The emergence of repetitive transcranial magnetic stimulation (rTMS) as a relatively noninvasive probe of cortical function provides an opportunity to explore the relationships between regional brain activity and symptomatology across neuropsychiatric illnesses. In this article, we briefly review evidence from functional neuroimaging studies (principally those using positron emission tomography [PET] or single-photon emission computed tomography [SPECT]) and other studies suggesting regional brain involvement in anxiety disorders, specifically obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). We also review an initial controlled study conducted by our group using rTMS as a probe of prefrontal mechanisms in OCD. This discussion is not intended to be comprehensive, but rather to provide examples of disorders that, based on current knowledge, might be good candidates for the use of rTMS as a probe. In addition, we present case reports from pilot studies of rTMS in three patients with different primary anxiety disorder diagnoses, which illustrate some of the issues involved in such studies, as well as the effects observed. The possibility that rTMS may have therapeutic potential in anxiety disorders is also discussed.

Transcranial magnetic stimulation (TMS), a relatively noninvasive probe of cortical function, permits new kinds of explorations of relationships between regional brain activity and symptomatology in obsessive-compulsive disorder (OCD). In TMS, a pulsed magnetic field affects activity in cerebral cortex underlying an electromagnetic coil placed on the scalp. Results of exploratory studies suggest that the single- or paired-pulse TMS techniques, and the newer repetitive method (rTMS), in which trains of stimuli are delivered at a given frequency, are potentially useful probes of cortical mechanisms involved in psychopathologic conditions, as in studies of motor, sensory, and cognitive physiology. For example, single-pulse TMS of motor cortex can produce muscle potentials or movement. Higher-frequency repetitive stimulation (rTMS) of occipital cortex can produce phosphenes or visual extinction, stimulation of Broca's area results in word-finding difficulties or speech arrest, and rTMS of prefrontal cortex affects verbal recall and other cognitive functions. Prefrontal rTMS can alter mood in healthy individuals. Both open and controlled clinical studies suggest that single-pulse TMS, and rTMS, may have antidepressant effects. Although the cerebral cortex is the only human brain structure subject to direct magnetic stimulation with current technology, TMS may influence activity in subcortical sites via their functional relationships with cortical areas. The effects of TMS on cortical excitability may depend on a combination of factors including coil design, stimulus frequency and intensity, and possibly the functional state of the cortex before stimulation.

The possibility that pharmacological response might help to refine psychiatric nosology has been the subject of recurrent speculation, but few clear-cut results have been obtained. Only bipolar depressives and several other minor patient subgroups manifest consistent drug responses in association with characteristic psychobiological features. The presence of multiple intervening variables, such as individual differences in drug metabolism, drug-taking behaviour and biological sensitivity to drugs, may mitigate against the reliable identification of clinically distinguishable drugresponding subgroups. Furthermore, the majority of available psychoactive drugs have either multiple or broad spectrum effects inconsistent with hypotheses utilizing the mechanism or site of drug action to argue for a diagnosis-specific biological disorder at such sites.

Nonetheless the successful use of drug-response models in other areas of medicine suggests a rationale for continued exploration in this area, and a number of recent advances make this approach potentially more productive. Pharmacological developments have rendered it possible to assess the biological availability of drugs in potential responders, thus eliminating some of the confounding intervening variables. Further consideration should also be given to the use of drugs with more specific neurochemical effects, even when they themselves are not necessarily therapeutic. The comparison of drug responder and non-responder groups has also been made more meaningful by the availability of more reliable methods of assessing clinical phenomena, more sophisticated diagnostic models and the introduction of other biological measures. Combining several of these approaches may allow the use of one to validate the other.

The present study, using a diathesis-stress model, attempted to confirm prior findings with platelet monoamine oxidase (MAO) activity and stress in a middle-aged, non-clinic population. One hundred and seventy-eight adult males from a statewide community club were tested for platelet MAO activity and stressful life events and were also given a variety of psychological measures of both psychopathology and psychosocial coping. The data were examined both for correlations across the total sample and for a comparison of high-risk groups (top and bottom 15% of MAO activity) with a middle MAO group. Low platelet MAO activity was related to a higher incidence of contact with mental health professionals, and more frequent use of alcohol and cigarette smoking. High MAO activity was related to higher levels of anxiety and somatization. High levels of stress were related to increased psychosocial problems reported for female and family members, higher scores on two schizophrenia-related MMPI scales (schizophrenia and paranoia subscales), but fewer idiosyncratic associations, elevated hypomanic, depression, and anxiety scores, increased alcohol use, and increased use of prescribed antianxiety and sedative medication. Neither MAO nor stress were related to current levels of psychosocial coping. Moreover, no interaction effects were uncovered for MAO activity and stress combined.

