Anatomical and fMRI-network comparison of multiple DLPFC targeting strategies for repetitive transcranial magnetic stimulation treatment of depression.

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.

Targeting location relates to treatment response in active but not sham rTMS stimulation.

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.

Paralimbic and lateral prefrontal encoding of reward value during intertemporal choice in attempted suicide.

BACKGROUND: Alongside impulsive suicide attempts, clinicians encounter highly premeditated suicidal acts, particularly in older adults. We have previously found that in contrast to the more impulsive suicide attempters' inability to delay gratification, serious and highly planned suicide attempts were associated with greater willingness to wait for larger rewards. This study examined neural underpinnings of intertemporal preference in suicide attempters. We expected that impulsivity and suicide attempts, particularly poorly planned ones, would predict altered paralimbic subjective value representations. We also examined lateral prefrontal and paralimbic correlates of premeditation in suicidal behavior. METHOD: A total of 48 participants aged 46-90 years underwent extensive clinical and cognitive characterization and completed the delay discounting task in the scanner: 26 individuals with major depression (13 with and 13 without history of suicide attempts) and 22 healthy controls. RESULTS: More impulsive individuals displayed greater activation in the precuneus/posterior cingulate cortex (PCC) to value difference favoring the delayed option. Suicide attempts, particularly better-planned ones, were associated with deactivation of the lateral prefrontal cortex (lPFC) in response to value difference favoring the immediate option. Findings were robust to medication exposure, depression severity and possible brain damage from suicide attempts, among other confounders. Finally, in suicide attempters longer reward delays were associated with diminished parahippocampal responses. CONCLUSIONS: Impulsivity was associated with an altered paralimbic (precuneus/PCC) encoding of value difference during intertemporal choice. By contrast, better-planned suicidal acts were associated with altered lPFC representations of value difference. The study provides preliminary evidence of impaired decision processes in both impulsive and premeditated suicidal behavior.

Investigating work-related neoplasia associated with solar radiation.

BACKGROUND: Both solar and non-solar exposures associated with occupation and work tasks have been reported as skin carcinogens. In the UK, there are well-established surveillance schemes providing relevant information, including when exposures took place, occupation, location of work and dates of symptom onset and diagnosis. AIMS: To add to the evidence on work-related skin neoplasia, including causal agents, geographical exposure and time lag between exposure and diagnosis. METHODS: This study investigated incident case reports of occupational skin disease originating from clinical specialists in dermatology reporting to a UK-wide surveillance scheme (EPIDERM) by analysing case reports of skin neoplasia from 1996 to 2012 in terms of diagnosis, employment, suspected causal agent and symptom onset. RESULTS: The suspected causal agent was 'sun/sunlight/ultraviolet light' in 99% of the reported work-related skin neoplasia cases. Most cases reported (91%) were in males, and the majority (62%) were aged over 65 at the time of reporting. More detailed information on exposure was available for 42% of the cases, with the median time from exposure to symptom onset ranging from 44 (melanoma) to 57 (squamous cell carcinoma) years. Irrespective of diagnostic category, the median duration of exposure to 'sun/sunlight/ultraviolet light' appeared longer where exposures occurred in the UK (range 39-51 years) rather than outside the UK (range 2.5-6.5 years). CONCLUSIONS: It is important to provide effective information about skin protection to workers exposed to solar radiation, especially to outdoor workers based outside the UK.

A combined spectroscopic and functional MRI investigation of the dorsal anterior cingulate region in opiate addiction.

