Resting Hypoconnectivity of Theoretically Defined Addiction Networks during Early Abstinence Predicts Subsequent Relapse in Alcohol Use Disorder.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

Modeling and treating internalizing psychopathology in a clinical trial: a latent variable structural equation modeling approach.

BACKGROUND: Clinical trials are typically designed to test the effect of a specific treatment on a single diagnostic entity. However, because common internalizing disorders are highly correlated ('co-morbid'), we sought to establish a practical and parsimonious method to characterize and quantify changes in a broad spectrum of internalizing psychopathology targeted for treatment in a clinical trial contrasting two transdiagnostic psychosocial interventions. METHOD: Alcohol dependence treatment patients who had any of several common internalizing disorders were randomized to a six-session cognitive-behavioral therapy (CBT) experimental treatment condition or a progressive muscle relaxation training (PMRT) comparison treatment condition. Internalizing psychopathology was characterized at baseline and 4 months following treatment in terms of the latent structure of six distinct internalizing symptom domain surveys. RESULTS: Exploratory structural equation modeling (ESEM) identified a two-factor solution at both baseline and the 4-month follow-up: Distress (measures of depression, trait anxiety and worry) and Fear (measures of panic anxiety, social anxiety and agoraphobia). Although confirmatory factor analysis (CFA) demonstrated measurement invariance between the time-points, structural models showed that the latent means of Fear and Distress decreased substantially from baseline to follow-up for both groups, with a small but statistically significant advantage for the CBT group in terms of Distress (but not Fear) reduction. CONCLUSIONS: The approach demonstrated in this study provides a practical solution to modeling co-morbidity in a clinical trial and is consistent with converging evidence pointing to the dimensional structure of internalizing psychopathology.

Drinking to cope with negative emotions moderates alcohol use disorder treatment response in patients with co-occurring anxiety disorder.

BACKGROUND: Epidemiological studies and theory implicate drinking to cope (DTC) with anxiety as a potent moderator of the association between anxiety disorder (AnxD) and problematic alcohol use. However, the relevance of DTC to the treatment of alcohol use disorder (AUD) in those with a co-occurring AnxD has not been well studied. To address this, we examined whether DTC moderates the impact of two therapies: (1) a cognitive behavioral therapy (CBT) designed to reduce DTC and anxiety symptoms; (2) a progressive muscle relaxation training (PMRT) program designed to reduce anxiety symptoms only. METHODS: Patients undergoing a standard AUD residential treatment with a co-occurring AnxD (N=218) were randomly assigned to also receive either the CBT or PMRT. DTC in the 30 days prior to treatment was measured using the Unpleasant Emotions subscale of the Inventory of Drinking Situations. RESULTS: Confirming the predicted moderator model, the results indicated a significant interaction between treatment group and level of pre-treatment DTC behavior. Probing this interaction revealed that for those reporting more pre-treatment DTC behavior, 4-month alcohol outcomes were superior in the CBT group relative to the PMRT group. For those reporting less pre-treatment DTC behavior, however, 4-month alcohol outcomes were similar and relatively good in both treatment groups. CONCLUSIONS: These findings establish a meaningful clinical distinction among those with co-occurring AUD-AnxD based on the degree to which the symptoms of the two disorders are functionally linked through DTC. Those whose co-occurring AUD-AnxD is more versus less strongly linked via DTC are especially likely to benefit from standard AUD treatment that is augmented by a brief CBT designed to disrupt this functional link.

The effects of alcohol consumption on laboratory-induced panic and state anxiety.

BACKGROUND: This study tested whether alcohol consumption reduces anxiety and panic associated with a panic-challenge procedure. METHODS: Subjects with panic disorder were randomly assigned to consume either a moderate dose of alcohol or a nonalcoholic placebo. All subjects were told that they were drinking alcohol to control beverage expectancies. Following the beverage administration, subjects underwent a panic challenge (35% carbon dioxide) and a series of anxiety symptom assessments. RESULTS: Subjects who consumed alcohol reported significantly less state anxiety both before and after the challenge. In response to the challenge, subjects who consumed alcohol experienced significantly fewer panic attacks when applying liberal panic criteria; however, this effect only approached significance when applying conservative panic criteria. CONCLUSIONS: These findings suggest that alcohol acts acutely to reduce both panic and the anxiety surrounding panic, and they lend support to the view that drinking behavior among those with panic disorder is reinforced by this effect. We suggest that this process may contribute to the high rate at which alcohol-use disorders co-occur with panic disorder.

