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Cannabis (CB) use and psychological stressors increase oxidative stress in the brain. Glutathione (GSH), the most abundant antioxidant in the brain, protects against oxidative stress. Furthermore, distress intolerance, the inability to tolerate psychological or physiological stress is a risk factor for CB use. The relationship between CB use, brain GSH levels and distress intolerance remains unknown. Therefore, we examined GSH levels in the anterior cingulate cortex (ACC), as a measure of oxidative stress, and its relationship with distress intolerance in adolescent CB users and healthy controls (HC). Sixteen HC and 17 CB-using adolescents were included in the analysis. GSH levels were measured in the ACC using a metabolite-edited proton magnetic resonance spectroscopy sequence on a 3T scanner. Distress intolerance was assessed using the Distress Intolerance Index (DII) and CB use was evaluated using a structured clinical interview. In the CB group, lower CSF-corrected GSH levels in the ACC were correlated with higher DII scores. However, no significant between group differences were observed for ACC CSF-corrected GSH levels or on DII scores. No significant correlations were observed in the HC group between GSH levels and DII. Our findings suggests that the association between lower GSH levels and greater distress intolerance in CB users might reflect alterations in the balance between protective and oxidative stress conditions linked to the ability to tolerate distress. Further examination into this relationship can provide important insights into neurobiological correlates and risk factors associated with CB use to help inform preventive and treatment targets in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Adolescent marijuana (MJ) use has been associated with alterations in brain structure and function as well as behavior. Examination of neurochemical correlates such as GABA (gamma-aminobutyric acid) and Glx (glutamate + glutamine) in MJ users remains limited. Impulsivity, identified as a risk factor and consequence of MJ use, has been associated with GABA and Glx levels in healthy and clinical populations. However, this relationship has not been investigated in MJ users. In this study, we examined levels of GABA and Glx in the anterior cingulate cortex (ACC) and its relationship with impulsive behavior in MJ-using adolescents and healthy controls., Methods: Healthy control subjects (HC; N = 21) and MJ-using adolescents (N = 18) completed a metabolite-edited 1 H MRS exam to measure ACC GABA and Glx levels, a structured clinical interview to assess MJ use, and the Barratt Impulsivity Scale (BIS-11) to evaluate impulsive behavior., Results: Adolescent MJ users had significantly lower tissue-corrected GABA (with macromolecules; GABA+) levels (p = 0.029) compared to HC's. No significant between-group differences were observed in ACC Glx levels. Assessment of impulsive behavior demonstrated no significant between-group differences in motor, non-planning, attention, and total impulsivity scores. Additionally, impulsivity measures and tissue-corrected GABA+ or Glx levels were not significantly correlated in either group., Conclusion: Lower GABA levels in MJ users may indicate alterations in excitatory-inhibitory mechanisms critical for neurodevelopment. Although no significant relationships were observed between impulsive measures and GABA or Glx levels in both groups, further investigations are needed examining the relationship between neurochemical correlates, behavior, and adolescent MJ use., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance., Objective: In rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks., Methods: Forty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed., Results: Scalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response., Conclusion: EEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems., Competing Interests: Declaration of competing interest Dr. Rosen, Ms. Bhat, Dr. Cardenas, Dr. Ehrlich, Ms. Horwege, Mr. Lavacot, Mr. Roach, Dr. Glover, Dr. Forman, Dr. Yurgelun-Todd, and Dr. Yesavage have no conflicts to disclose. Dr. Mathalon is a consultant for Boehringer Ingelheim and Caden Therapeutics. Dr. Badran owns a minority stake in Bodhi NeuroTech Inc., which manufactures meditation enhancing devices and holds patents in this area assigned to the Medical University of South Carolina. Dr. George holds research grants through the Medical University of South Carolina with Brainsway and LivaNova. He is on the scientific advisory board, uncompensated, for Magstim, Brainsway. He has equipment loaned from MECTA and Nexstim. He is on the scientific advisory board for Neuralief (compensated). He has no ownership of any brain stimulation device company. He is the editor in chief of Brain Stimulation, published by Elsevier. Dr. Thase reports no conflicts of interest with this research. Dr. Thase reports the following other relationships over the past three years: Advisory/Consultant—Acadia, Alkermes, Allergan (Forest, Naurex), Axsome, Clexio, Johnson & Johnson (Janssen, Ortho-McNeil), Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda; Grant Support—Acadia, Allergan (Forest, Naurex), Alkermes, Axsome, Clexio, Myriad (AssureRx), Axsome, Intracellular, Janssen, National Institute of Mental Health, Otsuka, Patient Centered Outcomes Research Institute, Takeda; Royalties—American Psychiatric Press, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Dr. Thases's spouse, Diane Sloan, PharmD, is a Senior Medical Director for Peloton Advantage, which does business with a number of pharmaceutical companies., (Copyright © 2021. Published by Elsevier Inc.)

