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.

Psychopathology factors in first-episode affective and non-affective psychotic disorders.

BACKGROUND: Since the onset, prevalence, and course of specific psychopathological features rarely have been analyzed simultaneously from the start of dissimilar psychotic illnesses, we compared symptom-clusters in first-episode DSM-IV affective and non-affective psychotic disorders. METHODS: Subjects (N=377) from the McLean-Harvard First Episode Project hospitalized for first-lifetime primary psychotic illnesses were followed prospectively for 2 years to verify stable DSM-IV diagnoses. We ascertained initial symptoms from baseline SCID and clinical assessments, applying AMDP and Bonn psychopathology schemes systematically to describe a broad range of features. Final consensus diagnoses were based on intake and follow-up SCID assessments, family interviews, and medical records. Factor-analytic methods defined first-episode symptom-clusters (Factors), and multiple-regression modeling related identified factors to initial DSM-IV diagnoses and to later categories (affective, non-affective, or schizoaffective disorders). RESULTS: Psychopathological features were accommodated by four factors: I represented mania with psychosis; II a mixed depressive-agitated state; III an excited-hallucinatory-delusional state; IV a disorganized-catatonic-autistic state. Each factor was associated with characteristic prodromal symptoms. Factors I and III associated with DSM-IV mania, II with major depression or bipolar mixed-state, III negatively with delusional disorder, IV with major depression and negatively with mania. Factors I and II predicted later affective diagnoses; absence of Factor I features predicted non-affective diagnoses, and no Factor predicted later schizoaffective diagnoses. CONCLUSION: The findings contribute to descriptive categorizations of psychopathology from onset of dissimilar psychotic illnesses. This approach was effective in identifying and subtyping affective psychotic disorders early in their clinical evolution, but non-affective and schizoaffective conditions appear to be more complex and unstable.

Neurologic abnormalities in schizophrenic patients and their families. I. Comparison of schizophrenic, bipolar, and substance abuse patients and normal controls.

The prevalence of neurologic abnormalities detectable on standard clinical examination by neurologists blind to diagnosis was compared for DSM-III-diagnosed, age- and sex-matched groups consisting of 24 schizophrenic (SCZ) patients, 24 patients with bipolar affective disorder (MDI) with history of psychosis, 24 patients hospitalized for alcohol or other drug abuse (D/A), and 24 normal volunteers (NL). The SCZ group had significantly more total abnormalities than the other three; both the MDI and D/A groups in turn had more total abnormalities than normal controls. After exclusion of findings due to medication or otherwise unrelated to the pathogenesis of psychiatric illness, only the SCZ-NL, SCZ-MDI, and D/A-NL differences remained significant. When neurologic abnormalities were further restricted to those indicating localized dysfunction of the corticospinal tracts, basal ganglia, or cerebellum, the only two persistent significant differences were between SCZ-NL and SCZ-MDI groups.

Neurologic abnormalities in schizophrenic patients and their families. II. Neurologic and psychiatric findings in relatives.

Neurologic abnormalities in 21 nonschizophrenic siblings and parents of schizophrenics, 24 DSM-III schizophrenics, and 24 normal "control" subjects were assessed by experienced neurologists blind to the subjects' psychiatric status. Medication artifacts and other neurologic signs likely to be etiologically irrelevant to psychiatric illness were excluded. Psychiatric diagnostic assessments of subjects were made blind to neurologic results. The prevalence of neurologic abnormalities in relatives was significantly greater than in controls, but similar to that among the schizophrenics. Relatives and controls differed even more markedly on signs involving motor system abnormalities of localizing significance. Finally, the relatives showed a suggestive dissociation of psychopathology and neurologic signs. The results appear most consistent with the hypothesis that overt schizophrenia may often result from the combined operation of two independent familial factors--one "psychopathologic," the other "neurologic".

Neuropsychological performance in long-term cannabis users.

BACKGROUND: Although cannabis is the most widely used illicit drug in the United States, its long-term cognitive effects remain inadequately studied. METHODS: We recruited individuals aged 30 to 55 years in 3 groups: (1) 63 current heavy users who had smoked cannabis at least 5000 times in their lives and who were smoking daily at study entry; (2) 45 former heavy users who had also smoked at least 5000 times but fewer than 12 times in the last 3 months; and (3) 72 control subjects who had smoked no more than 50 times in their lives. Subjects underwent a 28-day washout from cannabis use, monitored by observed urine samples. On days 0, 1, 7, and 28, we administered a neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Test results were analyzed by repeated-measures regression analysis, adjusting for potentially confounding variables. RESULTS: At days 0, 1, and 7, current heavy users scored significantly below control subjects on recall of word lists, and this deficit was associated with users' urinary 11-nor-9-carboxy-Delta9-tetrahydrocannabinol concentrations at study entry. By day 28, however, there were virtually no significant differences among the groups on any of the test results, and no significant associations between cumulative lifetime cannabis use and test scores. CONCLUSION: Some cognitive deficits appear detectable at least 7 days after heavy cannabis use but appear reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use.