Converging neuropsychological and functional neuroimaging evidence indicates that the dorsal anterior cingulate cortex (dACC) is dysfunctional in drug-addicted populations. Few studies, however, have investigated the biochemical and physiological properties of the dACC in such populations. We used proton magnetic resonance spectroscopy ((1)H-MRS) together with functional magnetic resonance imaging (fMRI) to probe dACC biochemistry and physiological activity during performance of a behavioural control task in 24 opiate-dependent individuals (maintained on a stable dose of methadone or buprenorphine at the time of study) and 24 age, gender, intelligence and performance-matched healthy subjects. While both groups activated the dACC to comparable levels, the opiate-using group displayed relatively increased task-related activation of frontal, parietal and cerebellar regions, as well as reduced concentrations of dACC N-acetylaspartate and glutamate/glutamine. In addition, the opiate-using group failed to show the expected correlations between dACC activation and behavioural measures of cognitive control. These findings suggest that the dACC is biochemically and physiologically abnormal in long-term opiate-dependent individuals. Furthermore, opiate addicts required increased, perhaps compensatory, involvement of the fronto-parietal and cerebellar behavioural regulation network to achieve normal levels of task performance/behavioural control. These neurobiological findings may partly underpin key addiction-related phenomena, such as poor inhibitory control of drug-related behaviour in the face of adverse consequences, and may be of relevance to the design of future treatment studies.

Sensitivity of prefrontal cortex to changes in target probability: a functional MRI study.

Electrophysiological studies suggest sensitivity of the prefrontal cortex to changes in the probability of an event. The purpose of this study was to determine if subregions of the prefrontal cortex respond differentially to changes in target probabilities using functional magnetic resonance imaging (fMRI). Ten right-handed adults were scanned using a gradient-echo, echo planar imaging sequence during performance of an oddball paradigm. Subjects were instructed to respond to any letter but "X". The frequency of targets (i.e., any letter but X) varied across trials. The results showed that dorsal prefrontal regions were active during infrequent events and ventral prefrontal regions were active during frequent events. Further, we observed an inverse relation between the dorsal and ventral prefrontal regions such that when activity in dorsal prefrontal regions increased, activity in ventral prefrontal regions decreased, and vice versa. This finding may index competing cognitive processes or capacity limitations. Most importantly, these findings taken as a whole suggest that any simple theory of prefrontal cortex function must take into account the sensitivity of this region to changes in target probability.

Factor structure of neurologic examination abnormalities in unmedicated schizophrenia.

The heterogeneity and uncertain significance of neurologic exam abnormalities in schizophrenia prompted us to evaluate their factor structure. We administered a modified version of the Neurological Evaluation Scale (NES) to 103 unmedicated patients with schizophrenia. Data were distilled by combining right- and left-side scores, and by eliminating superfluous, rarely abnormal and unreliable items from the analysis. Exploratory principal components analysis yielded four factors: repetitive motor tasks (fist-ring, fist-edge-palm, alternating fist-palm, dysdiadochokinesis); cognitive-perceptual tasks (memory, audiovisual integration, right-left orientation, face-hand test, rhythm tapping reproduction); balancing tasks (Romberg, tandem gait); and the palmomental reflex. Evaluation of the relationship between these factors and clinical and demographic variables revealed a robust correlation between the cognitive-perceptual factor and full-scale IQ score. This analysis is a step toward developing empirical subscales of a modified NES, which may provide insights into the nature of neurologic impairment in schizophrenia and may prove clinically useful.

Neurologic examination abnormalities in schizophrenia with and without a history of alcoholism.

OBJECTIVE: The current investigation examines the impact of a past history of alcoholism on neurologic examination abnormalities in schizophrenia (SZ). BACKGROUND: Individuals with SZ have a high rate of comorbid alcohol use disorders (AUDs), but relatively little is known about the potential adverse consequences of alcoholism for neuropsychological and neurologic functioning in SZ. Recent evidence suggests consistent but subtle neurocognitive differences between groups, with more prominent differences in neurologic examination abnormalities. METHOD: Thirty-three male patients with SZ or SZ/AUDs were evaluated using a modified Neurologic Evaluation Scale (NES) and ratings for positive and negative symptoms. RESULTS: The SZ/AUD group exhibited a greater impairment in the Cognitive-Perceptual factor of the Neurologic Evaluation Scale. Greater impairment in the tandem-Romberg factor or in motor items was not found, nor were groups different based on positive or negative symptoms. CONCLUSIONS: A history of alcoholism in SZ is associated with greater overall neurologic impairment, particularly in the area of cognitive-perceptual dysfunction, an area often found to be impaired in patients with schizophrenia without alcoholism.

