Yechiel Levkovitz

Transcranial Magnetic Stimulation and Antidepressive Drugs Share Similar Cellular Effects in Rat Hippocampus

Transcranial magnetic stimulation (TMS) has been proposed as a safe and efficient treatment of human clinical depression. Although its antidepressive mechanism of action remained unknown, our previous studies indicate that TMS has a long-lasting effect on neuronal excitability in the hippocampus. We now compare the effects of chronic TMS with those of the antidepressant drugs desipramine and mianserin. The three treatments did not affect basal conduction in the perforant path to the dentate gyrus, but markedly suppressed paired-pulse and frequency-dependent inhibition, resulting from a reduction in local circuit inhibition in the dentate gyrus. Concomitantly, these treatments enhanced the expression of long-term potentiation in the perforant path synapse in the dentate gyrus. Finally, chronic TMS as well as mianserin suppressed the serotonin-dependent, potentiating action of fenfluramine on population spike in the dentate gyrus. Thus, TMS, mianserin, and desipramine are likely to affect the same neuronal populations, which may be relevant to their antidepressant action.

Repetitive transcranial magnetic stimulation in the treatment of depression in adolescents: an open-label study.

Objective: This open-label pilot study examined repetitive transcranial magnetic stimulation as a possible treatment of adolescent resistant depression. Method: Nine adolescents (aged 16-18 years) with severe resistant depression (determined by SCID) were recruited, and their depression, suicidality, and cognitive functions were evaluated before, during, and after a course of twenty 10-Hz, 2-second trains (intertrain intervals of 58 seconds) given over 20 min/d over 14 working days. Results: Lower levels of depression with progression in therapy were recorded by both the Beck Depression Inventory and Child Depression Rating Scale measures (F1.7,14.01 = 4.52, P < 0.05; F4,32 = 6.645, P < 0.01, respectively). Three patients reached the primary outcome measure of less than 30% reduction in their Child Depression Rating Scale. The effect on suicidality was not significant. Side effects were considered mild. Conclusions: Repetitive transcranial magnetic stimulation might be a possible therapy for adolescent depression. Our preliminary findings warrant double-blind, controlled studies.

rTMS for adolescents: Safety and efficacy considerations

In light of both the FDAs clearance of repetitive transcranial magnetic stimulation (rTMS) for adult major depressive disorder and concerns about safety and efficacy of existing antidepressant therapies for adolescent depression, there is increasing interest in rTMS as a novel treatment for adolescent depression. We reviewed English-language studies using rTMS in persons under the age of 18, yielding 6 published reports. Because rTMS is typically delivered at or above 1 Hz for psychiatric indications, our search was confined to these frequencies. Also included are studies involving rTMS above 1 Hz for non-psychiatric indications. Articles were retrieved from the MEDLINE database. There were 19 reported subjects under age 18 who have been administered rTMS at a frequency above 1 Hz: 10 for major depression, 5 for spastic cerebral palsy and 4 for epilepsia partialis continua. We found that most subjects responded favorably to rTMS and no adverse events have been reported. However data are insufficient for drawing firm conclusions about safety and efficacy. Further studies of rTMS as a treatment for adolescent depression are warranted.

Aging affects transcranial magnetic modulation of hippocampal evoked potentials

Transcranial magnetic stimulation (TMS) is being proposed as a method of choice for the treatment of clinical depression, yet its action in the brain is still not well understood. In previous studies we found that TMS has a long-term effect on reactivity of the hippocampus to perforant path stimulation. Since the efficacy of antidepressants is highly age-dependent, we studied possible age-related effects of TMS on hippocampal evoked responses. Young adult (3 months), aging (10 months) and aged (24-26 months) awake rats were subjected to daily TMS for one week, followed by measurements of several parameters of reactivity to perforant path stimulation in the anesthetized rat. TMS did not affect responses of the hippocampus to single perforant path stimulation, but reduced drastically paired-pulse and frequency dependent depression in the young and aging but not the old rats. Likewise, TMS increased LTP expression in the young but not the old rats, and reduced the efficacy of serotonin modulation of reactivity of the hippocampus, in the young but not the old rats. Thus, long term effects of chronic TMS on local GABAergic inhibition are highly age dependent.

Effect of 5-hydroxytryptophane on behavior and hippocampal physiology in young and old rats.

