By F. Akascha. University of Pennsylvania.
Eddy Memorial Award for lifetime excellence in drug abuse lin: Springer-Verlag order generic liv 52, 1996:563–592 purchase liv 52 in united states online. Methadone-related opioid agonist pharmacotherapy 1999: proceedings of the 61st annual scientific meeting of the Col- for heroin addiction: history purchase liv 52 cheap online, recent molecular and neurochemi- lege on Problems of Drug Dependence order 200 ml liv 52 with mastercard. NIDA Res Monogr 2000; cal research and the future in mainstream medicine. A range of research-based pharmacotherapies for nucleotide polymorphisms of the human mu opioid receptor addiction. Pharmacologic treatment of heroin- oligonucleotide gelpad microchips: potential in studies of addic- dependent patients. Symposium XIII: allelic polymor- 1504 Neuropsychopharmacology: The Fifth Generation of Progress phisms of human opioid receptors. Functional studies: Genetic tosis and activation of MAP kinase pathway. Mol Brain Res contributions to protection from, or vulnerability to, addictive 2000;76:220–228. Mu and delta-opioid receptor agonists proceedings of the 61st annual scientific meeting of the College induce mitogen-activated protein kinase (MAPK) activation in on Problems of Drug Dependence. NIDA Res Monogr 2000; the absence of receptor internalization. Quantitative immunolo- preproenkephalin and the mu opiate receptor. Ann NY Acad calization of mu opioid receptors: regulation by naltrexone. Binding of 3H-nalox- phosphorylation and desensitization induced by agonists and one in the mouse brain: effects of ions and tolerance develop- phorbol esters. Narcotic receptor sites in morphine- opioid receptors in selected neural pathways following chronic dependent rats. The role of dopaminergic systems in opioid phin binding and activity: possible implications for opiate addic- receptor desensitization in nucleus accumbens and caudate pu- tion. Opioid receptor- using herpes simplex virus vector expressing GluR1. J Neurosci coupled G-proteins in rat locus coeruleus membranes: decrease 2000;20:RC62. Mu-Opioid receptor mouse model of chronic morphine tolerance. Mol Brain Res desensitization by beta-arrestin-2 determines morphine toler- 1998;55:237–242. Opioids excite dopamine neurons by administration desensitizes mu opioid receptor-activated G-pro- hyperpolarization of local interneurons. J Neurosci 1992;12: teins in specific regions of rat brain. Involvement of phospho- ference to cocaine and amphetamine in mice lacking the dopa- lipid signal transduction pathways in morphine tolerance in mine transporter. Morphine activates opioid administration in dopamine-transporter knockout mice. Nat receptors without causing their rapid internalization. Phosphorylation is not properties of morphine in dopamine-transporter knockout required for dynamin-dependent endocytosis of a truncated mu- mice. Mu-opioid receptor nucleus accumbens extracellular dopamine concentrations dur- internalization: opiate drugs have differential effects on a con- ing self-administration of cocaine/heroin combinations served endocytic mechanism in vitro and in the mammalian (Speedball) in rats. Specific G protein activa- accumbens during heroin self-administration is modulated by tion and mu-opioid receptor internalization caused by mor- kappa opioid receptors: an in vivo fast-cyclic voltammetry study. Eur J Pharmacol 1998; J Pharmacol Exp Ther 1998;284:151–161. Phosducin, beta-ar- dynorphin A1-17 reduces extracellular dopamine levels in the restin and opioid receptor migration. Functional dissociation of the College on Problems of Drug Dependence. NIDA Res of mu opioid receptor signaling and endocytoses: implications Monogr 1997;174:113. Ligand-induced changes mine concentrations as determined by in vivo microdialysis. J in surface mu-opioid receptor number: relationship to G protein Pharmacol Exp Ther 1995;273:591–598. Opioid receptor endocy- and spontaneous withdrawal are associated with modifications Chapter 104: Neurobiology and Pathophysiology of Opiate Addiction 1505 of dopamine receptor and neuropeptide gene expression in the treatment. NAPAN, National Institute of Mental Health, 1972: rat striatum. Medical safety and side effects of methadone in toler- and repeated morphine administration on the prodynorphin ant individuals. New York: Stratton Intercontinental Medical opiate and opioid antagonist treatment on striatal opioid pep- Book, 1975:88–97. Cellular responses of nucleus exogenous opioid administration on levels of one endogenous accumbens neurons to opiate-seeking behavior. Synapse 1999;33: Advances in endogenous and exogenous opioids. Chronic repeated chronic methadone maintenance treatment in humans. Life Sci cocaine administration alters basal and opioid-regulated ade- 1983;33:409–411. Repeated cocaine beta-endorphin response to metyrapone testing during chronic administration upregulates kappa and mu, but not delta opioid methadone maintenance treatment in humans. Cortisol levels during a cocaine 'binge' alters basal extracellular levels in male rats: chronic naltrexone maintenance treatment in ex-opiate addicts. J Pharmacol Exp Ther 1995;272: Biol Psychiatry 1986;21:217–220. Chronic morphine of beta-endorphin during chronic naltrexone maintenance treat- induces visible changes in the morphology of mesolimbic dopa- ment in ex-opiate addicts. Psychopharmacology: the third gen- istration induces a sustained increase of prodynorphin mRNA eration of progress. Rationale for maintenance pharmacotherapy of op- administration and correlation with preprodynorphin mRNA. Dopamine receptor antagonists prevent Acad Sci 2000;909:186–216. Beta-endorphin levels during J Pharmacol 1995;14:235–244. Abnormal metyrapone accumbens using both mu 1 and delta opioid receptors. Ann tific meeting of the College on Problems of Drug Dependence. Altered HPA axis responsivity elevation of serum levels of prolactin through an opioid receptor to metyrapone testing in methadone maintained former heroin mechanism in humans: gender differences and implications for addicts with ongoing cocaine addiction. Neuropsychopharmacol- modulations of dopaminergic tone in the treatment of addic- ogy 2001;24:568–575. Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al. Dynorphin A1-13 administration ment of opioid induced constipation with oral naloxone: a pilot causes elevation of serum levels of prolactin in human subjects. Reliability of se- ings of the 55th annual scientific meeting of the College on quential naloxone challenge tests. Am J Drug Alcohol Abuse Problems of Drug Dependence. 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When emotion is elicited in the laboratory buy liv 52 uk, in patients with several stress-related disorders buy generic liv 52 200 ml line, including something of a conflict arises because social norms dictate posttraumatic stress disorder (PTSD) (51) and depression certain rules for participant behavior that do not usually (52 liv 52 200 ml generic,53) generic 120 ml liv 52 visa, although several failures to replicate these findings include the display of strong emotion. In the studies in which hippo- cess of activating emotion in the unfamiliar context of a campal atrophy has been found, the implication is that ex- laboratory environment might activate the ACC. Carter et cessively high levels of cortisol associated with the stress- al. In most individuals, auto- all these studies have focused on the effects of hippocampal matic mechanisms of emotion regulation are likely invoked changes on cognitive function, particularly declarative to dampen strong emotion that may be activated in the memory, we have proposed that the hippocampus also plays laboratory. The initial call for the processes of emotional a key role in the context modulation of emotional behavior regulation may result from ACC activation. Moreover, we have suggested that it is in the affective realm that the impact of hippocampal involvement in psy- chopathology may be most apparent, and that in persons PROBING THE NEURAL CIRCUITRY OF with compromised hippocampal function, the normal con- AFFECT AND COGNITION IN PATIENTS text-regulatory role of this brain region is impaired, so that WITH MOOD AND ANXIETY DISORDERS: they consequently display emotional behavior