The effectiveness of the combined transcranial direct current stimulation (tDCS) and tailor-made notched music training (TMNMT) on psychoacoustic, psychometric, and cognitive indices of tinnitus patients.

PURPOSE: Tinnitus network(s) consists of pathways in the auditory cortex, frontal cortex, and the limbic system. The cortical hyperactivity caused by tinnitus may be suppressed by neuromodulation techniques. Due to the lack of definitive treatment for tinnitus and limited usefulness of the individual methods, in this study, a combination of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) and tailor-made notched music training (TMNMT) was used. MATERIAL AND METHODS: In this descriptive-analytic study, 26 patients with chronic unilateral tinnitus of the right ear were randomly divided into the clinical trial group (CTG) and the control group (CG). In both groups, six sessions of tDCS with 2 mA intensity for 20 min, with anode on F4 and cathode on F3, were conducted. Simultaneous with tDCS sessions, and based on TMNMT, the participant was asked to listen passively for 120 min/day, to a CD containing her/his favorite music with a proper notch applied in its spectrum according to the individual's tinnitus The treatment outcome was measured by, psychoacoustic (loudness-matching), psychometric (awareness, loudness and annoyance Visual Analogue Scale (VAS) scores, and Tinnitus Handicap Inventory (THI)) scores, and cognitive assessments (randomized dichotic digits test (RDDT) and dichotic auditory-verbal memory test (DAVMT)). Repeated measurement test was used for statistical analyses. RESULTS: In the CTG, the tinnitus loudness and annoyance VAS scores, and THI were reduced significantly (p = 0.001). In addition, the DAVMT and RDDT scores were enhanced (p = 0.001). Such changes were not observed in the CG (p > 0.05). CONCLUSION: The combination of tDCS and TMNMT led to a reduction in the loudness, awareness, annoyance, and also disability induced by tinnitus in CTG. Furthermore, this method showed an improvement of cognitive functions (auditory divided attention, selective attention and working memory) in the CTG.

Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice.

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

Mental Health from Medical School to Medical Practice: Finding a Path Forward.

Medical students, residents, and practicing physicians experience high burnout, depression, and suicide rates, and the COVID-19 pandemic has exacerbated stress for many.1-6 While laudable, current well-being efforts appear insufficient to meet the challenges that so many are facing. This essay explores approaches that individuals and organizations can take to promote mental health and well-being from medical school to practice.

Altered functional connectivity between hypothalamus and limbic system in fibromyalgia.

The hypothalamus links the nervous system to the endocrine system and plays a crucial role in maintaining the human body's homeostasis. This study aims to investigate the resting state functional connectivity (rsFC) changes of the hypothalamus in fibromyalgia patients. 24 Fibromyalgia patients and 24 matched healthy controls (HCs) were recruited. Resting state fMRI data were collected from the fibromyalgia patients and HC's. Fibromyalgia patients went through a second scan after 12 weeks of Tai Chi mind-body intervention. Data analysis showed that fibromyalgia patients displayed less medial hypothalamus (MH) rsFC with the thalamus and amygdala when compared to the functional connectivity in the HCs. After the Tai Chi mind-body intervention, fibromyalgia patients showed increased MH rsFC with the thalamus and amygdala accompanied by clinical improvement. Effective connectivity analysis showed disrupted MH and thalamus interaction in the fibromyalgia patients, which was altered by mind-body exercise. Our findings suggest that fibromyalgia is associated with altered functional connectivity within the diencephalon and limbic system. Elucidating the roles of the diencephalon and limbic system in the pathophysiology and development of fibromyalgia may facilitate the development of a new biomarker and effective treatment methods for this prevalent disorder.Trial Registration ClinicalTrials.gov, NCT02407665. Registered: 3 April 2015, https://clinicaltrials.gov/ct2/show/NCT02407665?term=NCT02407665&draw=2&rank=1.

Limbic cortico-striato-thalamo-cortical functional connectivity in drug-naïve patients of obsessive-compulsive disorder.