Family histories obtained from 27 patients with obsessive-compulsive disorder failed to find a single parent with the disorder. To augment the family history data the Leyton Obsessional Inventory was completed by a subset of 10 patients and by their 20 parents. Although as a group parents showed lower Leyton Obsessional Inventory symptom scores than their obsessional offspring, 3 parents who had not been identified by family history were distinguished by high symptom scores in the absence of significant resistance or interference.

Twelve patients with obsessive compulsive disorder were studied with psychophysiological measures during a randomised, double-blind placebo-controlled drug trial. Significant clinical improvement followed six weeks of treatment with the tricyclic antidepressant clomipramine, but was not evident after an equal period of treatment with the monoamine oxidase inhibitor (MAOI) clorgyline. Compared to placebo, both drugs reduced skin conductance indices of baseline arousal, but only clomipramine reduced skin conductance and heart rate responses to loud tones and tonic and phasic skin conductance responses in a two-flash discrimination task. This suggests that reductions in autonomic responses to important and/or aversive stimuli may be critical to clinical improvement in obsessive compulsive disorder.

We have observed a lesser growth hormone response to intravenous clonidine administration in nine obsessive-compulsive disorder patients meeting research diagnostic criteria than in nine matched controls. The obsessive-compulsive disorder patients had higher plasma free 3-methoxy-4-hydroxyphenylglycol and plasma norepinephrine levels before clonidine than the controls. As blunted growth hormone responses to clonidine are also characteristic of affective disorder patients, these results support other observations of a psychobiologic affinity between these two groups and are also compatible with an association between increased presynaptic noradrenergic activity and decreased post-synaptic receptor responsiveness.

The possible effects of clinical depression on intellectual function were investigated in unipolar and bipolar patients. Ninety-six hospitalized depressed patients completed the Wechsler Adult Intelligence Scale (WAIS) on admission and 34 were retested on remission. The high average full scale IQs found remained relatively stable throughout, consistent with earlier studies indicating a limited relationship between intellectual function and clinical severity of depression. No evidence was found for retarded psychomotor activity in bipolar groups or increased psychomotor activity in unipolar groups on three WAIS subtests of psychomotor function, but full scale IQ increased slightly in hypomania.

Platelet and plasma amine oxidase activity was determined in a group of 99 healthy male (active duty military) alcoholics referred for hospital treatment who had been abstinent from alcohol for 2–10 days, and compared with that of a control military group. Platelet MAO activity was slightly but significantly lower in the alcoholic group. Both groups were significantly lower in MAO activity compared to a group of 42 non-military controls. In the alcoholic group there was no correlation between platelet MAO and severity or chronicity of drinking, nor was there evidence of iron deficiency to account for the lowered MAO activity. When the alcoholic and military control groups were split at the median, the first degree relatives of both the ‘low’ MAO alcoholics and the ‘low’ MAO military controls had a higher incidence of alcoholism than did the relatives of both ‘high’ MAO subgroups. No personal or family history data of alcohol-related problems were available on the non-military control group.

Reported reductions in the activity of platelet monoamine oxidase (MAO) in chronic schizophrenic patients might be contributed to by alterations in hormones, platelet numbers or other non-specific factors thought to affect enzyme activity. In this study, MAO activity in 27 patients with chronic schizophrenia was measured, using benzylamine as the substrate in an assay based on platelet counts instead of platelet protein, and was found to be markedly lower than mean MAO activity in 375 normal controls. These results were similar to those previously reported with tryptamine as a substrate for the enzyme. Serum testosterone, triiodothyronine, iron and iron-binding capacity were within normal ranges in individuals with reduced MAO activity, and none of these measurements was significantly correlated with MAO activities. Platelet MAO activity remained stable over time in patients and controls.

It has repeatedly been demonstrated that hyperactive children improve in behaviour and school functioning when treated with amphetamine, methylphenidate and, according to recent studies, imipramine (Conners, 1972). While these drugs affect catecholamine and indoleamine metabolism, there have been few studies intercorrelating the clinical and biochemical effects of these agents. A small number of untreated hyperactive children have been found to have normal urinary catecholamine and indoleamine excretion (Rapoport et al., 1970; Wender, 1971) although whole blood hydroxyindole concentrations have been reported as reduced (Coleman, 1971). In the present study, platelet serotonin content was examined before and during treatment with methylphenidate and imipramine of a group of boys with the hyperactivity syndrome.