in inappro- CONCEPTUAL AND METHODOLOGIC priate contexts. For example, in the case of PTSD, extreme fear functions in the underlying neural circuitry of cognition and anxiety were likely very adaptive in the original trau- and affect in patients with mood and anxiety disorders are matic context. This extreme emotional response probably considered. However, in PTSD, recent review by Davidson and Slagter (59). A key issue this response is elicited in inappropriate situations. The pa- that is often neglected in the design of activation studies is tient with PTSD behaves like the animal with a hippocam- the specification of how deficits in the process that is being Chapter 28: The Neuronal Circuitry Underlying Mood and Anxiety Disorders 377 studied may account for the symptoms of the disorder. In this way, example, many of the early PET studies in patients with effects that may be specifically associated with the symptoms various types of psychopathology used easy continuous per- of the disorder can be disentangled from those associated formance tasks in which behavioral differences between with vulnerability to the disorder. The latter class of effects groups were not expected to occur, or they used unilateral may also arise as a consequence of scarring—effects pro- somatosensory stimulation (see ref. Just what the hypothesized relation was between designs that require subjects to be scanned and administered abnormalities in activation patterns in response to such tasks tasks on two or more occasions, it is imperative to have data and symptoms of the disorder being studied was most often on the test–retest stability of the effects in question. The better the concep- effects do not show stability over time, it becomes difficult tual link between task performance and symptomatology, to interpret group differences in change over time in task the more useful an activation paradigm will be for revealing activations. We have strongly advocated the psychometric the underlying deficits in the disorder in question. Several assessment of both psychophysiologic (64) and neuroimag- examples of strong conceptual connections between specific ing (65) measures. Such assessments can turn up important task-related deficits and symptomatology in both the cogni- surprises. Resting regional glucose metabolism measured tive and affective domains are available and can be consulted with PET is frequently used to assess baseline differences by the interested reader (see ref. Using MRI coregistration and regions of interest, we domain). One of the most found that all the regions we examined showed good important of these is matching the difficulty of an experi- test–retest stability, including the left and right hippocam- mental task with that of a control task. This is an issue with pus, left and right anterior caudate region, left and right a long history in experimental research in psychopathology thalamus, and the left amygdala, but not the right amygdala (62), although the neuroimaging field has yet to appreciate (65). The right amygdala apparently varied over time, in its significance fully. When performance on two tasks is part because metabolic rate in this region was more affected compared between groups, it is imperative that the difficulty by the stress of the first scan in comparison with activation of the two tasks be matched. When these pic- of differences in task difficulty and not specific to the pro- tures are used to compare patients and controls over time, cesses that are putatively required for performance of the it is again important to establish that the effects produced task. Chapman and Chapman (62) have provided many are stable over time in normal subjects. We used startle to examples of such artifactual group differences that are prod- probe the test–retest stability of the potentiation produced ucts of variation in task performance rather than reflections by negative pictures and the attenuation produced by posi- of differential deficit. It is therefore essential in neuroimag- tive pictures, and we found poor stability when the same ing studies for activation tasks to be matched in this way. It was only when If the tasks that are being compared in imaging studies are different pictures were used, matched on valence and arousal not matched, then any difference found in activation be- characteristics to the original set, that we found better stabil- tween tasks may arise as a consequence of differences in the ity (64). These data underscore the importance of not as- difficulty level of the tasks. Unfortunately, the neuroimag- suming that effects will be stable over time and the utility ing literature is replete with task comparisons for tasks that of actually measuring the test–retest stability of both task do indeed differ in the level of difficulty and thus are partic- performance and activation changes in normal subjects be- ularly problematic for comparisons between groups. The fore conducting a longitudinal study of changes in patients. In such as pleasant and unpleasant pictures, guided imagery, one of the few studies to have addressed this potential source monetary rewards and punishments, and symptom provoca- of confound, Barch et al. When such paradigms are used, it is function of specific task requirements when they compared imperative for the investigator to verify independently the such tasks to control tasks that were matched in level of presence of the intended affective state. Ideally, such verifi- difficulty but did not require working memory. For In studies with patients, investigators frequently wish to example, peripheral biological indices (e. Moreover, over, in this study, measures of brain electric activity paral- when such measures are used, correlations between activa- leled the performance data and revealed deficits in activation tions produced by the task in question and changes in the in the right posterior scalp. In more flow in the right amygdala during conditioning. Moreover, the magnitude of MR signal change in the amygdala predicts treatment response (55). Most of the extant imaging studies of patients with mood A unique strategy used in research on mood disorders disorders have been performed with PET while the subjects is the short-term depletion of tryptophan among remitted are in a baseline state. These findings have been recently depressed patients maintained on selective serotonin reup- reviewed elsewhere (68). The depletion of tryptophan, which reduces have reported associations between the severity of particular the presynaptic availability of serotonin, often results in de- symptom clusters and patterns of regional blood flow or pressive relapse. Thus, this method can be powerfully har- metabolism (69–71). These studies have underscored the nessed to examine activation patterns during the production importance of differentiating among various symptoms of of depressive relapse in mood-disordered patients. Bremner depression and illustrate the lawful relations that can be at al. When they com- toms and patterns of regional brain activity. The few studies pared subjects who showed a depletion-induced relapse in using activation paradigms that have been conducted in symptoms with those without relapse, they found that tryp- patients with mood disorders have utilized complex cogni- tophan depletion resulted in decreases in regional metabo- tive tasks designed to activate the PFC and ACC. Furthermore, patients who relapsed had a higher planning tasks during depressed mood in normal subjects baseline (i. Depressed subjects failed to show ing the dorsolateral PFC, orbitofrontal cortex, hippocam- normal task-related increases in blood flow in regions of the pus, and amygdala, than those who did not relapse, which PFC, ACC, basal ganglia, and thalamus. For example, Merriam et earlier in this article, is probably implemented at least in al. We have hypothesized that large group of patients with major depression who had been this form of positive affect is abnormally decreased in pa- without medication for at least 28 days. In riques and Davidson (77), using extremely carefully psycho- general, most studies that have used either symptom provo- metrically matched verbal and spatial tasks chosen to reflect cation or other procedures designed to