BACKGROUND: The pathophysiology of obsessive-compulsive disorder (OCD) remains unclear despite extensive neuroimaging work on the disorder. Exposure to medication and comorbid mental disorders can confound the results of OCD studies. The goal of this study was to explore differences in brain functional connectivity (FC) within the cortico-striato-thalamo-cortical (CSTC) loop of drug-naïve and drug-free OCD patients and healthy controls (HCs). METHODS: A total of 29 drug-naïve OCD patients, 22 drug-free OCD patients, and 25 HCs matched on age, gender and education level underwent functional magnetic resonance imaging scanning at resting state. Seed-based connectivity analyses were conducted among the three groups. The Yale Brown Obsessive Compulsive Scale and clinical inventories were used to assess the clinical symptoms. RESULTS: Compared with HCs, the drug-naïve OCD patients had reduced FC within the limbic CSTC loop. In the drug-naïve OCD participants, we also found hyperconnectivity between the supplementary motor area and ventral and dorsal putamen (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Exposure to antidepressants such as selective serotonin reuptake inhibitors may affect the function of some brain regions. Future longitudinal studies could help to reveal the pharmacotherapeutic mechanisms in these loops.

Functional constipation is associated with alterations in thalamo-limbic/parietal structural connectivity.

BACKGROUND: Functional constipation (FCon) is a common functional gastrointestinal disorder (FGID) with a high prevalence in clinical practice. Previous studies have identified that FCon is associated with functional and structural alterations in the primary brain regions involved in emotional arousal processing, sensory processing, somatic/motor-control, and self-referential processing. However, whether FCon is associated with abnormal structural connectivity (SC) among these brain regions remains unclear. METHODS: We selected the brain regions with functional and structural abnormalities as seed regions and employed diffusion tensor imaging (DTI) with probabilistic tractography to investigate SC changes in 29 patients with FCon and 31 healthy controls (HC). KEY RESULTS: Results showed lower fractional anisotropy (FA) in the fibers connecting the thalamus, a region involved in sensory processing, with the amygdala (AMY), hippocampal gyrus (HIPP), precentral (PreCen) and postcentral gyrus (PostCen), supplementary motor area (SMA) and precuneus in patients with FCon compared with HC. FCon had higher mean diffusivity (MD) and radial diffusivity (RD) in the thalamus connected to the AMY and HIPP. In addition, FCon had significantly increased RD of the thalamus-SMA tract. Sensation of incomplete evacuation was negatively correlated with FA of the thalamus-PostCen and thalamus-HIPP tracts, and there was a negative correlation between difficulty of defecation and FA of the thalamus-SMA tract. CONCLUSIONS AND INFERENCES: These findings reflected that FCon is associated with alterations in SC between the thalamus and limbic/parietal cortex, highlighting the integrative role of the thalamus in brain structural network.

Cerebellar-limbic neurocircuit is the novel biosignature of physio-cognitive decline syndrome.

Both physical and cognitive deficits occur in the aging process. We operationally defined the phenomenon as physio-cognitive decline syndrome (PCDS) and aimed to decipher its corresponding neuroanatomy patterns and neurocircuit. High resolution 3T brain magnetic resonance imaging (MRI) images from a community-dwelling longitudinal aging cohort were analysed. PCDS was defined as weakness (handgrip strength) and/or slowness (gait speed) concomitant with impairment in any cognitive domain (defined by 1.5 standard deviation below age, sex-matched norms), but without dementia or disability. Among 1196 eligible ≥ 50-year-old (62±9 years, 47.6%men) subjects, 15.9% had PCDS. Compared to the other participants, individuals with PCDS had significantly lower gray-matter volume (GMV) in the bilateral amygdala and thalamus, right hippocampus, right temporo-occipital cortex, and left cerebellum VI and V regions. The regions of reduced GMV in people with PCDS were similar between the middle-aged and older adults; whereas larger clusters with more extensive GMV-depleted regions were observed in ≥65-year-olds with PCDS. Diffusion-weighted tractography showed disrupted hippocampus-amygdala-cerebellum connections in subjects with PCDS. The neuroanatomic characteristics revealed by this study provide evidence for pathophysiological processes associated with concomitant physio-cognitive decline in the elderly. This neurocircuit might constitute a target for future preventive interventions.