Simultaneous glutamate and perfusion fMRI responses to regional brain stimulation.

Functional magnetic resonance imaging (fMRI) rests on the assumption that regional brain activity is closely coupled to regional cerebral blood flow (rCBF) in vivo. To test the degree of coupling, cortical brain activity was locally stimulated in rats by reversed microdialysis infusion of picrotoxinin, alphagamma-aminobutyric acid-A antagonist. Before and during the first 30 minutes of infusion, simultaneous fMRI (rCBF) and neurochemical (interstitial glutamate concentration) measures of brain activity were highly correlated (r = 0.83). After 30 minutes of picrotoxinin-induced stimulation, glutamate levels decreased but rCBF remained elevated, suggesting that additional factors modulate the relationship between neuronal neurotransmitters and hemodynamics at these later stages.

Inter-rater reliability of the neurological examination in schizophrenia.

Neurological Examination Abnormalities (NEA) are prevalent in schizophrenia, but the significance of this is obscured by methodological problems. The Neurological Evaluation Scale (NES), the most widely used structured neurological examination in schizophrenia research, has had limited study of its inter-rater reliability (IRR). An augmented version of the NES was jointly administered (one examiner-rater and one observer-rater) by three pairs of psychiatrists to two populations of patients with idiopathic psychotic disorders. In addition to the ordinal and categorical data yielded by the original NES, continuous data were recorded in one of the series. Reliability analyses of our populations and a previously published study, reveal consistently adequate IRR in 12 of the 26 items assessed, and inconsistently adequate IRR in an additional 11. Consistent with studies using other NEA schedules, IRR was unacceptably low for some items that rely on subjective severity ratings. Certain rare abnormalities, which posed difficulties for the estimation of IRR, are probably not generally useful in the study of schizophrenia. Reliability estimates of continuous, ordinal and dichotomous data were comparable in most cases. We recommend that certain items from the NES be deleted, and that other studies of NEA in psychiatry follow similar procedures before undertaking further analyses.

Dissociating working memory from task difficulty in human prefrontal cortex.

A functional magnetic resonance imaging (fMRI) study was conducted to determine whether prefrontal cortex (PFC) increases activity in working memory (WM) tasks as a specific result of the demands placed on WM, or to other processes affected by the greater difficulty of such tasks. Increased activity in dorsolateral PFC (DLPFC) was observed during task conditions that placed demands on active maintenance (long retention interval) relative to control conditions matched for difficulty. Furthermore, the activity was sustained over the entire retention interval and did not increase when task difficulty was manipulated independently of WM requirements. This contrasted with the transient increases in activity observed in the anterior cingulate, and other regions of frontal cortex, in response to increased task difficulty but not WM demands. Thus, this study established a double-dissociation between regions responsive to WM versus task difficulty, indicating a specific involvement of DLPFC and related structures in WM function.

Estimating test-retest reliability in functional MR imaging. II: Application to motor and cognitive activation studies.

Functional magnetic resonance imaging (fMRI) using blood oxygenation contrast has rapidly spread into many application areas. In this paper, a new statistical model is used to evaluate the reliability of fMRI activation in a finger opposition motor paradigm for both within-session and between-session data and in a working memory paradigm for between-session data. A slice prescription procedure for between-session reproducibility is introduced. Estimates are made for the probabilities of correctly and falsely classifying voxels as active or inactive and receiver operator characteristic curves are generated. In the motor paradigm, estimated between-session reliability was found to be somewhat reduced relative to within-session reliability; however, this includes additional sources of variation and may not reflect intrinsically lower reliability. After matching false-positive classification probabilities, between-session reliability was found to be nearly identical for both motor and cognitive activation paradigms.

