Application of TMS
A fundamental problem with conventional functional imaging has been an inability to probe the causal relationship between regional brain activity and behaviour. For example, if a brain region utilizes more glucose or oxygen while the subject performs a behavioural task, it is only possible to conclude that the change in regional activity correlates with the behaviour; a causal relationship between the metabolic and behavioural changes can only be inferred. By combining TMS with fMRI it is now possible to directly test how information flows within the brain. With TMS, a brief but powerful electric current is passed through a small coil held against the scalp of a conscious patient. This generates a powerful local magnetic field which passes unimpeded through the skull and induces a weaker, less focused electric current within the brain. Due to the noninvasive nature of this method, the important physiological effects of TMS are likely to be a consequence of the density of the electric current and the electric field which is induced in the cortex. It is believed that the induced electrical fields cause neuronal depolarization which changes the neurotransmitter release mechanisms.
TMS has now been combined with glucose utilization studies and fMRI. Repetitive TMS, unlike electroconvulsive therapy (ECT), uses subconvulsive stimuli to treat depression. Compared to ECT, TMS has a potential to target specific brain regions and to stimulate brain areas thought to be primarily involved in depression while sparing areas like the hippocampus, thereby reducing the probability of cognitive side effects. However, the therapeutic efficacy of TMS as a treatment for depression is, unlike ECT, modest. Most TMS studies use high-frequency, fast stimulation (410 Hz) over the left dorsolateral prefrontal cortex, an area which has beenshown to be hypofunctional in PET and electroencephalogram (EEG) studies of depressed patients. Most ‘‘open’’ and double-blind studies have confirmed that TMS has a modest antidepressant response in nonpsychotically depressed patients. No seizures or cognitive side effects have so far been reported following fast TMS, pain at the treatment site being the only recorded problem. Hopefully the combination of TMS with fMRI will enable the more precise location of the regional dysfunction in depression to be located and thereby enable the neuronal pathways concerned to be identified. To date, the early studies of TMS with fMRI have shown that the effects of TMS occur in brain regions distant from the site of stimulation, including the caudate, orbitofrontal cortex and the cerebellum. Classification of neurotransmitter receptors The British physiologist Langley, in 1905, was first to postulate that most drugs, hormones and transmitters produce their effects by interacting with specific sites on the cell membrane which we now call receptors. Langley’s postulate was based on his observation that drugs can mimic both the specificity and potency of endogenous hormones and neurotransmitters, while others appear to be able to selectively antagonize the actions of such substances. Thus, substances which stimulate the receptor, or mimic the action of natural ligands for the receptor, are called agonists, while those substances blocking the receptor are called antagonists. This revolutionary hypothesis was later extended by Hill, Gaddum and Clark, who quantified the ways in which agonists and antagonists interacted with receptors both in vitro and in vivo. More recently the precise structures of a large number of different types of transmitter receptors have been determined using cloning and other techniques, so that it is now possible to visualize precisely how an agonist or antagonist interacts with certain types of receptor. To date, different types of cholinergic, b-adrenergic and serotonergic receptors have been cloned, and their essential molecular features identified. In addition, a number of peptide receptors such as the insulin, gonadotrophin, angiotensin, glucagon, prolactin and thyroid stimulating hormone receptors have also been identified and their key structures determined. The location and possible functional importance of the different types of neurotransmitter receptors which are of relevance to the psychopharmacologist are summarized below. It must be emphasized that this list is by no means complete and that many of these receptor types are likely to be further subdivided as a result of the development of highly selective ligands.
A fundamental problem with conventional functional imaging has been an inability to probe the causal relationship between regional brain activity and behaviour. For example, if a brain region utilizes more glucose or oxygen while the subject performs a behavioural task, it is only possible to conclude that the change in regional activity correlates with the behaviour; a causal relationship between the metabolic and behavioural changes can only be inferred. By combining TMS with fMRI it is now possible to directly test how information flows within the brain. With TMS, a brief but powerful electric current is passed through a small coil held against the scalp of a conscious patient. This generates a powerful local magnetic field which passes unimpeded through the skull and induces a weaker, less focused electric current within the brain. Due to the noninvasive nature of this method, the important physiological effects of TMS are likely to be a consequence of the density of the electric current and the electric field which is induced in the cortex. It is believed that the induced electrical fields cause neuronal depolarization which changes the neurotransmitter release mechanisms.
TMS has now been combined with glucose utilization studies and fMRI. Repetitive TMS, unlike electroconvulsive therapy (ECT), uses subconvulsive stimuli to treat depression. Compared to ECT, TMS has a potential to target specific brain regions and to stimulate brain areas thought to be primarily involved in depression while sparing areas like the hippocampus, thereby reducing the probability of cognitive side effects. However, the therapeutic efficacy of TMS as a treatment for depression is, unlike ECT, modest. Most TMS studies use high-frequency, fast stimulation (410 Hz) over the left dorsolateral prefrontal cortex, an area which has beenshown to be hypofunctional in PET and electroencephalogram (EEG) studies of depressed patients. Most ‘‘open’’ and double-blind studies have confirmed that TMS has a modest antidepressant response in nonpsychotically depressed patients. No seizures or cognitive side effects have so far been reported following fast TMS, pain at the treatment site being the only recorded problem. Hopefully the combination of TMS with fMRI will enable the more precise location of the regional dysfunction in depression to be located and thereby enable the neuronal pathways concerned to be identified. To date, the early studies of TMS with fMRI have shown that the effects of TMS occur in brain regions distant from the site of stimulation, including the caudate, orbitofrontal cortex and the cerebellum. Classification of neurotransmitter receptors The British physiologist Langley, in 1905, was first to postulate that most drugs, hormones and transmitters produce their effects by interacting with specific sites on the cell membrane which we now call receptors. Langley’s postulate was based on his observation that drugs can mimic both the specificity and potency of endogenous hormones and neurotransmitters, while others appear to be able to selectively antagonize the actions of such substances. Thus, substances which stimulate the receptor, or mimic the action of natural ligands for the receptor, are called agonists, while those substances blocking the receptor are called antagonists. This revolutionary hypothesis was later extended by Hill, Gaddum and Clark, who quantified the ways in which agonists and antagonists interacted with receptors both in vitro and in vivo. More recently the precise structures of a large number of different types of transmitter receptors have been determined using cloning and other techniques, so that it is now possible to visualize precisely how an agonist or antagonist interacts with certain types of receptor. To date, different types of cholinergic, b-adrenergic and serotonergic receptors have been cloned, and their essential molecular features identified. In addition, a number of peptide receptors such as the insulin, gonadotrophin, angiotensin, glucagon, prolactin and thyroid stimulating hormone receptors have also been identified and their key structures determined. The location and possible functional importance of the different types of neurotransmitter receptors which are of relevance to the psychopharmacologist are summarized below. It must be emphasized that this list is by no means complete and that many of these receptor types are likely to be further subdivided as a result of the development of highly selective ligands.
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