Spatial memory ability, tested in a water maze, was severely impaired in control, 24-month-old hooded rats. A daily injection of the serotonin precursor, 5-hydroxytryptophane (5-HTP), prior to training sessions, had no effect on the behavior of the young rats but improved considerably the performance of the old rats in the watermaze. In the same groups of young and aged rats, the response properties of the hippocampal dentate gyrus to perforant path stimulation was assessed before and after parenteral administration of 5-HTP. The dentate gyrus of aged rats produces a smaller EPSPs in response to perforant path stimulation but a larger population spike for a given EPSP than that produced in young rat brains. These differences are not affected by 5-HTP. In young brains, priming commissural stimulation suppresses subsequent reactivity to perforant path stimulation. This priming effect is nearly absent in aged rat hippocampus but reappears when the rat is injected with 5-HTP. It is suggested that the serotonergic innervation of the rat hippocampus plays a major role in regulation of the excitability of the hippocampus and in behavioral functions associated with this structure.

Acetylcholine mediates the effects of fenfluramine on dentate granule cell excitability in the rat

Reactivity of the hippocampal system to stimulation of its main afferent, the perforant path, was studied in the intact, anesthetized rat. Parentral administration of fenfluramine caused a marked elevation of population spike response to perforant path stimulation. An injection of atropine before, but not after fenfluramine, blocked the potentiating effect of fenfluramine. The atropine blockade was dose-dependent and not mimicked by the peripheral muscarinic receptor antagonist methyl atropine. This effect of fenfluramine was also prevented by an injection of the 5-HT receptor antagonist spiperone. The effect of fenfluramine was mimicked by the anticholinesterase physostigmine, which was not affected by spiperone pretreatment. It is proposed that release of 5-HT (5-hydroxytryptamine) by fenfluramine potentiates reactivity to afferent stimulation by interacting with cholinergic terminals in the hippocampus.

Suicidal behavior in minors-diagnostic differences between children and adolescents

Background: To date, the study of suicidal behavior among minors has focused on the age group in which it is more prevalent: adolescents. We hypothesized that suicidal behavior in children stems from a different diagnosis than suicidal behavior in adolescents, and thus merits its own investigation. Method: We studied all minors (266) who were referred to a psychiatric emergency department due to a suicide attempt or suicidal ideation during a 3-year period. Result: There was an age-related difference in diagnostic distribution among minors who were referred to the emergency department because of suicidal behavior (&khgr;2 (7) = 24.297, P < 0.01). Attention deficit hyperactivity disorder was more prevalent among children (under 12 years old), whereas mood disorders were more prevalent among adolescents (12–18 years old). Conclusion: The findings of this study highlight a diagnostic difference between suicidal children and suicidal adolescents.

Can Computerized Cognitive Tests Assist in the Clinical Diagnosis of Attention-Deficit Hyperactivity Disorder?

A group of 34 children and adolescents suspected of having attention-deficit hyperactivity disorder were referred for a computerized evaluation that included sustained attention, working memory, planning, and set-shifting. Although only sustained attention had reasonable specificity, all tests had questionable contribution to the diagnostic evaluation.

Age-dependent local modulation of hippocampal-evoked responses to perforant path stimulation

Local modulation of hippocampal-evoked responses to perforant path stimulation was studied by leaking drugs from the recording pipette placed in the dentate gyrus of anesthetized young (3 months old), aging (17 months old) and old (28 months old) rats. In old rats, the excitatory postsynaptic potential (EPSP) slope was much reduced compared to young and aging rats. The population spike (PS) size was similar in all age groups. Bicuculline caused a marked increase in PS size relative to population EPSP, and reversed the response to the second pulse in a paired-pulse paradigm from inhibition to facilitation. The effect of bicuculline was only slightly reduced in old rats. The 5-HT1a agonist 8-OH-DPAT potentiated PSs in the dentate gyrus, while not affecting paired-pulse inhibition. The effect of 8-OH-DPAT was slightly reduced in old rats. Carbachol, a cholinergic agonist, reversed paired-pulse inhibition into facilitation in the young brain, but not in aging and old rats. These results demonstrate that age affects differentially the action of biogenic amines on hippocampal reactivity to afferent stimulation.

Methylphenidate Reduces State Anxiety During a Continuous Performance Test That Distinguishes Adult ADHD Patients From Controls.

Objective: We hypothesized that patients with ADHD were typified by distress more than by functional difficulties. Thus, a decline in state anxiety while performing a cognitive task when taking methylphenidate would discriminate between ADHD patients and controls. Method: State anxiety and cognitive performance on a continuous performance test were assessed in ADHD patients and controls with and without taking methylphenidate. Results: State anxiety and cognitive performance improved from baseline in 36 ADHD adults after taking methylphenidate. In 25 controls, cognitive performance improved, but state anxiety did not abate after a recess. In two additional studies, 5 controls were evaluated at baseline and after receiving methylphenidate, and showed improvement in cognitive assessment but not in state anxiety. Five ADHD adults were assessed at baseline and after a recess, and showed no improvement. Conclusion: Our results support the hypothesis that adult ADHD patients are characterized by distress and the relief of this distress under effective therapy as expressed by a decline in state anxiety while they perform a cognitive task.