Electro-acupuncture alleviates adolescent cocaine exposure-enhanced anxiety-like behaviors in adult mice by attenuating the activities of PV interneurons in PrL.

We recently found that adolescent cocaine exposure (ACE) resulted in an enhancement of the γ-aminobutyric acid (GABA) neurotransmitter system in the prelimbic cortex (PrL) of adult mice. Here, we aim to further investigate the role of GABAergic transmission, especially parvalbumin (PV) interneurons within PrL in the development of ACE-induced anxiety-like behavior, and to assess whether and how electro-acupuncture (EA) therapeutically manage the ACE-induced abnormal behaviors in adulthood. ACE mice exhibited the enhanced anxiety-like behaviors in their adulthood, accompanied by increased GABAergic transmission and PV interneurons in PrL. Chemogenetic blocking PV interneurons in PrL alleviated ACE-enhanced anxiety-like behaviors in mice. Importantly, 37-day EA treatments (mixture of 2 Hz/100 Hz, 1 mA, 30 minutes once a day) at the acupoints of Yintang (GV29) and Baihui (GV20) also alleviated ACE-induced anxiety-like behaviors, and rescued ACE-impaired GABAergic neurotransmitter system and PV interneurons in PrL. In parallel, EA treatments further suppressed the activities of pyramidal neurons in PrL, suggesting that EA treatments seem to perform it beneficial effects on the ACE-induced abnormal emotional behaviors by "calming down" the whole PrL. Collectively, these findings revealed that hyper-function of GABAergic transmission, especially mediating by PV interneurons in PrL may be key etiology underlying ACE-induced anxiety-like behaviors. At least by normalizing the function of GABAergic and PV interneurons, EA may represent a promising therapeutic strategy for managing adolescent substance use-related emotional disorders.

Disrupted pathways from limbic areas to thalamus in schizophrenia highlighted by whole-brain resting-state effective connectivity analysis.

BACKGROUND: Numerous neuroimaging studies have revealed that schizophrenia was characterized by wide-spread dysconnection among brain regions during rest measured by functional connectivity (FC). In contrast with FC, effective connectivity (EC) provides information about directionality of brain connections and is thus valuable in mechanistic investigation of schizophrenic brain. However, a systematic characterization of whole-brain resting-state EC (rsEC) and how it captures different information compared with resting-state FC (rsFC) in schizophrenia are still lacking. AIMS: To systematically characterize the abnormalities of rsEC, compared with rsFC, in schizophrenia, and to test its discriminative power as a neuroimaging marker for schizophrenia diagnosis. METHOD: Whole-brain rsEC and rsFC networks were constructed using resting-state fMRI data and compared between 103 patients with schizophrenia and 110 healthy participants. Pattern classifications between patients and controls based on whole-brain rsEC and rsFC were further performed using multivariate pattern analysis. RESULTS: We identified 17 rsEC significantly disrupted (mostly decreased) in patients, among which all were associated with the thalamus and 15 were from limbic areas (including hippocampus, parahippocampus and cingulate cortex) to the thalamus. In contrast, abnormal rsFC were widely distributed in the whole brain. The classification accuracies for distinguishing patients and controls using whole-brain rsEC and rsFC patterns were 78.6% and 82.7%, respectively, and was further improved to 84.5% when combining rsEC and rsFC. CONCLUSIONS: Schizophrenia is featured by disrupted 'limbic areas-to-thalamus' rsEC, in contrast with diffusively altered rsFC. Moreover, both rsEC and rsFC contain valuable and complementary information which may be used as diagnostic markers for schizophrenia.

Dynamic Changes of Functional Neuronal Activities Between the Auditory Pathway and Limbic Systems Contribute to Noise-Induced Tinnitus with a Normal Audiogram.