activate the amygdala left- and right-sided posterior cortical function, found a se- have found greater activation in this region in response to Chapter 28: The Neuronal Circuitry Underlying Mood and Anxiety Disorders 379 such stimuli in anxious patients than in controls. For exam- to the underlying symptoms of the disorder should be made ple, in two studies using script-driven imagery and PET to explicit in this type of research. Several psychometric prob- assess regional blood flow, increased activation was found lems were then considered, including the issues of matching in the amygdala of patients with PTSD (84,85). In a more experimental and control tasks according to level of diffi- recent study comparing patients with PTSD and controls, culty and of establishing the reliability of tasks before using Rauch et al. Finally, in stud- expressions of fear versus masked expressions of happiness. It should be apparent from this anxiety disorders (e. In a series of studies that used despite its obvious importance in revealing the abnormali- PET to measure regional cerebral blood flow, Fredrikson ties in circuitry that underlie basic cognitive and affective and colleagues (88; see ref. It is imperative that the next generation of clinical in secondary visual associative regions in patients with snake investigators be trained in the methods and techniques of phobia in response to the presentation of phobia-relevant affective and cognitive neuroscience, the area where such visual stimuli (e. Interestingly, in a separate group of patients with It is also imperative that the results of burgeoning re- arachnophobia, this pattern did not change after the admin- search on cognitive and affective information-processing istrative of diazepam when the subjects were rescanned (90). For example, an extensive faces and aversive odor stimuli. The subjects in this study corpus of literature has now documented biases in forms of were all male; seven had been given a DSM-IV diagnosis explicit memory in depression and biases in attention in of social phobia and five were healthy controls matched for various types of anxiety disorders.
Psychotherapy may be conducted as individual or group sessions order liv 52 with visa. In specialized practice the patient may attend both individual and group sessions trusted 60 ml liv 52. Dialectical Behavior Therapy (DBT) is a form of psychological treatment designed specifically for individuals with self-harm behaviors order 120 ml liv 52 fast delivery, such as self-cutting discount 100 ml liv 52 otc, suicide thoughts, and suicide attempts (that is, common features of borderline personality disorder). While there is great enthusiasm for DBT in borderline personality disorder, it may not be superior to all other forms of treatment (Andreasson et al, 2016). Medication has a place in the treatment of personality disorder. The aim is to assist with circumscribed symptoms (Ripoll, et al, 2011). Avoidant personality disorder is indistinguishable from “social anxiety”, and anxiolytic medication may have a place. There is some evidence for the use of gabapentin and pregabalin (Pande et al, 2004). In schizotypal personality disorder, psychotic-like symptoms and cognitive deficits may be assisted by use of low-dose anti-psychotics. In antisocial personality disorder, impulsive aggression of incarcerated males has been reduced with lithium therapy. In borderline personality disorder fluoxetine has been used to reduce impulsive aggression, and flupenthixol deconoate has reduced suicidal behaviour. Lithium and anticonvulsants have been used for affective instability. However, many of the central symptoms of the disorder, such as chronic emptiness and interpersonal dysfunction are unresponsive to medication. Benzodiazepines are best avoided in the management of borderline personality disorder, due in part to the potential for abuse, but also because these medications may disinhibit and worsen symptoms (Cowdry & Gardner, 1988). It is important to involve the family if possible (but frequently personality disorder has led to family disintegration and animosity). A clear explanation at an early stage, of the diagnosis, the difficulties experienced by the patient and the clinician, and the likely prognosis, will be of assistance to all involved. The management of people with borderline personality presents special challenges. These people are usually angry much of the time and can move from happy to unhappy in response to minor events. They are particularly inclined to self-mutilation (cutting) and suicidal behaviour. Many people with borderline personality disorder have a limited ability to understand and describe the way they are feeling; they are limited to feeling good/happy or bad/distressed/tense/angry. They have limited ability to deal with their bad/distressed/tense/angry state. When they are in this unwelcome state they often get relief from cutting themselves. They report feeling a sense of relief when their blood flows. Such cutting can be distinguished from both attention seeking behaviour (although some subsequent attention may also be rewarding) and the intention to die. However, suicide may be attempted and may be successful. People with borderline personality (as with people with other personality disorders) are best managed in the community with the help of an experienced psychotherapist/counsellor. It is better for them to live in the “real world” and learn to deal with the challenges which the “real world” presents. However, admission to hospital for a brief time (2-3 days) may be indicated when they are in the grip of the bad/distressed/tense/angry state. Being in hospital for long periods increases dependency and a sense of impotence and failure. Hospital is an artificial environment with little opportunity for the growth of a sense of autonomy and competence. The best outcome may be achieved where the patient, an out-patient psychotherapist and a psychiatric inpatient unit cooperate in formulating a plan of regular out-patient psychotherapy and easy admission and rapid discharge (no inpatient psychotherapy) at times of crisis. Effectiveness of dialectical behaviour therapy versus collaborative assessment and management of suicidality treatment for reduction of self-harm in adults with borderline personality traits and disorder – a randomized observer-blinded clinical trial. Globally and locally reduced MRI gray matter volumes in neroleptic-naïve men with schizotypal personality disorder: association with negative symptoms. An empirical study of personality disorders among treatment-seeking problem gamblers. J Gambl Stud 2016 [Epub ahead of print] Cloninger C, Svrakic D, Przybeck T. A psychobiological model of temperament and character. Cerebrospinal fluid and plasma C-reactive protein and aggression in personality-disordered subjects: a pilot study. Journal of Neural Transmission 2014 [Epub ahead of print] Cowdry R, Gardner D. Pharmacotherapy of borderline personality disorder: alprazolam, carbamazepine, trifluoperazine, and tranylcypromine. Anterior cingulate volume reduction in adolescents with borderline personality disorder and co-morbid depression. Alexithymia and breain gray matter volumes in a general population sample. Human brain Mapping 2014, Aug 1 [Epub ahead of print]. Anterior limb of the internal capsule in schizotypal personality disorder: fiber –tract counting, volume, and anisotropy. Jacob C, Muller J, Schmidt M, Hoenberger K, Gutknecht L, Reif A, Schmidtke A, Mossner R, Lesch K. Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity. The alexithymic brain: the neural pathways linking alexithymia to physical disorders. Limbic abnormalities in affective processing by criminal psychopaths as revealed by functional magnetic resonance imaging. Kiehl K, Smith A, Mendrek A, Forster B, Hare R, Liddle P. Temporal lobe abnormalities in sematic processing by criminal psychopaths as revealed by functional magnetic resonance imaging. The latest neuroimaging dindings in borderline personality disorder. Morphometric differences in central stress-regulating structures between women with and without borderline personality disorder. Journal of Psychiatry and Neuroscience 2012 May 22, DOI: 10. Linking novelty seeking and harm avoidance personality traits to cerebellar volumes. Human Brain Mapping, 2012, 00:000-000 Mann J, Waternaux C, Haas G, Malone K. Towards a clinical model of suicidal behaviour in psychiatric patents. Visuo-spatial learning and memory in schizotypal personality disorder: continued evidence for the importance of working memory in the schizophrenia spectrum. Archives of Clinical Neuropsychology 2007; 22:109-116. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