Background: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12., Methods: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD)., Primary Results: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p's<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03)., Conclusions: ABCD Study participants aged 9-10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Precise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression., Objective: To use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations., Methods: An imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks., Results: The average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome., Conclusion: These results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans., Competing Interests: Declaration of competing interest Dr. Rosen, Ms. Bhat, Dr. Cardenas, Dr. Ehrlich, Ms. Horwege, Mr. Roach, Dr. Glover, Dr. Forman, Dr. Yurgelun-Todd, Dr. Scott, Dr. Tian, and Dr. Yesavage have no conflicts to disclose. Dr. Mathalon is a consultant for Boehringer Ingelheim and Caden Therapeutics. Dr. Badran owns a minority stake in Bodhi NeuroTech Inc., which manufactures meditation enhancing devices and holds patents in this area assigned to the Medical University of South Carolina. Dr. George holds research grants through the Medical University of South Carolina with Brainsway and LivaNova. He is on the scientific advisory board, uncompensated, for Magstim, Brainsway. He has equipment loaned from MECTA and Nexstim. He is on the scientific advisory board for Neuralief (compensated). He has no ownership of any brain stimulation device company. He is the editor in chief of Brain Stimulation, published by Elsevier. Dr. Thase reports no conflicts of interest with this research. Dr. Thase reports the following other relationships over the past three years: Advisory/Consultant—Acadia, Alkermes, Allergan (Forest, Naurex), Axsome, Clexio, Johnson & Johnson (Janssen, Ortho-McNeil), Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda; Grant Support—Acadia, Allergan (Forest, Naurex), Alkermes, Axsome, Clexio, Myriad (AssureRx), Axsome, Intracellular, Janssen, National Institute of Mental Health, Otsuka, Patient Centered Outcomes Research Institute, Takeda; Royalties—American Psychiatric Press, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Dr. Thases’s spouse, Diane Sloan, PharmD, is a Senior Medical Director for Peloton Advantage, which does business with a number of pharmaceutical companies. Dr. Doyen and Dr. Sughrue are directors of Onminscient Neurotechnology Pty. and hold company shares. Dr. Doyen, Dr. Sughrue, and Mr. Nicholas are employees of Omniscient Neurotechnology Pty. Mr. Nicholas holds company employee options in Omniscient Neurotechnology Pty., (Copyright © 2021. Published by Elsevier Inc.)