Tinnitus is thought to be triggered by aberrant neural activity in the central auditory pathway and is often accompanied by comorbidities of emotional distress and anxiety, which imply maladaptive functional connectivity to limbic structures, such as the amygdala and hippocampus. Tinnitus patients with normal audiograms can also have accompanying anxiety and depression, clinically. To test the role of functional connectivity between the central auditory pathway and limbic structures in patients with tinnitus with normal audiograms, we developed a murine noise-induced tinnitus model with a temporary threshold shift (TTS). Tinnitus mice exhibited reduced auditory brainstem response wave I amplitude, and an enhanced wave IV amplitude and wave IV/I amplitude ratio, as compared with control and non-tinnitus mice. Resting-state functional magnetic resonance imaging (fMRI) was used to identify abnormal connectivity of the amygdala and hippocampus and to determine the relationship with tinnitus characteristics. We found increased fMRI responses with amplitude of low-frequency fluctuation (ALFF) in the auditory cortex and decreased ALFF in the amygdala and hippocampus at day 1, but decreased ALFF in the auditory cortex and increased ALFF in the amygdala at day 28 post-noise exposure in tinnitus mice. Decreased functional connectivity between auditory brain regions and limbic structures was demonstrated at day 28 in tinnitus mice. Therefore, aberrant neural activities in tinnitus mice with TTS involved not only the central auditory pathway, but also limbic structures, and there was maladaptive functional connectivity between the central auditory pathway and limbic structures, such as the amygdala and hippocampus.

Nuclei-specific thalamic connectivity predicts seizure frequency in drug-resistant medial temporal lobe epilepsy.

BACKGROUND AND OBJECTIVES: We assessed correlations between the resting state functional connectivity (RSFC) of different thalamic nuclei and seizure frequency in patients with drug-resistant medial temporal lobe epilepsy (mTLE). METHODS: Seventeen patients with mTLE and 17 sex-/age-/handedness-matched controls participated. A seed-based correlation method for the resting-state FMRI data was implemented to get RSFC maps of 70 thalamic nuclei seed masks. Group statistics for individual RSFC for subjects and seed masks were performed to obtain within-group characteristics and between-group differences with age covariates. A linear regression was applied to test whether seizure frequency correlated with thalamic nuclear RSFC with the whole brain in mTLE patients. RESULTS: RSFC of thalamic nuclei showed spatially distinguishable connectivity patterns that reflected principal inputs and outputs that were derived from priori anatomical knowledge. We found group differences between normal control and mTLE groups in RSFC for nuclei seeds located in various subdivisions of thalamus. The RSFCs in some of those nuclei were strongly correlated with seizure frequency. CONCLUSIONS: Mediodorsal thalamic nuclei may play important roles in seizure activity or in the regulation of neuronal activity in the limbic system. The RSFC of motor- and sensory-relay nuclei may help elucidate sensory-motor deficits associated with chronic seizure activity. RSFC of the pulvinar nuclei of the thalamus could also be a key reflection of symptom-related functional deficits in mTLE.

Limbic response to stress linking life trauma and hypothalamus-pituitary-adrenal axis function.

Trauma alters neuroendocrine responses to stress and increases vulnerability to stress-related disorders. Yet, relationships among trauma, stress-induced neural changes and hypothalamic-pituitary-adrenal (HPA) axis activity have not been determined. The present study used functional magnetic resonance imaging to investigate the impact of life trauma on basal cortisol levels and neural responses to acute stress in 73 healthy individuals during brief stress and neutral-relaxing imagery using a well-established, individualized imagery method. We hypothesized that trauma experience would have a negative impact on brain function, resulting in altered basal cortisol levels via dysregulated neural control over the HPA axis system. Results showed that higher life trauma exposure was significantly associated with lower basal cortisol levels. Neuroimaging results indicated that both higher life trauma and low morning cortisol levels were associated with increased response to acute stress in limbic-medial temporal lobe (MTL) regions including the amygdala and hippocampus. A mediation analysis showed that increased limbic-MTL response to stress mediated the relationship between life trauma and low cortisol levels. Findings revealed a significant impact of lifetime trauma on neural responses to acute stress and HPA axis activity. Life trauma may sensitize limbic-MTL regions and its related peripheral systems, which could compromise stress regulation and HPA axis function, and increase risk for negative stress-related health outcomes.