Introducing the agonist at a into the brain (17 purchase liv 52 120 ml mastercard,89) order cheap liv 52 line. Two new drugs that inhibit COMT liv 52 200 ml with amex, low dose order liv 52 online from canada, and slowly titrating to the desired effect reduces tolcapone (Tasmar) and entacapone (Comtan), have re- the probability that they will occur. Dopamine agonists can cently been introduced to the market as an adjunct to levo- acutely cause or intensify dyskinesias, but in the long term dopa therapy. Both drugs inhibit COMT in the periphery, they have the potential to lessen dyskinesias and motor fluc- although tolcapone has mild central effects as well. Entaca- tuations because of their long duration of action (see above). The ergot-derived dopamine ag- reach peak plasma concentration (Tmax) and effects are seen onists, bromocriptine, pergolide, and cabergoline, may have with both immediate and controlled release formulations ergot-related side effects including pleuropulmonary and (90–93). COMT inhibitors thus modulate peak and trough retroperitoneal fibrosis, erythromyalgia, and digital vaso- plasma levodopa concentrations, leading to a smoother spasm, although these are rare (84). The newer non-ergot plasma curve with reduced fluctuations in levodopa level dopamine agonists are less likely to induce these problems, (94). These pharmacokinetic effects have been shown to although there is anecdotal suggestion that they may still translate into enhanced levodopa entry into the brain on occur. Dose-related sedation may occur with dopamine ago- positron emission tomography (PET) (95) and clinical ben- nists (69,78), as with other dopaminergic agents including efits particularly for patients experiencing mild to moderate levodopa. More recently, sudden episodes of unintended motor fluctuations. Double-blind placebo-controlled clini- sleep while at the wheel of a motor vehicle have been de- cal trials in fluctuating PD patients demonstrate that scribed in PD patients and attributed to dopamine agonists COMT inhibitors increase the duration of beneficial effect (85). The episodes were termed 'sleep attacks' because they following a single levodopa dose (96). They also provide an occurred suddenly, although others have argued that there increase daily 'on' time of 15% to 25%, a decrease in is no evidence to support the concept of a sleep attack even 'off' time of 25% to 40%, improvement in UPDRS motor in narcolepsy. They have suggested that it is more likely scores, and a reduction in levodopa dose requirement of that these patients have unintended sleep episodes as a mani- 15% to 30% (97–100). Benefits with COMT inhibitors festation of excess daytime sedation due to nocturnal sleep have also been observed in nonfluctuating PD patients with disturbances that occur in 80% to 90% of PD patients and a stable response to levodopa. Two placebo-controlled trials to the sedative effect of dopaminergic medications (86). It showed improved motor scores and reduced levodopa dose is now apparent that these types of episodes can be associ- requirements in the group receiving the COMT inhibitor ated with all dopaminergic agents including levodopa (87). Physicians should be aware of the potential of dopaminergic There has also been interest in using COMT inhibitors agents to induce sleepiness, and that patients themselves from the time levodopa is first initiated in order to reduce may not be aware that they are sleepy. To detect excess the risk of developing motor complications (103). As de- sleepiness and to thereby introduce appropriate manage- scribed in the section on motor complications, laboratory ment strategies, it is necessary to employ sleep question- evidence supports the notion that treatment for PD patients naires such as the Epworth sleepiness scale, which inquires should be employed in such a way as to try and avoid pulsa- into the propensity to fall asleep and does not rely upon tile stimulation of dopamine receptors (51). Indeed, there subjective estimates of sleepiness (88). However, these patients Catechol O-Methyltransferase (COMT) eventually require levodopa, and when levodopa is adminis- Inhibitors tered the frequency of motor complications increases. It Orally ingested levodopa is massively transformed in the therefore has been postulated that administering levodopa periphery by two enzymatic systems—AADC and from the time it is first introduced with a COMT inhibitor 1802 Neuropsychopharmacology: The Fifth Generation of Progress to extend its half-life and deliver levodopa to the brain in data indicate that tolcapone is the more potent agent. How- a more continuous fashion might further reduce the risk of ever, because of the greater risk of hepatotoxicity and diar- motor complications. Based on a similar hypothesis, studies rhea, entacapone has become the more widely employed comparing controlled-release levodopa to regular levodopa COMT inhibitor. It should be emphasized that COMT failed to demonstrate any difference between the two formu- inhibitors provide antiparkinsonian benefit only when used lations (104,105). However, controlled-release formula- as an adjunct to levodopa. Further, the drug was prescribed advance in the medical treatment of PD and may be useful twice daily in these studies, and that may not have been in all stages of the illness (110). Used in combination with frequent enough to prevent fluctuations in plasma levodopa levodopa, they extend the half-life of levodopa, smooth the concentrations. Clinical trials to test this hypothesis using plasma levodopa concentration curve, and enhance clinical entacapone as an adjunct to levodopa are currently being dopaminergic benefits. Dyskinesia is the most common, but best left to the Parkinson specialist. There are preliminary nausea, vomiting, and psychiatric complications may occa- data suggesting that they enhance motor function in the sionally occur. Both the benefits and dopaminergic adverse milder patient with a stable response to levodopa, and this effects develop within hours to days after initiating treat- is being further evaluated. In general, they are easy to manage by simply reduc- to suggest that administering levodopa with a COMT in- ing the dose of levodopa (by approximately 15% to 30%), hibitor from the time it is first introduced may prevent not the dose of the COMT inhibitor. Dyskinesia is more pulsatile stimulation of dopamine receptors and minimize likely to be a problem in patients who already experience the risk of developing motor complications. The drugs are dyskinesia, and the need for a levodopa dose reduction can easy to use and require no titration. Dopaminergic side ef- be anticipated in these patients. An explosive diarrhea has fects tend to occur within days and can be managed by been seen in 5% to 10% of tolcapone-treated and necessi- tapering the levodopa dose. Because of the restrictions in tates discontinuing the drug. This has been much less of a the use of tolcapone due to liver toxicity, entacapone is now problem with entacapone and rarely requires stopping the the COMT inhibitor of choice. Brownish-orange urine discoloration may occur with tablet will soon be developed that contains the combination either drug due to accumulation of a metabolite. This is a of levodopa, an AADC inhibitor, and a COMT inhibitor. Of greater seriousness is the problem of liver toxicity that Other Antiparkinson Agents has been reported in association with tolcapone (106). No Anticholinergics evidence of liver dysfunction was detected in preclinical tox- icity studies, but in clinical trials elevated liver transaminase Anticholinergic drugs were first used as a treatment for PD levels were observed in 1% to 3% of patients. For this rea- in the 1860s, using extracts from the alkaloids Atropa bella- son, liver monitoring was required. Following approval