The neural causes of most complex behaviors are still not understood. It is thought that much of this is due to the fact that complex behavior depends on distributed neural control. Disruption in this causal web can produce effects that are difficult to trace back to their origin. Against this background, the finding that focal lesions of the ventromedial prefrontal cortex could lead to immoral and even criminal behavior has generated considerable interest. While a number of rare cases have now been described in which a focal lesion caused criminality, these are neither very consistent (the lesions occur in several different anatomical locations) nor at all reliable (only a small fraction of patients, for any lesion location, showed criminal behavior). To explain the effects of a lesion on criminal behavior, one needs to understand what it is that the lesion does to the rest of the brain. A network-level understanding of lesion effects is now provided by the new study of Darby and colleagues. In this study, all lesions were functionally connected to the same network of brain regions. This criminality-associated connectivity pattern was unique compared with lesions causing four other neuropsychiatric syndromes. The network includes regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Finally, the results were replicated in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was implied but not definitive. The results suggest that lesions in criminals occur in different brain locations but localize to a unique resting state network, providing insight into the neurobiology of criminal behavior.

 

Darby RR, Horn A, Cushman F and Fox MD: Lesion network localization of criminal behavior. Proc. Natl. Acad. Sci. USA  [Epub ahead of print, Dec. 18, 2017; doi: 10.1073/pnas.1706587115.]

https://www.ncbi.nlm.nih.gov/pubmed/29255017

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“Early life adversities including harsh parenting, maternal depression, neighborhood deprivation, and low family economic resources are more prevalent in low-income urban environments and are potent predictors of psychopathology, including, for boys, antisocial behavior. However, little research has examined how these stressful experiences alter later neural function. Moreover, identifying genetic markers of greater susceptibility to adversity is critical to understanding biopsychosocial pathways from early adversity to later psychopathology.

Within a sample of 310 low-income boys followed from age 1.5 to 20, multimethod assessments of adversities were examined at age 2 and age 12. At age 20, amygdala reactivity to emotional facial expressions was assessed using fMRI, and symptoms of Antisocial Personality Disorder were assessed via structured clinical interview. Genetic variability in cortisol signaling (CRHR1) was examined as a moderator of pathways to amygdala reactivity.

Observed parenting and neighborhood deprivation at age 2 each uniquely predicted amygdala reactivity to emotional faces at age 20 over and above other adversities measured at multiple developmental periods. Harsher parenting and greater neighborhood deprivation in toddlerhood predicted clinically-significant symptoms of antisocial behavior via less amygdala reactivity to fearful facial expressions and this pathway was moderated by genetic variation in CRHR1. These results elucidate a pathway linking early adversity to less amygdala reactivity to social signals of interpersonal distress 18 years later, which in turn increased risk for serious antisocial behavior. Moreover, these findings suggest a genetic marker of youth more susceptible to adversity.”

Gard AM, Waller R, Shaw DS, Forbes EE, Hariri AR and Hyde LW: The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2(7):582-590 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29170760

and

https://www.ncbi.nlm.nih.gov/pubmed/26386294

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Abstract: Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.

Chen G, Højer AM, Areberg J, Nomikos G: Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin. Pharmacokinet.  (Epub ahead of print, Nov. 30, 2017; doi: 10.1007/s40262-017-0612-7).

https://www.ncbi.nlm.nih.gov/pubmed/29189941

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The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. This study shows that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. Neurons with mixed-selective responses were necessary and sufficient for the morphing of code and it was observed that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. The authors suggest that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.

Parthasarathy A, Herikstad R, Bong JH, Medina FS, Libedinsky C, Yen SC: Mixed selectivity morphs population codes in prefrontal cortex. Nature Neuroscience 20(12): 1770-1779 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29184197

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Mutations in presenilin 1 and 2, which encode components of the γ-secretase complex, cause familial Alzheimer’s disease. It is hypothesized that altered γ-secretase mediated processing of the amyloid precursor protein to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. This paper describes an in vitro model system that enables analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In familial Alzheimer patient-derived fibroblast cultures, CRISPR activation of amyloid precursor protein or BACE unmasked an occult processivity defect in downstream γ-secretase -mediated carboxypeptidase cleavage of amyloid precursor protein, ultimately leading to higher Aβ42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on familial Alzheimer-mutant γ-secretase complexes, promoting CNS Aβ42 accumulation. These results introduce an additional platform for analysis of neurological disease.