The Adolescent Brain and Cognitive Development (ABCD) Study incorporates a comprehensive range of measures assessing predictors and outcomes related to both mental and physical health across childhood and adolescence. The workgroup developed a battery that would assess a comprehensive range of domains that address study aims while minimizing participant and family burden. We review the major considerations that went into deciding what constructs to cover in the demographics, physical health and mental health domains, as well as the process of selecting measures, piloting and refining the originally proposed battery. We present a description of the baseline battery, as well as the six-month interim assessments and the one-year follow-up assessments. This battery includes assessments from the perspectives of both the parent and the target youth, as well as teacher reports. This battery will provide a foundational baseline assessment of the youth's current function so as to permit characterization of stability and change in key domains over time. The findings from this battery will also be utilized to identify both resilience markers that predict healthy development and risk factors for later adverse outcomes in physical health, mental health, and substance use and abuse., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Observational neuroimaging studies with children and adolescents may identify neurological anomalies and other clinically relevant findings. Planning for the management of this information involves ethical considerations that may influence informed consent, confidentiality, and communication with participants about assessment results. Biomedical ethics principles include respect for autonomy, beneficence, non-maleficence, and justice. Each project presents unique challenges. The Adolescent Brain and Cognitive Development study (ABCD) collaborators have systematically developed recommendations with written guidelines for identifying and responding to potential risks that adhere to biomedical ethics principles. To illustrate, we will review the ABCD approach to three areas: (1) hazardous substance use; (2) neurological anomalies; and (3) imminent potential for self-harm or harm to others. Each ABCD site is responsible for implementing procedures consistent with these guidelines in accordance with their Institutional Review Board approved protocols, state regulations, and local resources. To assure that each site has related plans and resources in place, site emergency procedures manuals have been developed, documented and reviewed for adherence to ABCD guidelines. This article will describe the principles and process used to develop these ABCD bioethics and medical oversight guidelines, the concerns and options considered, and the resulting approaches advised to sites., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies investigating the neurochemical changes that correspond with suicidal behavior (SB) have not yielded conclusive results. Suicide correlates such as aggression have been used to explore risk factors for SB. Yet the neurobiological basis for the association between aggression and SB is unclear. Aggression and SB are both prevalent in veterans relative to civilian populations. The current study evaluated the relationship between brain chemistry in the anterior (ACC) and the posterior cingulate cortex (POC), as well as the relationship between aggression and SB in a veteran population using proton magnetic resonance spectroscopy ( 1 H-MRS). Single-voxel MRS data at 3 Tesla (T) were acquired from the ACC and POC voxels using a 2-dimensional J-resolved point spectroscopy sequence and quantified using the ProFit algorithm. Participants also completed a structured diagnostic interview and a clinical battery. Our results showed that the myoinositol (mI)/H2O ratio in the ACC and POC was significantly higher in veterans who reported SB when compared to veterans who did not. The two groups did not differ significantly with regard to other metabolites. Second, verbal aggression and SB measures positively correlated with mI/H2O in the ACC. Finally, verbal aggression mediated the relationship between mI/H2O in the ACC and SB., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Suicide is a public health concern for United States veterans and civilians. Prior research has shown neurobiological factors in suicide. However, studies of neuroimaging correlates of suicide risk have been limited. This study applied complex weighted network analyses to characterize the neural connectivity in white matter in veterans with suicide behavior., Methods: Twenty-eight veterans without suicide behavior (NS), 29 with a history of suicidal ideation only (SI), and 23 with prior suicide attempt (SA) completed diffusion tensor brain imaging, the Columbia Suicide Severity Rating Scale and Barratt Impulsiveness Scale (BIS). Structural connectivity networks among 82 parcellated brain regions were produced using whole-brain tractography. Global and nodal metrics of network topology have been calculated., Results: SA had shorter characteristic path length and greater global efficiency and mean weighted degree of global network metrics ( p  < 0.024). SA had more hub nodes than NS and SI. The left posterior cingulate cortex (PCC) showed significantly greater weighted degree in SA relative to others ( p  < 0.0003). Nonplanning subscale of BIS correlated with the weighted degrees of the left PCC within SA. In rich club connectivity, SA had higher local connections than others ( p  = 0.001)., Conclusion: Veterans with prior suicide attempt had altered connectivity networks characteristics in the white matter. These findings may be distinctive neurobiological markers for individuals with suicide attempt. Strong connectivity in the left PCC may be implicated in impulsivity in veterans with suicide attempt.