Top-down and bottom-up control of stress-coping.

In this 30th anniversary issue review, we focus on the glucocorticoid modulation of limbic-prefrontocortical circuitry during stress-coping. This action of the stress hormone is mediated by mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that are co-expressed abundantly in these higher brain regions. Via both receptor types, the glucocorticoids demonstrate, in various contexts, rapid nongenomic and slower genomic actions that coordinate consecutive stages of information processing. MR-mediated action optimises stress-coping, whereas, in a complementary fashion, the memory storage of the selected coping strategy is promoted via GR. We highlight the involvement of adipose tissue in the allocation of energy resources to central regulation of stress reactions, point to still poorly understood neuronal ensembles in the prefrontal cortex that underlie cognitive flexibility critical for effective coping, and evaluate the role of cortisol as a pleiotropic regulator in vulnerability to, and treatment of, trauma-related psychiatric disorders.

Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment.

BACKGROUND AND PURPOSE: In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI). METHODS: We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load. RESULTS: We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant. CONCLUSIONS: Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

Epileptic Seizures are Reduced by Autonomic Biofeedback Therapy Through Enhancement of Fronto-limbic Connectivity: A Controlled Trial and Neuroimaging Study.

BACKGROUND: Thirty-percent of patients with epilepsy are drug-resistant, and might benefit from effective noninvasive therapeutic interventions. Evidence is accumulating on the efficacy of autonomic biofeedback therapy using galvanic skin response (GSR; an index of sympathetic arousal) in treating epileptic seizures. This study aimed to extend previous controlled clinical trials of autonomic biofeedback therapy with a larger homogeneous sample of patients with temporal lobe epilepsy. In addition, we used neuroimaging to characterize neural mechanisms of change in seizure frequency following the therapy. METHODS: Forty patients with drug-resistant temporal lobe epilepsy (TLE) (age: 18 to 70years old), on stable doses of anti-epileptic medication, were recruited into a controlled and parallel-group trial from three screening centers in the UK. Patients were allocated to either an active intervention group, who received therapy with GSR biofeedback, or a control group, who received treatment as usual. Allocation to the group was informed, in part, by whether patients could travel to attend repeated therapy sessions (non-randomized). Measurement of outcomes was undertaken by an assessor blinded to the patients' group membership. Resting-state functional and structural MRI data were acquired before and after one month of therapy in the therapy group, and before and after a one-month interval in the control group. The percentage change of seizure frequency was the primary outcome measure. The analysis employed an intention-to-treat principle. The secondary outcome was the change in default mode network (DMN) and limbic network functional connectivity tested for effects of therapy. The trial was registered with the National Institute for Health Research (NIHR) portfolio (ID 15967). FINDINGS: Data were acquired between May 2014 and October 2016. Twenty participants were assigned to each group. Two patients in the control group dropped out before the second scan, leaving 18 control participants. There was a significant difference in reduction of seizure frequency between the therapy and control groups (p<0.001: Mann Whitney U Test). The seizure frequency in the therapy group was significantly reduced (p<0.001: Wilcoxon Signed Rank Test) following GSR biofeedback, with a mean seizure reduction of 43% (SD=± 32.12, median=-37.26, 95% CI -58.02% to -27.96%). No significant seizure reduction was observed in the control group, with a mean increase in seizure frequency of 31% (SD=±88.27, median=0, 95% CI -12.83% to 74.96%). The effect size of group comparison was 1.14 (95% CI 0.44 to 1.82). 45% of patients in the therapy group showed a seizure reduction of >50%. Neuroimaging analysis revealed that post-therapy seizure reduction was linearly correlated with enhanced functional connectivity between right amygdala and both the orbitofrontal cortex (OFC) and frontal pole (FP). INTERPRETATION: Our clinical study provides evidence for autonomic biofeedback therapy as an effective and potent behavioral intervention for patients with drug-resistant epilepsy. This approach is non-pharmacological, non-invasive and seemingly side-effect free.