Regional brain function in schizophrenia. II. Repeated evaluation with positron emission tomography.

Cerebral glucose metabolism was measured twice in a sample of 15 schizophrenics and eight controls, using positron emission tomography (PET) with 18-F-fluorodeoxyglucose. Studies were separated by three to 33 weeks. Patients were unmedicated during the first study, and the majority were receiving neuroleptics during the second study. There were no changes from study 1 to study 2 in average whole-brain metabolic rates, regional cortical activity, or the gradient of subcortical to cortical activity. The steeper subcortical to cortical gradient in schizophrenics, present in the first study, persisted in the second. Changes in this gradient were uncorrelated with changes in clinical status. Laterality (right-left) was stable across studies, and changes toward higher right relative to left hemispheric metabolism were correlated with clinical improvement. The results support the hypothesis of abnormal hemispheric activity in schizophrenia and implicate the subcortical-cortical gradient as another dimension that merits further exploration.

Regional brain function in schizophrenia. I. A positron emission tomography study.

Local cerebral glucose metabolism was determined with 18-F-fluorodeoxyglucose using positron emission tomography in a sample of 12 unmedicated schizophrenics and 12 matched normal controls. The data were analyzed for absolute metabolic rates and region/whole-brain ratios using the cortical-subcortical, antero-posterior, and laterality dimensions. Lobar areas within cortical regions were also compared. Across groups, subcortical metabolism was higher than cortical metabolism. Patients had lower metabolism, cortically and subcortically, and a steeper subcortical to cortical gradient. Patients with higher scores on the Brief Psychiatric Rating Scale had higher absolute metabolism and higher left relative to right hemispheric metabolism than did patients with lesser severity. The results did not show "hypofrontality" in schizophrenia. These findings provide some support for cerebral dysfunction in schizophrenia and indicate the need for further examination of the cortical-subcortical dimension.

Gender differences in corpus callosum size in first-episode schizophrenics.

Previous studies indicate differences between schizophrenics and normals in thickness and overall size of the corpus callosum, particularly in female subjects. The present study compares the area of the corpus callosum as measured by magnetic resonance imaging (MRI) in men and women experiencing first-episode cases of schizophrenia. The corpus callosum area is also correlated with measures of neuropsychological function. The results of this study suggest that women who are first-episode schizophrenic patients have a smaller total corpus callosum area than female controls, with no difference noted for men. In normal controls, a larger corpus callosum was associated with better cognitive function, whereas in schizophrenics, no such relationship emerged.

A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings.

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

Phenomenological and pharmacological study of provoked obsessive/anxiety symptoms in obsessive-compulsive disorder: a preliminary study.

BACKGROUND: Inclusion of obsessive-compulsive disorder (OCD) as an anxiety disorder in DSM-i.v. assumes that anxiety is the primary symptom of OCD; however, persuasive empirical evidence in support of this view has not been presented yet. In the present study we hypothesized that provoked anxiety symptoms respond better to intravenous diazepam than would provoked obsessions. We, therefore, reasoned that anxiety symptoms are secondary symptoms of OCD. METHODS: To test the hypothesis we designed a double-blind, randomized, placebo-controlled crossover study. Patients underwent four experimental conditions in which the sequence of symptom provocation and i.v. injection of (placebo or diazepam) were alternated. Baseline and i.v. injection-induced symptom changes were assessed using visual analogs. RESULTS: Obsessions and anxiety correlated strongly for all four experimental conditions in which the sequence of the symptom provocation and diazepam i.v. injections was alternated. i.v. diazepam injection before and after symptom provocation failed to preferentially modulate anxiety symptoms over obsessions. Unexpectedly, in the group in which i.v. diazepam injection preceded the symptom provocation, reduction of mean obsessions was even more pronounced. CONCLUSIONS: Strong correlations between anxiety and obsessions at baseline, during symptom provocation, and after i.v. diazepam infusion suggest that anxiety and obsessions are tightly coupled phenomena in OCD.

The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome.

The present study is an examination of ventricular and temporal lobe size in 50 DSM-III-R first-episode schizophreniform or schizoaffective patients who were ill for less than 6 months. Two-year clinical follow-up and magnetic resonance imaging (MRI) scan analyses are also reported from data collected on an initial group of 30 first-episode schizophrenic patients and controls. Left ventricular enlargement, which was present in our previously published report of first-episode cases of schizophrenia, is not present to the same extent in this larger group of schizophreniform patients closer to the onset of their illness, and no temporal lobe volume reduction was detected. However, lateral ventricular size at the time of the first-episode was generally correlated with outcome--the larger the ventricles, the poorer the outcome. No mean change in ventricular or temporal lobe size was found at rescanning 2 years later, but the degree of ventricular change was inversely correlated with the number of hospitalizations and the amount of time spent in hospital; it did not correlate with temporal lobe size. When rescanned, some patients showed change greater than 20% in ventricular size and 10% in temporal lobe size. Thus, these findings need further evaluation by serial scans over a longer time period before it can be determined that no progression of brain structural abnormalities is occurring as part of the pathology of schizophrenia, even in a subgroup of patients.