First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe.

BACKGROUND: Schizophrenia is associated with central (sagittal) midline reductions of the P300 cognitive event-related potential and topographic asymmetry of P300, with reduced left temporal voltage. This P300 asymmetry is, in turn, linked to tissue volume asymmetry in the posterior superior temporal gyrus. However, it is unknown whether P300 asymmetry is specific to schizophrenia and whether central and lateral P300 abnormalities are due to chronic morbidity, neuroleptic medication, and/or hospitalization, or whether they are present at the onset of illness. METHODS: P300 was recorded in first-episode schizophrenia, first-episode affective psychosis, and control subjects (n = 14 per group). Subjects silently counted rare (15%) target tones (1.5 kHz) among trains of standard tones (1.0 kHz). Averages were constructed from brain responses to target tones. RESULTS: Peak amplitude of P300 and integrated voltage over 300 to 400 milliseconds were significantly different between first-episode schizophrenics and controls over the posterior sagittal midline of the head. First-episode schizophrenics displayed smaller amplitudes over the left temporal lobe than first-episode affective psychotics and controls, but the groups showed no differences over the right temporal lobe. CONCLUSIONS: Left-sided P300 abnormality in first-episode schizophrenia relative to first-episode affective psychosis and controls suggests that P300 asymmetry is specific to schizophrenic psychosis and present at initial hospitalization. This P300 asymmetry suggests left temporal lobe dysfunction at the onset of schizophrenia.

Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients.

BACKGROUND: Magnetic resonance imaging studies in schizophrenia have revealed abnormalities in temporal lobe structures, including the superior temporal gyrus. More specifically, abnormalities have been reported in the posterior superior temporal gyrus, which includes the Heschl gyrus and planum temporale, the latter being an important substrate for language. However, the specificity of the Heschl gyrus and planum temporale structural abnormalities to schizophrenia vs affective psychosis, and the possible confounding roles of chronic morbidity and neuroleptic treatment, remain unclear. METHODS: Magnetic resonance images were acquired using a 1.5-T magnet from 20 first-episode (at first hospitalization) patients with schizophrenia (mean age, 27.3 years), 24 first-episode patients with manic psychosis (mean age, 23.6 years), and 22 controls (mean age, 24.5 years). There was no significant difference in age for the 3 groups. All brain images were uniformly aligned and then reformatted and resampled to yield isotropic voxels. RESULTS: Gray matter volume of the left planum temporale differed among the 3 groups. The patients with schizophrenia had significantly smaller left planum temporale volume than controls (20.0%) and patients with mania (20.0%). Heschl gyrus gray matter volume (left and right) was also reduced in patients with schizophrenia compared with controls (13.1%) and patients with bipolar mania (16.8%). CONCLUSIONS: Compared with controls and patients with bipolar manic psychosis, patients with first-episode schizophrenia showed left planum temporale gray matter volume reduction and bilateral Heschl gyrus gray matter volume reduction. These findings are similar to those reported in patients with chronic schizophrenia and suggest that such abnormalities are present at first episode and are specific to schizophrenia.

Attributes of heavy vs. occasional marijuana smokers in a college population.

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.

Relationship of neurological abnormalities in schizophrenics to family psychopathology.

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.

Neurological "hard" signs and family history of psychosis in schizophrenia.

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.

Neuroimaging in bipolar disorder: what have we learned?

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.

Frontal brain volume and context effects in short-term recall in schizophrenia.

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.

MRI brain abnormalities in chronic schizophrenia: one process or more?

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.

Hemispheric asymmetry of frontal and temporal gray matter and age of onset in schizophrenia.

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.

Familial hyperkalemic periodic paralysis and bipolar disorder: a linkage and treatment study.

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.

A quantitative magnetic resonance imaging study of cerebral and cerebellar gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity.

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.

Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study.

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.

Progressive ventricular enlargement in schizophrenia: comparison to bipolar affective disorder and correlation with clinical course.

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.

Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia.

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.