of donna and Hyscyamus niger, which contain hyosciamine and the drug, there have been reports of four cases of severe scopolamine (111,112). Synthetic anticholinergic drugs liver dysfunction leading to the death of three of the individ- were developed in the 1940s, and they became the mainstay uals (106,107). These observations led to the drug being of PD treatment until the emergence of levodopa (113, withdrawn from the market in Europe and Canada and to 114). These drugs have largely been replaced by the newer the issuance of a 'black box' warning in the United States antiparkinsonian drugs, but are still used occasionally in the (108). This requires biweekly monitoring of liver enzymes modern era particularly for the treatment of tremor (115). No preclinical toxicity, neton), orphenadrine (Disipal), and procyclidine (Kema- clinical trial, or postmarket reports of liver dysfunction have drin). An interaction between dopaminergic and cholinergic been described to date with entacapone, and no laboratory neurons in the basal ganglia has long been recognized, and monitoring is required with its use (109). Cholinergic agents have been administered at a dose of 100 or 200 mg three times daily. Certainly when these agents neurons is regulated by cholinergic interneurons (119). De- are employed, side effects should be sought and the drug spite these observations, the relationship between the cho- discontinued when they occur. Clinical studies demonstrate that anticholinergic agents The discovery of the antiparkinson properties of the anti- provide a 10% to 25% improvement in rest tremor, whereas viral agent amantadine (Symmetrel) was fortuitous (125). In The primary mechanism of action of amantadine in PD is practice, anticholinergic agents can be used in early PD not established with certainty. The drug has been described patients to treat tremor when it is the predominant com- to increase dopamine release, block dopamine reuptake, and plaint and to delay the introduction of levodopa, provided stimulate dopamine receptors.
The evidence suggested topics that should be covered but the detailed content of education packages would vary depending on the individual buy liv 52. People at different stages of CKD required different information discount liv 52 200 ml visa, and discount liv 52 100 ml with mastercard, for example buy cheap liv 52 line, people with stable stage 3A or 3B CKD did not need detailed information about dialysis. However, it was 180 15 Information needs agreed that it was important that people were given information about their prognosis and that they should be aware of options for dialysis access prior to having to make a decision about this. The GDG agreed that it was not sufficient for people simply to be given information about CKD and its treatment. This information had to form part of a programme that educated them about the disease. Older people do not always learn easily from information given on paper and some people may need psychological support to help them cope with the consequences of the information that they have been given. We do not believe this recommendation will have a big cost impact for the NHS since this is part of the existing National Service Framework and such programmes are already widespread. R71 When developing information or education programmes, involve people with CKD in their development from the outset. The following topics are suggested: q What is CKD and how does it affect people? R72 Offer people with CKD high quality information or education programmes at appropriate stages of their condition to allow time for them to fully understand and make informed choices about their treatment R73 Healthcare professionals providing information and education programmes should ensure they have specialist knowledge about CKD and the necessary skills to facilitate learning. R74 Healthcare professionals working with people with CKD should take account of the psychological aspects of coping with the condition and offer access to appropriate support (for example, support groups, counselling or a specialist nurse). A number of tools have recently been introduced to help identify people with CKD and aid early intervention and appropriate management to reduce/prevent complications and progression of CKD. In March 2006 guidelines for the identification, management and referral of adult patients with chronic kidney disease were published by the Royal College of Physicians of London on behalf of a number of collaborating agencies. Participation by practices in the QOF is voluntary, but participation rates are high possibly because there is a financial incentive to do this. In March 2006, four renal domains were included for the first time in the QOF. These indicators focused on creating a register of people with chronic kidney disease with an eGFR <60 ml/min/1. These national tools have increased referral of people with CKD to their local specialist and in turn have resulted in a number of local initiatives aimed at providing a structured delivery of care for people with kidney disease in partnership with primary care. This section was aimed at identifying whether any of these tools had yet improved the identification and management of adults with CKD. Outcomes of interest were appropriate investigations and follow-up, referral, medicines management, and achieving clinical targets. The New Opportunities for Early Renal Intervention by Computerised Assessment (NEOERICA) project used computer searching to extract a retrospective dataset of all patients with a valid serum creatinine measurement from 17 primary care practices in the UK (N=38,262 with valid serum creatinine measures). Manual searching 182 15 Information needs of medical records from 1 practice (N=492 with stages 3–5 CKD identified by computer searching) was used to test the validity of computer searching to estimate the prevalence of CKD. Serum creatinine measurements were calibrated to the original MDRD study in Stevens et al. Two publications from the Optimal Renal Care UK (ORC UK) study assessed the utility of a disease management programme (DMP) that was guideline- and algorithm-based to identify, manage, and appropriately refer people with CKD. Medications dispensed prior to the index creatinine measurements were used to determine disease categories, which were considered in a stepwise logistic regression analysis. Risk scores were calculated for each subject and then categorised into risk classes (I to V). Another study investigated the ability of the Framingham prediction equation to predict 5 year and 10 year risk of cardiac events (myocardial infarction and fatal coronary heart disease) in people with CKD from the pooled ARIC and CHS studies (N=934). Manual checking of medical records identified only 4 additional cases of CKD missed by the computer search. The recording of a renal diagnosis improved as renal function declined. Only 270/1313 (20%) of people with diabetes, hypertension, and eGFR <60 ml/min/1. In people with stage 3–5 CKD without diabetes and a PCR <100, the percentage of systolic blood pressure measurements in target range increased significantly after 9 months of the DMP (37. In people with stage 3–5 CKD, with diabetes or a PCR >100, there were NS differences in blood pressure measurements in target range at baseline compared to after 9 months on the DMP. This was also true for people with eGFR fall ≥5 ml/min/1. After introduction of a referral assessment service, the referral rate decreased rapidly and by 6 months, an average of five new CKD stage 4 or 5 patients were being referred (0. This referral rate was within the capacity of local nephrology services. In both the derivation (N=6789) and validation cohorts (N=3395), people in the Class V risk index had triple the risk of rapid renal disease progression compared with people in the Class I risk index. The Framingham equation correctly identified men with CKD who would develop a cardiac event within 10 years only 184 15 Information needs 60% of the time, compared with 69% of the time in the non-CKD male cohort and 73% in the original Framingham cohort. In women with CKD, discrimination was 73% for 10-year cardiac events compared with 76% in the original Framingham cohort. The 5-year calibration for men