Since the sample size of a typical neuroimaging study lacks sufficient statistical power to explore unknown genomic associations with brain phenotypes, several international genetic imaging consortia have been organized in recent years to pool data across sites. The challenges and achievements of these consortia are considered here with the goal of leveraging these resources to study addiction. The authors of this review have joined together to form an Addiction working group within the framework of the ENIGMA project, a meta-analytic approach to multisite genetic imaging data. Collectively, the Addiction working group possesses neuroimaging and genomic data obtained from over 10,000 subjects. The deadline for contributing data to the first round of analyses occurred at the beginning of May 2015. The studies performed on this data should significantly impact our understanding of the genetic and neurobiological basis of addiction., (© 2016 Elsevier B.V. All rights reserved.)

Introduction: Orbitofrontal (OFC) circuits have been implicated in the pathophysiology of substance use disorders. The current study examined OFC functional connectivity differences in marijuana-using adolescents (MJ) and non-using healthy controls (HC)., Methods: Functional magnetic resonance imaging (fMRI) resting-state data were obtained on a 3T MRI scanner on 31 HC and 43 heavy MJ smokers. Image analyses were performed between groups (MJ, HC) for the left and right OFC separately. Regression analyses between OFC functional connectivity and lifetime MJ use, age of first MJ use and impulsivity also were performed., Results: Increased OFC functional connectivity to frontal and motor regions was observed in heavy MJ users compared to HC. Earlier age of first MJ use was associated with increased functional connectivity of the right OFC to motor regions. High lifetime MJ use was associated with increased OFC functional connectivity to posterior brain regions in MJ youth., Discussion: Findings indicate atypical OFC functional connectivity patterns in attentional/executive, motor and reward networks in adolescents with heavy MJ use. These anomalies may be related to suboptimal decision making capacities and increased impulsivity. Results also suggest different OFC connectivity patterns may be present in adolescents with early onset of MJ use and high lifetime exposure to MJ., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Regional homogeneity measures synchrony of resting-state brain activity in neighboring voxels, or local connectivity. The effects of age and gender on local connectivity in healthy subjects are unknown. We performed regional homogeneity analyses on resting state BOLD time series data acquired from 58 normal, healthy participants, ranging in age from 11 to 35 (mean 18.1 ± 5.0 years, 32 males). Regional homogeneity was found to be highest for gray matter, with brain regions within the default mode network having the highest local connectivity values. There was a general decrease in regional homogeneity with age with the greatest reduction seen in the anterior cingulate and temporal lobe. Greater female local connectivity in the right hippocampus and amygdala was also noted, regardless of age. These findings suggest that local connectivity at the millimeter scale decreases during development as longer connections are formed, and underscores the importance of examining gender differences in imaging studies of healthy and clinical populations.

Background: Hallucinogens are widely used, both by drug abusers and by peoples of traditional cultures who ingest these substances for religious or healing purposes. However, the long-term residual psychological and cognitive effects of hallucinogens remain poorly understood., Methods: We recruited three groups of Navajo Native Americans, age 18-45: 1) 61 Native American Church members who regularly ingested peyote, a hallucinogen-containing cactus; 2) 36 individuals with past alcohol dependence, but currently sober at least 2 months; and 3) 79 individuals reporting minimal use of peyote, alcohol, or other substances. We administered a screening interview, the Rand Mental Health Inventory (RMHI), and ten standard neuropsychological tests of memory and attentional/executive functions., Results: Compared to Navajos with minimal substance use, the peyote group showed no significant deficits on the RMHI or any neuropsychological measures, whereas the former alcoholic group showed significant deficits (p < .05) on every scale of the RMHI and on two neuropsychological measures. Within the peyote group, total lifetime peyote use was not significantly associated with neuropsychological performance., Conclusions: We found no evidence of psychological or cognitive deficits among Native Americans using peyote regularly in a religious setting. It should be recognized, however, that these findings may not generalize to illicit hallucinogen users.

