Identifying canonical and replicable multi-scale intrinsic connectivity networks in 100k+ resting-state fMRI datasets.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Depression, marijuana use and early-onset marijuana use conferred unique effects on neural connectivity and cognition.

OBJECTIVE: Marijuana (MJ) use is common. Research shows risks for psychiatric illnesses, including major depressive disorder (MDD) and cognitive deficits with MJ use, particularly early-onset use. We investigated cognitive function, functional connectivity, and genetic risk with MDD alone and combined with MJ use, and differences between early-vs. late-onset/non-MJ use in youth. METHOD: A total of 74 youth in four groups were studied: healthy control, MDD, frequent MJ use and current/past MDD plus frequent MJ use. Psychiatric symptoms, cognitive performance and demographics were measured. Default mode network (DMN) brain connectivity was determined. Risk alleles in six genes of interest were evaluated. RESULTS: DMN differences among groups in reward-processing and motor control regions were found; the effects of MJ use and MDD were distinct. Early-onset MJ use was associated with lower IQ and hyperconnectivity within areas of the DMN. Early-onset MJ use was associated with the BDNF risk allele. CONCLUSIONS: Cognitive deficits linked with early-onset MJ use were present within several years after MJ use began and may result from, predispose to, or share a common cause with early-onset MJ use. The DMN was affected by MDD, MJ and their combination, as well as by early-onset MJ use. BDNF carrier state may predispose to early-onset MJ use.

Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men.

OBJECTIVE: Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender. METHOD: In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women. RESULTS: A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42). CONCLUSION: The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder.

BACKGROUND: Nuclear imaging studies have examined cerebral blood flow (rCBF) in subjects with posttraumatic stress disorder (PTSD) using symptom evocation paradigms. To date, no such studies have investigated rCBF as related to subjects' reports of flashback intensity. METHODS: Subjects with varying traumatic histories and longstanding PTSD were studied using [15O]-H2O positron emission tomography with an auditory script of their traumatic event. Eight subjects had three resting scans followed by their script and additional scans. Heart rate responses as well as the presence of flashbacks and their intensity were recorded. rCBF was correlated with flashback intensity in each subject's scan. Combined analysis of all subjects' data yielded common regions related to the flashback experience. RESULTS: rCBF correlated directly with flashback intensity in the brainstem, lingula, bilateral insula, right putamen and left hippocampal and perihippocampal, somatosensory and cerebellar regions. Inverse correlations with rCBF were found in bilateral dorsolateral prefrontal, right fusiform and right medial temporal cortices. CONCLUSIONS: This study correlated flashback intensity and rCBF in a group of patients with chronic PTSD suggesting involvement of brainstem, and areas associated with motor control, complex visual/spatial cues and memory.

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients.

BACKGROUND: We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity. METHODS: Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons. RESULTS: After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.

Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review.

Recent evidence suggests that lithium therapy (even as supplemented by antidepressants and neuroleptics) is inadequate for the majority of patients with bipolar illness, and particularly those with rapid cycling. Valproate and carbamazepine have emerged as adjuncts and alternatives, but they, too, often require additional approaches with lithium, thyroid hormones, and other putative mood stabilizers, including nimodipine (and related dihydropyridine calcium channel blockers), lamotrigine, gabapentin, topiramate, and the atypical neuroleptics. Evaluating how these agents and the unimodal antidepressants are optimally applied and sequenced in the treatment of bipolar illness with its multiple subtypes, patterns and comorbidities will require much future investigation and the development of new methodological clinical trial approaches.

CSF thyrotropin-releasing hormone gender difference: implications for neurobiology and treatment of depression.

In light of the postulated role of thyrotropin-releasing hormone (TRH) as an endogenous anti-depressant, 56 refractory mood-disordered patients and 34 healthy adult control subjects underwent lumbar puncture for cerebrospinal fluid (CSF) TRH analysis. By two-way analysis of variance, there was no difference between CSF TRH in patients (as a group or by diagnostic subtype) and control subjects (n = 90, F = 0.91, df = 2.84, P = 0.41). There was, however, a CSF TRH gender difference (females, 2.95 pg/ml; males, 3.98 pg/ml; n = 90, F = 4.11, df = 1.84, P < 0.05). A post hoc t-test revealed the greatest gender difference in the bipolar group (t = 2.52, P < 0.02). There was no significant difference in CSF TRH in "ill" vs. "well" state (n = 20, P = 0.41). The role of elevated levels of CSF TRH in affectively ill men--or the role of decreased levels of CSF TRH in affectively ill women--remains to be investigated but could be of pathophysiological relevance.

Repetitive transcranial magnetic stimulation as a neuropsychiatric tool: present status and future potential.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic intervention in the treatment of affective disorders. The differences in the type of electrical stimulation required for therapeutic efficacy by rTMS and electroconvulsive therapy (ECT) are discussed. In contrast to ECT, rTMS would not appear to require the generation of a major motor seizure to achieve therapeutic efficacy. Accordingly, it carries the potentially important clinical advantages of not requiring anesthesia and of avoiding side effects such as transient memory loss. Preclinical studies on long-term potentiation (LTP) and long-term depression (LTD) in hippocampal and amygdala slices, as well as clinical data from neuroimaging studies, have provided encouraging clues for potential frequency-dependent effects of rTMS. Preliminary evidence from position emission tomography (PET) scans suggests that higher frequency (20 Hz) stimulation may increase brain glucose metabolism in a transsynaptic fashion, whereas lower frequency (1 Hz) stimulation may decrease it. Therefore, the ability of rTMS to control the frequency as well as the location of stimulation, in addition to its other advantages, has opened up new possibilities for clinical explorations and treatments of neuropsychiatric conditions.

The motivations for self-injury in psychiatric inpatients.

Nonsuicidal self-injurious behavior (SIB) occurs in both culturally appropriate and culturally inappropriate forms. It is one of the diagnostic criteria for borderline personality disorder, but it occurs in several psychiatric and neurological populations. The personal intent of SIB in psychiatric populations is incompletely understood. A self-report scale (Self-Injury Motivation Scale; SIMS) to assess motivation for self-injury was developed. Relationships among motivation for SIB, characteristics of SIB, and psychopathology were explored. A semistructured interview and the SIMS, Dissociative Experiences Scale, Beck Depression Inventory, Davidson Trauma Scale, and Millon Clinical Multiaxial Inventory-II were given to 99 consecutively admitted inpatients. The SIMS had good reliability and validity. A high SIMS score suggested distinct psychopathology. Several factors on the SIMS differentiated motivations for SIB. Patients with different SIMS factor profiles had different psychopathology.

Neural plasticity and emotional memory.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.