was poor (chi-square 33. The Framingham equation under-predicted cardiac events in women with CKD and had poor 5- and 10-year calibration. Recalibrated models performed better, although prediction remained poor in men with CKD. In women with CKD, re-calibration showed NS difference in predicted and observed cardiac events in 5- and 10-year probability models. It was also prior to the introduction of appropriate Read Codes and the renal NSF. All of these factors may have subsequently improved the identification of CKD in primary care populations. Nevertheless the GDG agreed that it was still possible that people with an abnormal GFR or proteinuria were not classified as having CKD. As this information is usually recorded on practice computer databases it appears that it would be quite simple to devise programmes to identify these people. The introduction of a disease management programme tailored to people with CKD resulted in significant improvements in blood pressure and lipid control. A significant reduction in progression of CKD also followed the introduction of the disease management programme. The GDG were surprised that the tool for predicting rapid decline in kidney function did not include known factors such as hypertension and proteinuria in the score whilst anti-emetic use was. It was agreed that the anti-emetic use was probably a marker of the presence of an acute illness which may have affected GFR. The GDG agreed that separate tools for the identification of people with CKD and the identification of people with CKD at risk of progressing would be useful. UK: London: National Institute for Health and Clinical Excellence, 2007. National Service Framework for Renal Services – Part Two: Chronic kidney disease, acute renal failure and end of life care. Prevalence, predictors, and consequences of late nephrology referral at a tertiary care center. Early deaths on renal replacement therapy: the need for early nephrological referral. Late referral to maintenance dialysis: detrimental consequences. Late diagnosis of chronic renal failure and mortality on maintenance dialysis. The pattern of referral of patients with end-stage renal disease to the nephrologist— a European survey. UK Renal Registry, The Renal Associaton, The Ninth Annual Report. A population-based study of the incidence and outcomes of diagnosed chronic kidney disease.
The relationship between ery after stroke: a placebo-controlled buy liv 52 from india, double-blind study order 100 ml liv 52. Am J intellectual impairment and mood disorder in the first year after Psychiatry 2000;157:351–359 liv 52 200 ml low cost. Dementia of depres- cally ill hospitalized older adults: prevalence cheap liv 52 on line, characteristics, and sion or depression of dementia in stroke? Acta Psychiatr Scand course of symptoms according to six diagnostic schemes. RYAN This chapter discusses critical conceptual and practical is- events. Today, as detailed by Keller and Kovacs (3), clinical sues confronting clinicians who must distill the massive neu- depressions are now recognized as far more chronic, more roscientific, psychopathologic, and clinical research infor- often recurrent (typically with a waxing and waning course), mation about the basis for clinical depression and its and more disabling. Historically, symptom severity has been treatment and who must apply that knowledge to individual used to distinguish different forms of depression (e. This chapter does not provide an encyclopedic depressive disorder versus dysthymia). More recent evi- review of antidepressant treatments. A more chronic course and greater symptom severity ment, and on practical dilemmas encountered in daily prac- both contribute to greater levels of disability. The latter often calls for types of information not prevalence rates and the degree of disability found in non- usually provided by standard clinical research protocols de- major forms of depression provide a basis for regarding even signed to obtain regulatory approval of new antidepressant modest levels of nontransient depressive symptoms as a agents. Consequently, efficacy studies After highlighting recent revisions in our knowledge have been undertaken with more chronic forms of depres- about depressive disorders, we discuss the implications of sion (9–11) and with 'nonmajor' forms of depression (e. We conclude with suggestions for further re- such as with myocardial infarction (24,25), stroke (26), de- search. Only two decades ago, clinical depression was seen as a That is, a chronic course may entail the development of an transient, typically self-limited reaction to 'untoward' underlying neurobiology that renders treatments less effec- tive acutely or over the longer term. Such an inference is suggested by apparently longer times to develop responses A. John Rush: Department of Psychiatry, University of Texas Southwest- and remissions in studies of chronic (10,11) as opposed to ern Medical Center, Dallas, Texas. Ryan: Western Psychiatric Institute & Clinic, University of nonchronic forms of depression (32,33). This recent em- Pittsburgh Medical Center, Pittsburgh, Pennsylvania. In many such cases, patient remission and full functional restoration (not simply re- preference with careful clinical monitoring, once therapy is sponse) are the targets of treatment. This conceptual shift has profound implications for prac- tice and development and use of newer agents. It also pro- vides a rationale for combining treatments when a mono- TRANSLATING KNOWLEDGE TO PRACTICE therapy does not lead to remission. Only a few clinical clues that recommend nature of these conditions. Whether different levels of func- one treatment over another have been established scientifi- tional impairment in the context of equivalent levels of re- cally. For example, the greater acute phase efficacy of mono- sidual symptoms herald a worse prognosis has yet to be amine oxidase inhibitors (MAOIs) as compared to tricyclic demonstrated. Furthermore, recent studies (21–23) suggest antidepressants (TCAs) in depressions with atypical symp- psychotherapy that effectively removes residual symptoms tom features is well established in double-blind, placebo- also improves prognosis, which in turn may reduce the need controlled trials (44,45). Furthermore, the greater efficacy for long-term maintenance medication. The need to most On the other hand, many practical dilemmas are con- aggressively pursue full symptom remission (also called fronted in routine practice, yet knowledge is sparse to ad- complete response), rather than to accept a clinically signifi- dress these issues. This lack of practical knowledge grounded cant reduction in symptoms (a response) is now accepted in empirical evidence, can be attributed to several factors: (a) because of the worse prognosis and functional impairment insufficient investment in clinical research that goes beyond associated with residual symptoms noted in the preceding. Mainte- conducted for regulatory purposes and representative prac- nance aims at preventing a new depressive episode—a recur- tices. When continuation ends and maintenance begins for Patients with minimally treatment-resistant, or non- an individual is unclear, although classically recovery from chronic forms of depressions enter trials. These patients are: the episode is estimated by when the episode would have (a) rarely severely ill; (b) rarely inpatients; (c) never psy- spontaneously ended based on the duration of prior epi- chotic; (d) rarely encumbered by common concurrent Axis sodes, if such information is available. The need for more III (general medical) or other Axis I (psychiatric) disorders; prolonged (i. Perhaps as a consequence, placebo response rates exactly how long to provide antidepressant treatment re- are often substantial (e. Consensus strongly recommends providing a 50% to 60% response rate (34). These recommenda- proval and the procedures characteristic of current practice. Whether patients with two episodes of major fore, also to adjust dosages); (c) use more frequent treatment depression plus a risk factor for recurrence should also be visits; (d) limit acute phase trial durations (e. Furthermore, recent regulatory and mar- toms with normalization of function) to define a clinical ket forces