Background: A substantial literature suggests that users of illicit 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") display residual cognitive deficits. Most MDMA users, however, use other illicit drugs as well, so it is difficult to be certain that these deficits are due to MDMA, as opposed to other drug use or additional confounding factors., Methods: We administered a battery of neuropsychological tests to 23 young MDMA users who reported minimal exposure to any other drugs, including alcohol, and to 16 comparison individuals equally involved with the rave subculture, but reporting no MDMA use. We compared the groups by regression analyses adjusting for numerous potentially confounding variables. To test for a possible dose-response effect, we also performed a median split of 12 moderate MDMA users (22-50 lifetime uses) and 11 heavy users (60-450 uses), and compared these subgroups with non-users., Results: MDMA users as a whole performed worse than non-users on most test measures, but these comparisons rarely reached statistical significance. This picture changed markedly in the subgroup analysis: although moderate users displayed virtually no differences from non-users on any measures, the heavy users displayed significant deficits on many measures, particularly those associated with mental processing speed and impulsivity. These differences did not appear explainable by differences in family-of-origin variables, verbal IQ, levels of depression, or time since last MDMA use., Conclusions: The presence of residual cognitive deficits, even among unusually "pure" frequent users of illicit MDMA, analyzed with adjustment for confounding variables, augments the evidence that MDMA itself, rather than some associated factor, is responsible for the deficits observed.

Background: Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life., Methods: We analyzed neuropsychological test results from 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure, all of whom had undergone a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. We compared early-onset cannabis users with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin., Results: The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late-onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, when we adjusted for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant., Conclusions: Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1). innate differences between groups in cognitive ability, antedating first cannabis use; (2). an actual neurotoxic effect of cannabis on the developing brain; or (3). poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture.

Background: The frontal lobe has been implicated in the pathology of depression in adults. Through the use of magnetic resonance spectroscopy, altered brain choline levels have also been linked to the pathophysiology of affective disorders., Methods: To identify possible alterations in orbitofrontal cortex levels of cytosolic choline in adolescents with and without depression, 22 depressed and 43 control adolescents were recruited. Of those recruited, usable proton magnetic resonance spectra were acquired from a voxel in the left anterior medial frontal lobe of 17 depressed (mean age 15.8+/-1.6) and 28 healthy adolescents (mean age 14.5+/-1.7)., Results: Orbitofrontal cytosolic choline/creatine (Cho/Cr) ratios (p =.032) and cytosolic choline/N-acetyl aspartate (Cho/NAA) ratios (p =.043) were significantly higher in the depressed subjects than in the control subjects. There were no significant differences between depressed and control subjects in gray or white matter content within the voxel., Conclusions: These findings suggest that brain cytosolic choline may be increased in depressed adolescents in comparison with control subjects and independent of a corresponding structural change. These results are consistent with similar, previously reported findings in adults and suggest that depression in adolescents is associated with alterations in orbitofrontal metabolism.

New technologies are offering increasingly powerful means to obtain structural, chemical, and functional images of the brain during life, often without the use of ionizing radiation. Bipolar disorder, with its clear physiologic features, would appear to be a prime candidate for the application of current brain imaging; however, only a modest number of studies have been reported to date, and most studies have small sample sizes and heterogeneous subject groups. Nonetheless, there are a few consistent findings among these studies, including the following: 1) Structural imaging studies suggest an increased number of white matter hyperintensities in patients with bipolar disorder. These may be lesions unique to bipolar disorder and its treatment, or related to cardiovascular risk factors, which are more common in bipolar patients. Decreased cerebellar size and anomalies of cerebellar blood volume have also been reported. Increased sulcal prominence and enlargement of the lateral and third ventricles are less consistently observed findings. 2) Spectroscopic imaging suggests abnormalities of metabolism of choline-containing compounds in symptomatically ill bipolar patients and, possibly, treatment-induced changes in choline- and myoinositol-containing compounds. Each of these groups of metabolites serves as a component of membrane phospholipids and cellular second-messenger cycles. 3) Metabolic and blood flow studies provide evidence for decreased activity of the prefrontal cortex (PFC) in bipolar patients during depression. It is not clear if these changes are restricted to particular subregions of the PFC, nor if they are reversed with mania. No single pathophysiologic mechanism yet explains these findings, although all might be due to regional alterations in cellular activity and metabolism or changes in cell membrane composition and turnover. The development of imaging technologies has far outpaced their use in bipolar disorder. The promise of future studies is great, with more powerful magnetic resonance scanners, additional ligands for positron emission tomography and single photon emission computed tomography imaging, and improved image generation and processing already available.