Minimum criteria for reporting child abuse from health care settings.

We evaluated how consistently clinicians of two hospitals reported child abuse and neglect, and the utility of specific, operational criteria for assessing hospital clinicians' compliance with the child abuse reporting laws. To evaluate clinicians' compliance, we audited the medical records of 85 children who had been reported to a child protective service (CPS) agency by clinicians at either of two hospitals and who had been seen at that hospital at least once before the index report of abuse. The time elapsed from first hospital visit to index abuse report among the 85 children averaged 4.3 years. In the children's records, we identified 28 earlier reports to the CPS agency and four episodes that met criteria we developed but that had not been reported. Thus, application of specific criteria resulted in the finding that 28 (88 percent) of 32 suspected abuse episodes were actually reported to the CPS agency (95 percent confidence interval: 76 to 99 percent). In a second phase of the study, we compared the content of 45 reported episodes of child abuse (4) index reports and four earlier reports) to the criteria in order to evaluate their utility. Thirty-five episodes (78 percent) met one of the criteria. Review of the remaining 10 episodes led to the development of one new criterion. We conclude that, although it has been estimated that hospital personnel nationwide report to CPS agencies only 69 percent of the child abuse cases they identify, clinicians at the hospitals we studied reported 88 percent of documented episodes of suspected abuse. We also conclude that specific, operational criteria can help in the assessment of hospital clinicians' compliance with their obligation to report child abuse and neglect.

A Developmental Functional MRI Study of Prefrontal Activation during Performance of a Go-No-Go Task.

This study examines important developmental differences in patterns of activation in the prefrontal cortex during performance of a Go-No-Go paradigm using functional magnetic resonance imaging (fMRI). Eighteen subjects (9 children and 9 adults) were scanned using gradient echo, echo planar imaging during performance of a response inhibition task. The results suggest four general findings. First, the location of activation in the prefrontal cortex was not different between children and adults, which is similar to our earlier pediatric fMRI results of prefrontal activation during a working memory task (Casey et al., 1995). Second, the volume of activation was significantly greater for children relative to adults. These differences in volume of activation were observed predominantly in the dorsal and lateral prefrontal cortices. Third, although inhibitory processes have typically been associated with more ventral or orbital frontal regions, the current study revealed activation that was distributed across both dorsolateral and orbitofrontal cortices. Finally, consistent with animal and human lesion studies, activity in orbital frontal and anterior cingulate cortices correlated with behavioral performance (i.e., number of false alarms). These results further demonstrate the utility of this methodology in studying pediatric populations.

Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold.

The typical functional magnetic resonance (fMRI) study presents a formidable problem of multiple statistical comparisons (i.e., > 10,000 in a 128 x 128 image). To protect against false positives, investigators have typically relied on decreasing the per pixel false positive probability. This approach incurs an inevitable loss of power to detect statistically significant activity. An alternative approach, which relies on the assumption that areas of true neural activity will tend to stimulate signal changes over contiguous pixels, is presented. If one knows the probability distribution of such cluster sizes as a function of per pixel false positive probability, one can use cluster-size thresholds independently to reject false positives. Both Monte Carlo simulations and fMRI studies of human subjects have been used to verify that this approach can improve statistical power by as much as fivefold over techniques that rely solely on adjusting per pixel false positive probabilities.

Cerebrospinal fluid corticotropin-releasing factor increases following haloperidol withdrawal in chronic schizophrenia.

Corticotropin-releasing factor (CRF), an endogenous neuropeptide, has been shown to coordinate endocrine, behavioral and autonomic responses to stress. However, while previous studies of cerebrospinal fluid (CSF) CRF in schizophrenia have not demonstrated significant differences compared to control groups, these studies have not examined the effects of symptom severity or antipsychotic medication. CSF CRF concentrations increased in 18 of 21 male schizophrenic (DSM-III-R) patients after maintenance haloperidol was replaced by placebo (P < 0.0001); there was also a trend for relatively greater increases in relapsers. CRF concentrations were not significantly related to severity of psychosis, depression, anxiety or negative symptoms. During haloperidol treatment, but not after medication withdrawal, worse childhood premorbid adjustment was associated with higher CSF CRF levels. Finally, in contrast to the positive correlation between CSF CRF and norepinephrine concentrations reported in depression, a negative trend was seen in this schizophrenic sample.

Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI.

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of the prefrontal cortex during performance of subjects in a nonspatial working memory task. Subjects observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Functional scanning was performed using a newly developed spiral scan image acquisition technique that provides high-resolution, multislice scanning at approximately five times the rate usually possible on conventional equipment (an average of one image per second). Using these methods, activation of the middle and inferior frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Effect sizes (2-4%) closely approximated those that have been observed within primary sensory and motor cortices using similar fMRI techniques. Furthermore, activation increased and decreased with a time course that was highly consistent with the task manipulations. These findings corroborate the results of positron emission tomography studies, which suggest that the prefrontal cortex is engaged by tasks that rely on working memory. Furthermore, they demonstrate the applicability of newly developed fMRI techniques using conventional scanners to study the associative cortex in individual subjects. © 1994 Wiley-Liss, Inc.

Characteristics of repeat users of a psychiatric emergency service.

OBJECTIVE: Patients who visited a psychiatric emergency service were studied to determine whether repeat visitors, who consume a disproportionate share of services, could be identified by demographic and diagnostic characteristics. METHODS: Data were obtained from a semistructured diagnostic interview given to all 16,257 persons who made 29,214 visits to an urban psychiatric emergency service in Pittsburgh, Pennsylvania, from 1985 to 1989. Patients were categorized into four groups based on the number of visits in the five-year period. Patients in group 1 made a single visit, while those in group 2 averaged less than one visit per year; those in group 3 made one or two visits per year, and those in group 4, more than two visits per year. RESULTS: Groups 3 and 4 constituted 5.1 percent of the sample but made 27.1 percent of the total visits. Repeat users were significantly more likely to be male, younger, unmarried, unemployed, and nonwhite and to have diagnoses of schizophrenia, other psychotic disorders, and personality disorders. CONCLUSIONS: Repeat users of psychiatric emergency services appear to have demographic and diagnostic characteristics that may permit their early identification. For such patients, implementation of alternative management strategies, such as intensive case management, may reduce their use of services.

Membrane-dependent coagulation reaction is independent of the concentration of phospholipid-bound substrate: fluid phase factor X regulates the extrinsic system.

Negatively charged phospholipids accelerate blood coagulation; one suggestion is that the binding of the gamma-carboxyglutamic acid-containing zymogens to these lipid surfaces increases their effective concentration as substrates. Alternatively, the charged phospholipids could enhance the direct interaction of substrate with the catalytic complex, which is localized at the membrane surface. We distinguished the alternatives by using prothrombin fragment 1 to compete with the substrate for membrane binding sites without interfering with the direct enzyme-substrate interaction. In a tissue factor-factor VIIa system containing neutral phospholipids (to which the substrate does not bind), prothrombin fragment 1 had no significant effect on factor X activation (Km, 877 +/- 111 nM and 791 +/- 103 nM, with and without prothrombin fragment 1, respectively). In contrast, in a system containing 30% phosphatidylserine, prothrombin fragment 1 displaced phospholipid-bound factor X, increasing the free factor X concentration and the reaction velocity in all 22 determinations. As the velocity increases correlated only with the free factor X concentration, we conclude that the free factor X concentration controls this reaction velocity. The Km in the 30% phosphatidylserine system, calculated using free factor X concentration, was 41 +/- 5 nM and 63 +/- 9 nM, with and without prothrombin fragment 1, respectively. Thus, the negatively charged lipids decreased the intrinsic Km by over 90%. The methodology employed should be applicable to ligand-receptor systems in which ligand binds nonspecifically to the membrane surface.