Cerebral blood flow with the continuous infusion of oxygen-15-labeled water.

This work describes the determination of CBF in eight normal human subjects with positron emission tomographic (PET) imaging using the continuous intravenous infusion of H2(15)O. A whole-brain CBF model is described that permits the comparison of the CBF values determined using PET with those obtained using other methods. This model includes a correction for whole-brain recovery coefficient, a correction for the underestimation of flow due to the nonlinearity of the CBF model when considering tissue that includes both gray and white matter, the use of in vitro-determined brain-blood partition coefficients for gray and white matter, and a variation of the equilibrium model that permits the arterial concentration to vary. CBF values using this method compare well with values determined previously. Regional determinations using a brain overlay atlas are presented. Radiation dosimetry for the continuous infusion of H2(15)O is also included.

Prospective analysis of the relation between DSM-III anxiety disorders and alcohol use disorders.

OBJECTIVE: Cross-sectional studies show a robust association between anxiety disorders and alcohol use disorders (comorbidity); however, this methodology does not allow for the testing of causal models. The authors attempted to overcome this limitation by examining comorbid relationships prospectively. METHOD: Male and female college students were assessed as freshmen (year 1), and then again at years 4 and 7, for selected 12-month anxiety disorders (generalized anxiety disorder, agoraphobia, and social phobia or panic) diagnosed according to the National Institute of Mental Health Diagnostic Interview Schedule (DIS) and DSM-III and for 12-month DIS/DSM-III alcohol use disorders (alcohol dependence alone and alcohol abuse or dependence). RESULTS: Cross-sectionally, the odds of having either an anxiety disorder or an alcohol use disorder were two- to fivefold greater when the other condition was present. Prospectively, the odds of developing a new alcohol dependence diagnosis at year 7 increased from 3.5 to five times for those diagnosed with an anxiety disorder at years 1 or 4. Conversely, the odds of developing a new anxiety disorder at year 7 increased by about four times for those diagnosed with alcohol dependence at years 1 or 4. When alcohol abuse and dependence were combined, the pattern of findings was similar, albeit weaker. Multivariate path models provide similar results and highlight the reciprocal influence of alcohol use disorders and anxiety disorders. CONCLUSIONS: Alcohol use disorders (especially alcohol dependence) and anxiety disorders demonstrate a reciprocal causal relationship over time, with anxiety disorders leading to alcohol dependence and vice versa.

The relation between alcohol problems and the anxiety disorders.

The idea that people suffering from anxiety have a proclivity to consume alcohol to relieve their symptoms is supported by reports showing high comorbidity rates of alcohol and anxiety problems. The authors reviewed relevant epidemiologic surveys, family studies, and field studies and conclude that the relationship between alcohol problems and anxiety appears to be variable among the anxiety disorders. In agoraphobia and social phobia, alcohol problems appear more likely to follow from attempts at self-medication of anxiety symptoms, but panic disorder and generalized anxiety disorder may be more likely to follow from pathological alcohol consumption. Simple phobia does not appear to be related to alcohol problems in any meaningful way.

Nonfearful panic disorder in neurology patients validated by lactate challenge.

OBJECTIVE: Nonfearful panic disorder meets the DSM-III-R criteria for panic disorder but is not associated with subjective fear and anxiety. The authors determined its prevalence in a group of neurology patients and assessed its diagnostic validity as a panic disorder subtype by evaluating the response of the patients with nonfearful panic disorder to sodium lactate and antipanic pharmacotherapy. METHOD: The subjects were all neurology patients referred over 1 year to a university hospital's psychiatric consultation service because of negative medical workups for their symptoms (N = 48). Patients who met the DSM-III-R criteria for panic disorder but did not report subjective anxiety or fear during panic episodes were diagnosed as having nonfearful panic disorder. Afterward, each of those patients received a sodium lactate infusion and, 5 hours later, a sodium chloride infusion. They were then treated with antipanic medication and followed for at least 6 months. RESULTS: Of the 48 neurology patients referred for psychiatric evaluation, 11 (23%) met the criteria for panic disorder, and all 11 met the criteria for nonfearful panic disorder. All 11 responded positively to lactate but not to placebo, and they each experienced an at least 75% reduction in symptoms during the 6-month follow-up period. Detailed case reports of three of these patients are presented. CONCLUSIONS: These findings support the construct and predictive diagnostic validity of nonfearful panic disorder as a subtype of panic disorder and suggest that a lack of attention to this group leads to both the underestimation of the prevalence of panic disorder and to the withholding of potentially successful treatments for this group.

Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia.

OBJECTIVE: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. METHOD: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. RESULTS: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. CONCLUSIONS: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.

Cortical gray matter volume deficit in patients with first-episode schizophrenia.

OBJECTIVE: A cortical gray matter deficit has been found in cross-sectional studies of patients with chronic schizophrenia. The purpose of this study was to examine whether this deficit is present early in the course of illness. METHOD: The authors measured cortical gray matter volume on magnetic resonance images acquired within 6 months of onset of illness from 22 patients with first-episode schizophrenia and 51 age-matched comparison subjects from the Stony Brook First Episode Study. RESULTS: A significant cortical gray matter deficit and lateral ventricular enlargement were found in schizophrenic patients relative to the comparison group. CONCLUSIONS: The presence of the cortical gray matter deficit close to onset of illness supports the role of preexisting structural brain deficits in the genesis of schizophrenia.

Panic disorder history in the families of patients with angiographically normal coronary arteries.

OBJECTIVE: The authors evaluated the diagnostic validity of an interview-based panic disorder diagnosis in cardiology chest pain patients with angiographically normal coronary arteries. METHOD: Patient probands with normal coronary arteries (N = 65) were first contracted immediately after their normal angiogram and were given a structured diagnostic interview. On the basis of the results of the interview, probands were grouped as having panic disorder (N = 19), panic attacks that did not meet frequency criteria for panic disorder (N = 17), or no panic (N = 29). At a later time, patient probands were recontacted and given a structured family history interview that inquired about psychopathology in their first-degree biological relatives (N = 544). RESULTS: As predicted, panic disorder was significantly more prevalent among the first-degree relatives of probands with normal coronary arteries diagnosed with panic disorder or panic attacks than among the family members of probands with normal coronary arteries without panic (17.4% versus 15.7% versus 4.0%). Family members of probands with panic attacks were significantly more likely to be diagnosed with major depression than were the family members of probands with no panic; however, differences did not reach significance for family members of the panic disorder proband group. Groups did not differ significantly in familial alcoholism. CONCLUSIONS: These data support the construct validity of an interview-based panic disorder diagnosis among patients with chest pain and normal coronary arteries and suggest that these patients could benefit from treatment for panic disorder.

The clinical manifestations of pontine hemorrhage.

The survival rate was 40% in 10 patients suffering hemorrhage into the pons who were admitted to an acute care facility. This rate is higher than previously reported. In addition to the "classic" pontine hematoma syndrome characterized by coma, quadriparesis, and eventual demise, two more benign syndromes arising from hemorrhage confined to one side of the pons were also recognized. In one of these hemipontine syndromes, hematoma involved both the basis pontis and tegmentum and was associated with hemiparesis, brainstem signs, and preserved consciousness. In the other, hemorrhage was confined to the tegmentum and was associated with gaze paresis, motor sparing, and preserved consciousness. All patients suffering hemipontine hemorrhage survived. An impressive degree of functional recovery occurred in these survivors.

Frontal lobe astrocytoma following radiotherapy for medulloblastoma.

A young woman had a frontal lobe astrocytoma 14 years after successful treatment of a posterior fossa medulloblastoma by surgery and whole-neuraxis irradiation. The association of these two tumors is rare, and it is unlikely that the second tumor was the result of metastasis and differentiation of residual or recurrent medulloblastoma. We review the evidence supporting this view and also the likelihood that the astrocytoma was induced by the prior radiation.

Brain single-photon emission computed tomography.

Single-photon emission computed tomography (SPECT) provides cost-effective information on regional cerebral perfusion and, indirectly, on regional cerebral metabolism. Its ease of use facilitates the application of SPECT in clinical neurology. SPECT is emerging as a useful tool for the management of patients with stroke, epilepsy, recurrent brain neoplasms, and some forms of dementia. The applications being investigated, such as in vivo receptor labeling for benzodiazepines, serotonin, dopamine, and muscarinic receptors, may expand the clinical usefulness of this technique in the future.