Background: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects., Methods: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression., Results: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders., Conclusions: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.

Objective: To examine further the role of the amygdala in the recognition of facial expression in adolescents., Method: Twelve healthy adolescents were studied using functional magnetic resonance imaging technology during a task of facial affect recognition and a visual control task., Results: All subjects demonstrated a significant increase in signal intensity in the amygdala for the facial expression recognition task., Conclusions: The data are consistent with previous work in healthy adult subjects implicating the amygdala as essential for the recognition of fearful facial expression.

Background: Investigators have reported lack of normal asymmetry of lateralization in some schizophrenic patients, as measured postmortem and by preference and/or performance. It has been suggested that this lack of asymmetry is related to early onset of schizophrenia. The present study extends the inquiry by magnetic resonance imaging (MRI) measurement of volumetric asymmetry., Methods: Hemispheric asymmetry of volume in regional gray matter was examined in 16 schizophrenic patients who had undergone MRI of brain volume., Results: Low levels of hemispheric asymmetry in the frontal and temporal areas were strongly associated with early onset of schizophrenia, the association with frontal volume being more marked than with temporal volume. No relationship was found in the other brain areas that were scanned. The findings were not artifacts of chronological age, nor of extreme scores in a small sample., Conclusions: These findings are consistent with the hypothesis that failure to develop asymmetry is an important component of the pathology underlying some forms of schizophrenia.

The authors investigated whether there were differences in cerebral and cerebellar gray and white matter volumes in depressed patients compared to controls, and whether this was associated with treatment response to fluoxetine. Brain magnetic resonance images were obtained from 38 unipolar depressed patients and 20 age, gender, and educationally matched comparison subjects. Patients were divided into groups of "responders" and "nonresponders" based on change in 17-item Hamilton Depression Rating Scale (HDRS) after an 8-week standardized trial of fluoxetine, 20 mg/day. There were no group mean differences in cerebral or cerebellar tissue volumes between patients and controls, or responders and nonresponders. For nonresponders to fluoxetine treatment, cerebral and cerebellar gray matter volume, and total cerebellar tissue volume decreased as baseline HDRS increased. The results suggest an association between gray matter volume and severity of illness in nonresponders to fluoxetine treatment.

We have investigated proton magnetic resonance spectra of the basal ganglia in 41 medication-free outpatients with major depression, prior to starting an 8-week standardized trial of open-label fluoxetine, and 22 matched comparison subjects. Upon completing the trial, depressed subjects were classified as treatment responders (n = 18) or nonresponders (n = 23), based on changes in the Hamilton Depression Rating Scale. Depressed subjects had a lower area ratio of the choline resonance to the creatine resonance (Cho/Cr) than comparison subjects. This statistically significant difference between the depressed subjects and comparison subjects was more pronounced in the treatment responders than in the nonresponders. There were no differences in the relative volumes of gray matter or white matter in the voxel used for proton spectroscopy in depressed subjects relative to comparison subjects. These results are consistent with an alteration in the metabolism of cytosolic choline compounds in the basal ganglia of depressed subjects and, in particular, those who are responsive to fluoxetine.

It has been suggested that schizophrenia is primarily a prefrontal-temporal-limbic circuitry disorder. Further, it has been argued that primary neurologic vulnerability to the illness is established only during early stages of brain development and is not progressive. We tested the hypothesis of whether brain volume losses in prefrontal and temporal-limbic regions have occurred either before or after brain growth was hypothesized to be complete in schizophrenia. Nineteen chronic schizophrenic patients and 19 age- and sex-matched normal controls underwent magnetic resonance imaging (MRI). All scans were segmented into gray and white matter and cerebrospinal fluid (CSF) compartments for the frontal and temporal lobes and posterior cerebral hemispheres. Multivariate analysis of variance was used to analyze absolute intracranial cerebrum and subregion volumes, i.e., gray, white and CSF, absolute tissue (i.e., gray plus white) volumes, and tissue to intracranial volume (TCV) ratios. Patients showed significant intracranial volume reductions only in the frontal lobes but highly significantly lower TCV ratios (i.e., greater relative tissue loss) in all three major regions. It is suggested that the observed decreases in frontal intracranial volumes reflect a pathologic process in schizophrenia that impacted the frontal regions before brain growth was complete. We hypothesize that the generalized lower patient TCV ratios are attributable to a process that affected the whole cerebrum over a time period after brain volume had reached its maximum levels.

