons. These neurons can be identified in live brain slices by the nitric oxide (NO) fluorescent indicator diaminofluorescein-2 diacetate (DAF-2DA). However, this indicator was found to be highly toxic to the stained neurons. We used this feature to induce acute phototoxic damage to NO-producing neurons in cortical slices, and measured subsequent alterations in parameters of cellular and network activity. Neocortical slices were briefly incubated in DAF-2DA and then illuminated through the 4× objective. Histochemistry for NADPH-diaphorase (NADPH-d), a marker for nNOS activity, revealed elimination of staining in the illuminated areas following treatment. Whole cell recordings from several neuronal types before, during, and after illumination confirmed the selective damage to non-fast-spiking (FS) interneurons. Treated slices displayed mild disinhibition. The reversal potential of compound synaptic events on pyramidal neurons became more positive, and their decay time constant was elongated, substantiating the removal of an inhibitory conductance. The horizontal decay of local field potentials (LFPs) was significantly reduced at distances of 300-400 µm from the stimulation, but not when inhibition was non-selectively weakened with the GABA(A) blocker picrotoxin. Finally, whereas the depression of LFPs along short trains of 40 Hz stimuli was linearly reduced with distance or initial amplitude in control slices, this ordered relationship was disrupted in DAF-treated slices. These results reveal that NO-producing interneurons in the neocortex convey lateral inhibition to neighboring columns, and shape the spatiotemporal dynamics of the network's activity.

Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood-brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

Time-dependent, layer-specific modulation of sensory responses mediated by neocortical layer 1.

An essential component of feedback and top-down information in the cortical column arrives at layer 1 (L1) where it contacts distal dendrites of pyramidal neurons. Although much is known about the anatomical organization of L1 fibers, their contribution to sensory information processing remains to be determined. We assessed the physiological significance of L1 inputs by performing extracellular recordings in vivo from neurons in the primary somatosensory cortex of rodents. We found that blocking activity in L1 increases whisker-evoked response magnitude and variance, suggesting that L1 exerts an inhibitory influence on whisker responses. However, when pairing L1 stimulation with whisker deflection, the interval between the stimuli determined the outcome of the interaction, with facilitation of sensory responses dominating the short intervals (10 ms). These temporal interactions resulted in a time-dependent regulation of direction tuning of cortical neurons. The synaptic mechanisms underlying L1 inputs' influences were examined using whole cell recordings in vitro while pairing L1 and white-matter stimulations. We found time-dependent, layer-specific differences in synaptic summation of the two inputs, with supralinearity at shorter intervals and sublinearity at longer intervals that resulted mainly from shunting inhibition. Taken together, our results demonstrate that L1 inputs impose a time- and layer-specific regulation on sensory-evoked responses. This in turn may lead to a dynamic transmission of sensory information in the somatosensory cortex.

Inhibitory effect of mouse neocortex layer I on the underlying cellular network.

The mammalian cortical layer I is a convergence site for axons of sub- and intracortical origin, and the apical dendritic tufts of pyramidal neurons. A prominent feature of layer I is an extensive plexus of inhibitory axons, which originate from stellate cells in all cortical laminae. The role of this inhibitory projection in the activity of cortical networks has yet to be determined. We investigated the degree to which inhibitory inputs within layer I affect the activity of the underlying cellular network. Field potentials (FPs) were recorded in layer II/III. Focal application of the GABAA blocker picrotoxin in layer I above the recording pipette or the removal of layer I resulted in larger FP amplitudes for stimulations at control-equal intensities. When inhibition was partially blocked, the removal of layer I caused a significant reduction in the threshold stimulus intensity required for generating epileptiform events, and a rise in the propagation velocity of these events. Immunocytochemistry for chemical markers of interneurons proved that the inhibitory input to layer I is predominantly somatostatin immunoreactive (SM-ir), such that layer I contains approximately one-third of all SM-ir axons in the cortex. Calretinin-immunoreactive axons were also present in layer I at a lower density. We conclude that the impact of layer I on the cortical cellular network includes a significant inhibitory component. This inhibition confers a moderate restraining influence, and its removal increases the excitability of cortical circuits, but not sufficiently to induce epileptic phenomena.