have encouraged studies in depressed children, 'success,' contrary to clinical practice recommendations adolescents, and geriatric patients. The National Institute of Mental Health (NIMH) has Routine clinical diagnoses often sharply disagree with recently begun to address some of the knowledge gaps noted those established by structured interviews (51) (Kashner et in the preceding by emphasizing effectiveness trials of anti- al. In addition, global judg- depressant treatments in children/adolescents, adults, and ments of the severity of illness, even if codified by the Clini- geriatric patients. The emphasis (50) was based on the reali- cal Global Impression-Improvement Scale (CGI-I) (52), zation that efficacy trials for regulatory approval are only may relate only modestly to symptom severity ascertained by the first step in defining a treatment. That is, they establish itemized clinician ratings, such as the Montgomery-Asberg˚ the safety and efficacy of an agent in carefully conducted, Depression Rating Scale (MADRS) (53) or the Hamilton highly internally valid designs. Generalizability of tolerabil- Rating Scale for Depression (HRS-D) (54,55) or the Inven- ity and efficacy findings requires different study designs. These When to use one as opposed to another agent (alone or in differences in clinical procedures used in efficacy RCTs and combination) requires still different study designs. For example, there is a reasonably strong basis DEPRESSION to believe that medications differ in their spectrum of ac- tions (1). That is, some patients/depressions respond to one Clinicians routinely confront a host of practical questions agent, whereas others respond to a different agent (58,59), that are not addressed in efficacy RCTs designed for regula- especially if the medications differ regarding presumed tory approval. These questions include the following: mechanisms of action. What is the 'next best' treatment following either an 'fit' into a multistep treatment plan is often left to tenuous unsatisfactory clinical response or intolerance to the inferences based on presumed mechanisms of action, to 'ex- first agent? What is a sufficient trial duration beyond which re- How to treat depressions that respond minimally or partially sponse is not likely (minimal duration)? What is a sufficient trial duration for those benefiting Perhaps pharmaceutical companies are reluctant to from the treatment beyond which further treatment search for specific indicators of when an agent is preferred (unchanged) is unlikely to produce any more sympto- or to study agents used as second or third steps in treatment- matic or functional improvement (maximal duration)? When is it best to augment the first agent with a second tors. Without specific indications of when to use an agent, treatment? When is it best to switch from the first agent a 'broad' spectrum of action can be claimed. Do antidepressants differ in their ability to produce largely avoided by the pharmaceutical industry, perhaps in response or remission, and if so, for which depression fear of finding that their agent will not fare as well as a is each better? Do different medications differ in the time to onset of economic forces within the industry provide a strong impe- clinical benefit or time to remission? What treatments are recommended if there is a return vital—information (e. Selecting the Initial Treatment In spite of these knowledge gaps, the industry has devel- oped a large number of newer antidepressants that are sim- All antidepressant medications have established efficacy in pler to take, better tolerated, and safer in overdose. Some even have placebo-con- 1084 Neuropsychopharmacology: The Fifth Generation of Progress trolled evidence supporting efficacy in dysthymic disorder drug–drug interactions, or likelihood of remission play a (sertraline) (15) or other 'nonmajor' disorders, such as pre- major role in selecting the first agent. However, when to How to Select the 'Next Best' Treatment select one over another agent is not well defined. Clinicians following an Unsatisfactory Response (or use 'rules of thumb' to make these judgments, but such Intolerance) to the First Agent reasonable guesses are rarely supported by prospective RCT evidence. A major clinical problem is selecting the 'next' agent if For example, more recently, efficacy for some antidepres- the first is ineffective, only partially effective, or not well sants has been established for other psychiatric conditions tolerated. When TCAs fail, the MAOIs have roughly a 50% commonly found in the presence of major depressive disor- response rate based on both open and randomized trials der, including: (a) venlafaxine for generalized anxiety disor- (58,59).
Note theincrease fromrest purchase 120 ml liv 52 overnight delivery, r discount 120 ml liv 52 visa,in absolutebloodoxygenation-dependent (BOLD)activity underneaththe coil when it discharges at 1 Hz (task order 100 ml liv 52 with mastercard, T) cheap generic liv 52 uk, and how it decreases afterward (post, P). With this method of scanning, images in which TMS was administered over motor cortex. This are steadily acquired at a rapid rate while the performance study showed that TMS at intensities slightly greater than of a single event is rapidly interspersed. One can image the motor threshold (110%) activates approximately the same brain activity associated with a single TMS pulse by repeat- number of pixels in the same region as does a volition move- ing the event many times and averaging the images acquired ment (Fig. This study also revealed the relative mag- at similar times after the events, much as electrophysiologists nitude of the TMS effect and the temporal relationship to have done with evoked responses (57). Applying TMS pulses to different brain regions with The method that is currently closest to the actual timing different interpulse interval times (milliseconds) may repre- of TMS and brain events is single-event fMRI, or averaged- sent a unique way of improving the temporal resolution 30: Measuring Brain Connectivity 401 A B FIGURE 30. One of the first studies in which this interleaved technique was used attempted to detect differences between volitional and transcranial magnetic stimulation (TMS)-induced movement of the thumb. In (A), the TMS device was placed over the left motor cortex of subjects, who alternately had TMS move their thumb (TMS) and then volitionally moved their thumb in response to a tone (VOL). In (B) are averaged group time series of brain activity during TMS, volition, or a noise control region (upper left). Note that for voxels that were activated in both tasks, the percentage rise in blood oxygenation-dependent (BOLD) activity does not differ from baseline. Thus, TMS produced BOLD changes that are dynamically similar to those of regular movement. In (C), the center of mass of the BOLD signal is virtually the same for both TMS and volition, within the limit of resolution of the magnetic resonance imaging scanner (2 mm). One can also use an averaged-single-trials approach of transcranial magnetic stimu- lation (TMS) and functional magnetic resonance imaging (fMRI)—that is, one can discharge a single TMS pulse and then measure the blood oxygenation-dependent (BOLD) response (top). The time series above show the BOLD response in a control region, for the auditory cortex, and in motor cortex. Note that a single pulse of TMS over motor cortex sufficient to cause the opposite thumb to move produces more blood flow changes in auditory cortex (caused by noise) than it does in the motor cortex under the coil. With further refinement, the combination of sin- sis would be that TMS increases blood flow in a manner gle-pulse and paired-pulse TMS and averaged-single-trials similar to that produced by volitional movement. Confu- fMRI will probably be of considerable interest in in vivo sion ensued when an early and still unpublished study of neurophysiology. Stimulation was REVIEW OF TRANSCRANIAL MAGNETIC performed at 1 Hz because FDG takes 20 minutes to settle STIMULATION FUNCTIONAL IMAGING into neurons and is thus a composite picture of brain activity STUDIES TO DATE over 20 minutes. This paradoxical decrease in localized Transcranial Magnetic Stimulation brain activity both under