Objective: Brain magnetic resonance images (MRIs) of 65 children and adolescents who were hospitalized with depressive disorders (DD) were compared with the brain MRIs of 18 hospitalized psychiatric controls (PC) without a depressive disorder., Method: Volumetric analyses were used to measure frontal lobe volumes (FLV), lateral ventricular volumes (VV), and total cerebral volumes (CV) for all subjects. To correct for differences in absolute cerebral volume associated with different body and head size, the ratios of FLV/CV and VV/CV were used to compare differences between the two groups. A multivariate analysis was used to control for the effects of several independent variables (age, sex, diagnosis)., Results: Significant differences were seen in the FLV/CV ratio and the VV/CV ratio when the results were compared between the two groups (DD versus PC). The DD group had a significantly smaller FLV/CV ratio (t = 2.148, df = 79, p = .035) and a significantly larger VV/CV ratio (t = -2.093, df = 79, p = .040)., Conclusion: The findings are consistent with previous reports in depressed adults and may implicate the frontal lobes in the pathogenesis of early-onset depressive disorders.

We sought to assess whether college students who smoked marijuana heavily were distinguishable from students who had used the drug only occasionally. We compared 45 long-term heavy marijuana smokers (individuals who had smoked daily for at least 2 years) with 44 "occasional" smokers (individuals who had never smoked more than 10 times in a month at any time in their lives), drawn from the student populations at two Boston-area colleges. measures included a questionnaire covering a range of demographic, drug use, and subjective items; the Rand Mental Health Inventory; and both the Axis I and Axis II sections of the Structured Clinical Interview for DSM-III-R. Heavy smokers reported higher rates of use of other substances, especially hallucinogens and cocaine, and they described greater subjective impairment of memory and motivation than occasional smokers; however, on a wide range of demographic, family background, and mental health measures, the heavy smokers proved almost indistinguishable from occasional smokers. Even the heaviest college marijuana smokers exhibit few demographic or psychiatric features that distinguish them from students who smoke only occasionally.

Evidence for the residual neuropsychological effects of cannabis must first be separated from evidence regarding (i) the acute effects of the drug, (ii) attributes of heavy cannabis users, and (iii) actual psychiatric disorders caused or exacerbated by cannabis. The remaining evidence must then be subdivided into (a) data supporting a 'drug residue' effect during the 12-24 h period immediately after acute intoxication and (b) data suggesting a more lasting toxic effect on the central nervous system which persists even after all drug residue has left the system. We reviewed the literature, comparing both 'drug-administration' studies in which known amounts of cannabis were administered to volunteers, and 'naturalistic studies' in which heavy marijuana users were tested after some period of abstinence. The data support a 'drug residue' effect on attention, psychomotor tasks, and short-term memory during the 12-24 h period immediately after cannabis use, but evidence is as yet insufficient to support or refute either a more prolonged 'drug residue' effect, or a toxic effect on the central nervous system that persists even after drug residues have left the body. We describe possible study designs to address these latter questions.

In a group of schizophrenic patients, magnetic resonance imaging (MRI) measures of relative frontal brain volume (total frontal volume/total cerebral volume) correlated highly with the capacity to use context as an aid to recall in a verbal memory task. The dorsolateral area of the prefrontal cortex appears to have contributed most to this effect. Recall of simple word lists without contextual features revealed no correlation with relative frontal volume. With increasing contextual organization of the material, correlations between frontal volume and recall scores increased significantly. These findings are consistent with the general proposition that impairment in the use of informational redundancy is a significant component of schizophrenic pathology.