Inoue K, Oliveira LMA, Abeliovich A:  CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts. Cell Rep. 21(7):1727-1736 (2017); doi: 10.1016/j.celrep.2017.10.075.

https://www.ncbi.nlm.nih.gov/pubmed/29141208

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During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, the authors used nonbiased analyses of microRNAs in the ventral hippocampus to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat.

Additionally, pharmacological approaches were used to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. The authors suggest that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the ventral hippocampus. Dampening inflammatory processes by administering anti-inflammatory agents appeared to reduce vulnerability to stress. These results have translational relevance as they suggest that administration of anti-inflammatory agents may reduce the impact of stress or trauma in vulnerable individuals.

Pearson-Leary J, Eacret D, Chen R, Takano H, Nicholas B, Bhatnagar S: Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. Transl. Psychiatry 7(6):e1160 (2017); doi: 10.1038/tp.2017.122.

https://www.ncbi.nlm.nih.gov/pubmed/28654094

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Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.

Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. The study is registered at ClinicalTrials.gov, number NCT00617162.

90 participants were randomly assigned to active or sham stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.

This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.

Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR, Abosch A, Pandurangi AK, Holloway KL, Lam RW, Honey CR, Neimat JS, Henderson JM, DeBattista C, Rothschild AJ, Pilitsis JG, Espinoza RT, Petrides G, Mogilner AY, Matthews K, Peichel D, Gross RE, Hamani C, Lozano AM, Mayberg HS: Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4(11):839-849 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28988904

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“GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, (the authors) tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. (The) data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development.”

Batista-Brito R, Vinck M, Ferguson KA, Chang JT, Laubender D, Lur G, Mossner JM, Hernandez VG, Ramakrishnan C, Deisseroth K, Higley MJ, Cardin JA: Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. Neuron 95(4): 884-895 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28817803

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Epigenetic modifications may underlie the influence of early life experiences on neuronal development and function, yet the molecular mechanisms are poorly understood.  In this paper, Stroud and colleagues report that deposition of repressive mCA marks by the methyltransferase DNMT3A across specific brain genes during early postnatal life is important for their regulation throughout life. DNMT3A preferentially binds across transcribed regions of lowly expressed genes, and changes in gene transcription activity affect this binding. Thus early life gene activity in the brain affects gene methylation and these changes persist into adulthood. This work has implications for drug treatments and other environmental factors which affect early life gene activity in the brain.

Stroud H, Su SC, Hrvatin S, Greben AW, Renthal W, Boxer LD, Nagy MA, Hochbaum DR, Kinde B, Gabel HW, Greenberg ME: Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States. Cell 171: 1-14 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29056337

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“The acetylcholine arousal system in the brain is needed for robust attention and working memory functions, but the receptor and cellular bases for its beneficial effects are poorly understood in the newly evolved primate brain. The current study found that cholinergic stimulation of nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhanced the firing of neurons in the primate prefrontal cortex that subserve top-down attentional control and working memory. α4β2-nAChR stimulation also protected neuronal responding from the detrimental effects of distracters presented during the delay epoch, when information is held in working memory. These results illuminate how acetylcholine strengthens higher cognition and help to explain why genetic insults to the α4 subunit weaken cognitive and attentional abilities.”

Sun Y, Yang Y, Galvin VC, Yang S, Arnsten AF and Wang M: Nicotinic α4β2 Cholinergic Receptor Influences on Dorsolateral Prefrontal Cortical Neuronal Firing during a Working Memory Task. J. Neurosci. 37(21): 5366-5377 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28450546

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