the coil and at the mirror or con- Interleaved tralateral site during TMS was surprising, but findings of decreased brain activity like this had been found in some Fluorodeoxyglucose PET electrophysiologic studies (12). The final image was a The first published combination of TMS and functional summed picture of 20 minutes of brain activity. It is likely neuroimaging in real time was performed with FDG PET that TMS has multiple different effects during that in a patient before and after rTMS treatment for refractory time—increased activity immediately with stimulation, de- depression (54). At a separate time, these investigators also creases during the rest time between TMS pulses, and dy- injected the glucose while the patient was intermittently namic changes across the 20 minutes. Peter Fox and one stimulated at 20Hz over the left prefrontal cortex for 20 of the chapter authors (MSG) (58) next sought to test this 15 minutes. In comparison with her depressed scan at baseline, finding directly by using O PET rather than FDG PET, with the TMS coil directly in the scanner. Also, the scan that was taken during left prefron- shorter time frame (approximately 1 minute for tracer up- take) than 18FDG PET (20 to 30 minutes). Therefore, im- tal TMS showed marked increases in activity, especially over aging with 15O PET during stimulation requires that the the prefrontal cortex. Conclusions from this single case study are limited. Using the exact same design as in the FDG study, but scanning every 10 Complexity of the Issues as Demonstrated by Initial minutes for 1 minute, we found that slow (1-Hz) rTMS Simple Studies over Motor Cortex over the motor cortex caused an increase in cerebral blood A basic question for TMS and functional imaging is what flow, although this was noted in only four subjects (58). Paradoxically, this group of the thumb and stimulated at or near the motor threshold found in these same subjects dose-dependent decreases in with visual confirmation that the TMS was producing activ- blood flow over prefrontal cortex. Thus, the results of these two initial motor threshold, we found similar decreases in eight healthy studies were confusing and frankly contradictory. In during fast (20-Hz) left dorsolateral prefrontal cortex rTMS this study, intermittent fast (10-Hz) rTMS over the frontal (60). In comparison with a control scan with sham TMS, eye fields for 1 minute caused dose-dependent increases in we found relative decreases under the coil site and in the blood flow at the stimulation site and in visual cortex. In contrast, a other words, when they increased the number of 10-Hz recent BOLD fMRI study over prefrontal cortex by our trains within the minute, blood flow increased. Surprisingly, group found increases in blood flow at 120% motor thresh- when the same investigators used the same rTMS param- old (61). With fMRI, one can examine individual differ- eters in the same subjects but shifted the coil to motor ences, and a great deal of heterogeneity of response was cortex, they found a dose-dependent reduction in cerebral noted across subjects. We are currently performing repeata- blood flow (59). Importantly, they positioned the coil based bility studies within subjects over time to address the inher- on a probabilistic brain, and they also stimulated below ent noise in this scanning system and the question of motor threshold. No thumb movement occurred in these whether repeated TMS/fMRI studies yield consistent re- subjects. Thus, the initial dream of using TMS and imaging to The two most likely explanations for the opposite find- address connectivity problems in the brain has been hind- ings over motor and prefrontal cortex are that different brain ered by a lack of consensus about basic imaging and TMS regions react differently, or that the method of TMS coil questions. Using yet a different technology, BOLD fMRI, placement matters, and that the effects of clear stimulation our group in several studies consistently found that over of large corticospinal neurons may be different from those much shorter time domains (7 to 30 seconds), TMS at of nonspecific stimulation of local inhibitory neurons with motor threshold or above, positioned by a functional behav- only probabilistic positioning. Obviously, a series of studies ioral approach, consistently produced increases in blood is needed to settle this most important issue. For example, flow at the stimulation site and in connected regions, such an important next study would be to test directly the issue as the contralateral motor cortex and cerebellum (51,52). In this study, Speer and colleagues found dose-depen- lation of excitatory versus inhibitory neurons. As mentioned above, the most promising, but also the most There is now a small consensus in the existing literature technically challenging, TMS imaging modality is a combi- that blood flow increases under the motor cortex in a dose- nation of TMS and fMRI. This technique (functional behavioral technique) and stimulation is above was initially thought impossible by many because of con- motor threshold (and activates large excitatory neurons). Our group has probabilistic approach, dose-dependent decreases have found that this technique, with the right precautions, is sometimes been found. Thus, some of the discrepancy in both feasible and safe. Considerable progress has been made the literature can be explained not only by differing time in devising a system for interleaving TMS with fMRI (53). The time–activ- In this vein, using an identical study paradigm as their most ity curve shows the changes in BOLD signal over the course recent TMS motor study, the National Institutes of Health of the experiment as the TMS machine is alternately trig- group (Speer and colleagues) stimulated the same subjects gered at 1 Hz for 18 seconds and then turned off. Additionally, direct comparisons of blood flow induced by a single TMS pulse, and to measure its time changes in motor cortex caused by TMS or volition show course. For example, son of different TMS events by means of their associated the location of the peak blood flow change is the same for BOLD responses. For example, with a single-event tech- TMS and normal movement (within 2 mm). Thus, although many have the perception that TMS tioning coil and one test coil). Such studies could provide is causing supraphysiologic changes in the brain, these data a bridge between electrophysiology (variation of motor imply that TMS at these parameters is acting remarkably evoked potential amplitudes) and fMRI (variation of BOLD like normal physiology. Moreover, combining TMS with precise timing relative to a behavior with the averaged-single-trials tech- nique would likely make it possible to image the activity of Using Interleaved TMS/fMRI to Address Issues of brain circuits and their connections. Connectivity: An Initial Study In an initial study in this area, five healthy volunteers Several electrophysiologic studies have suggested that 1-Hz were studied with interleaved TMS/fMRI and an averaged- TMS over time domains of 3 minutes or more is inhibitory single-trials protocol (57). To test whether this inhibitory effect occurs at time single TMS pulses over the motor cortex was detectable domains of several seconds, we performed TMS within an in both ipsilateral motor cortex under the TMS coil and fMRI scanner and measured blood flow with the interleaved contralateral motor cortex, and also bilaterally in auditory TMS/fMRI BOLD technique. The associated BOLD signal increase showed the ner, five adults were stimulated by applying a figure 8 TMS typical fMRI hemodynamic response time course. The re- coil over the left motor cortex at the optimal spot for pro- sponse of the brain to a single TMS pulse over motor cortex ducing movement in the contralateral (right) thumb (ab- at 120% of the level required to induce thumb movement ductor pollicis brevis). In alternating-movement accompanying the TMS pulse (1. Coronal echo-planar BOLD images were for more exact positioning of the TMS coil, with informa- acquired continuously throughout, interleaved so that TMS tion obtained about the magnetic field produced and also occurred 100 milliseconds after every fourth image acquisi- about alterations in physiology and biochemistry.