This preliminary study focused on the relationship between prefrontal and temporal lobe MRI measures and neuropsychological performance in chronic schizophrenia. Seventeen schizophrenic inpatients received an MRI and a neuropsychological test battery after clinical stabilization, on average 2 months after admission. The central finding was a significant inverse correlation between neurocognitive measures of prefrontal function and dorsolateral prefrontal cortex (DLPFC) area, strongest in the left hemisphere. Neurocognitive performance did not correlate significantly with orbital frontal area or total temporal lobe volume. The correlations of neuropsychological performance with total frontal volume and whole brain volume were generally not significant, although the pattern was similar to that associated with the DLPFC. Because a number of executive-attention and abstraction measures were significantly associated with the DLPFC, dysfunctions of this region may underlie a syndrome of cognitive dysfunctions. Long-term memory functions were also significantly correlated with the DLPFC, raising the possibility that recall memory defects in schizophrenia are, in part, associated with prefrontal contributions of attention, abstract reasoning, and executive function. This study needs replication with a larger sample of patients and more comprehensive volumetric morphometric analyses.

Previous research found schizophrenics to have significantly more neurological signs than normal controls, even when signs were screened to exclude possible artifacts, and limited to "hard" signs of localizing significance. Schizophrenics with a family history of psychosis also tended to have more neurological signs than those without such a history. The present study examined whether these findings could be confirmed in new samples of schizophrenics and controls, using interview-based DSM-III and DSM-III-R diagnoses. Schizophrenics had significantly more hard signs than controls, and schizophrenics with a family history for psychosis again had more signs than those without this history. When present study data were analyzed alone, as well as when pooled with data from previous research using similar methods, hard signs were significantly greater in both (a) schizophrenics versus controls and (b) schizophrenics with versus without a family history of psychosis, supporting the hypothesis that neurological signs reflect a significant etiologic factor in schizophrenia.

Previous studies of long-term serial changes in ventricular size in schizophrenia (SCZ) have yielded mixed, albeit predominantly negative results. The current study examined ventricular changes in CT scans over intervals of 1-to 4 1/2 years in chronic schizophrenic and bipolar patients. The results indicated significant progression of ventricular size from initial to final scan in the schizophrenia group but not in the bipolar or control groups; the percent increase in VBR over baseline was 25% (p less than 0.01) in the schizophrenia group as compared with 11% (n.s.) in the bipolar group. The increases in ventricular enlargement in the schizophrenic group did not correlate with duration of illness but did appear to show an irregular stepwise pattern in several patients. It is concluded that progressive ventricular enlargement after onset of illness does occur in a subgroup of schizophrenic patients characterized by a chronic or deteriorating clinical course. The etiological implications of this finding are discussed.

Familial hyperkalemic periodic paralysis and bipolar disorder are both hereditary disorders, characterized by episodes of illness separated by periods of remission, and possibly related to abnormalities in cellular ion transport. Recently we discovered a patient who suffered from both illnesses, as did his mother and grandmother. However, a detailed investigation of the pedigree suggested that these two disorders are not linked genetically. Furthermore, a placebo-controlled double-blind trial of lithium carbonate in this patient found lithium ineffective in preventing the attacks of paralysis, in contrast to another recent study which found lithium effective in hypermagnesemic periodic paralysis.

Competing etiological models make opposite predictions as to the relationship between focal neurological abnormalities in schizophrenics and the prevalence of psychosis in their families. In previous studies of neurological abnormalities in schizophrenia, the authors found an increased prevalence of focal neurological signs in both patients and their nonschizophrenic relatives. The current study examines the relationship between neurological abnormalities in 24 schizophrenic patients and psychopathology in their families. A family history of psychotic psychopathology was found to be associated with an increased prevalence of focal neurological abnormalities in the schizophrenics. The results are relevant to current models of the potential role of neurological factors in the etiology of schizophrenia and illustrate how family studies of the joint distribution of psychiatric and neurological data can potentially help to distinguish between different etiological models.