Central Modulation of Energy Homeostasis and Cognitive Performance After Bariatric Surgery.

In moderately or morbidly obese patients, bariatric surgery has been proven to be an effective therapeutic approach to control body weight and comorbidities. Surgery-mediated modulation of brain function via modified postoperative secretion of gut peptides and vagal nerve stimulation was identified as an underlying mechanism in weight loss and improvement of weight-related diseases. Increased basal and postprandial plasma levels of gastrointestinal hormones like glucagon-like peptide 1 and peptide YY that act on specific areas of the hypothalamus to reduce food intake, either directly or mediated by the vagus nerve, are observed after surgery while suppression of meal-induced ghrelin release is increased. Hormones released from the adipose tissue like leptin and adiponectin are also affected and leptin plasma levels are reduced in treated patients. Besides homeostatic control of body weight, surgery also changes hedonistic behavior in regard to food intake and cognitive performance involving the limbic system and prefrontal areas.

Genetic resistance to kindling associated with alterations in circuit function.

How a seizure spreads from a focal onset zone to other regions of the brain is not well understood, and animal studies suggest that there is a genetic influence. To understand how genetic factors may influence seizure spread, we examined whether the kindling resistance of WAG/Rij rats, which are slow to develop kindled motor seizures, is independent of the site of seizure induction and thus a global phenomenon, or whether it is circuit specific. We compared the kindling rates (number of stimulations to induce kindled motor seizures) of WAG/Rij rats to the rates of kindling in Sprague Dawley rats. Both groups underwent a standard hippocampal kindling protocol and a separate group was kindled from the medial dorsal nucleus of the thalamus, a site that has been previously demonstrated to result in the very rapid development of motor seizures. To examine whether there were differences in the interaction in a circuit involved with the motor seizures, evoked responses were obtained from the prefrontal cortex following stimulation of the subiculum or medial dorsal thalamic nucleus. The WAG/Rij rats once again demonstrated resistance to kindling in the hippocampus, but both strains kindled rapidly from the medial dorsal nucleus. In the WAG/Rij rats there was also a reduction in the duration of the afterdischarge in the frontal cortex during hippocampal stimulation, but there was no reduction during thalamic kindling. The prefrontal cortex evoked responses were reduced following stimulation of the subiculum in the WAG/Rij rats, but the evoked responses to thalamic stimulation were the same in both strains. These findings suggest that there are genetic influences in the strength of the input from the subiculum to the prefrontal cortex in WAG/Rij rats that could explain the resistance to limbic kindling because of reduced excitatory drive onto a key target region.

Limbic-thalamo-cortical projections and reward-related circuitry integrity affects eating behavior: A longitudinal DTI study in adolescents with restrictive eating disorders.

Few studies have used diffusion tensor imaging (DTI) to investigate the micro-structural alterations of WM in patients with restrictive eating disorders (rED), and longitudinal data are lacking. Twelve patients with rED were scanned at diagnosis and after one year of family-based treatment, and compared to twenty-four healthy controls (HCs) through DTI analysis. A tract-based spatial statistics procedure was used to investigate diffusivity parameters: fractional anisotropy (FA) and mean, radial and axial diffusivities (MD, RD and AD, respectively). Reduced FA and increased RD were found in patients at baseline in the corpus callosum, corona radiata and posterior thalamic radiation compared with controls. However, no differences were found between follow-up patients and controls, suggesting a partial normalization of the diffusivity parameters. In patients, trends for a negative correlation were found between the baseline FA of the right anterior corona radiata and the Eating Disorder Examination Questionnaire total score, while a positive trend was found between the baseline FA in the splenium of corpus callosum and the weight loss occurred between maximal documented weight and time of admission. A positive trend for correlation was also found between baseline FA in the right anterior corona radiata and the decrease in the Obsessive-Compulsive Inventory Revised total score over time. Our results suggest that the integrity of the limbic-thalamo-cortical projections and the reward-related circuitry are important for cognitive control processes and reward responsiveness in regulating eating behavior.

Circadian Rhythms and Substance Abuse: Chronobiological Considerations for the Treatment of Addiction.

Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.