Review Article

New perspectives on techniques for the clinical psychiatrist:Brain stimulation, chronobiology and psychiatricbrain imagingRaffaella Zanardi, MD,1* Barbara Barbini, MD,1 David Rossini, MD,1

Alessandro Bernasconi, MD,1 Felipe Fregni, MD, PhD,2 Frank Padberg, MD,3

Simone Rossi, MD,4 Anna Wirz-Justice, PhD,5 Michael Terman, PhD,6 Klaus Martiny, MD,7

Giuseppe Bersani, MD,8 Ahmad R. Hariri, PhD,9 Lukas Pezawas, MD,10

Jonathan P. Roiser, PhD,11 Alessandro Bertolino, MD, PhD,12 Giovanna Calabrese, MD,13

Lorenzo Magri, PhD,1 Francesco Benedetti, MD,1 Adriana Pontiggia, MD,1

Alessia Malaguti, MD,1 Enrico Smeraldi, MD1 and Cristina Colombo, MD1

1San Raffaele Hospital Department of Psychiatry, Vita-Salute University, 13Radiology Service, G. Salvini Hospital,Garbagnate Milanese, Milan, 4Brain Stimulation and Evoked Potentials Laboratory, Policlinico Le Scotte Hospital,Department of Neuroscience, University of Siena, Siena, 8Department of Psychiatric Sciences and Psychological Medicine,Università ‘La Sapienza’, Rome, 12Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatricand Neurological Sciences, University of Bari, Bari, Italy, 2Center for Noninvasive Brain Stimulation, Department ofNeurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 6Center for LightTreatment and Biological Rhythms, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NewYork, 9Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA, 3Department of Psychiatry,Ludwig-Maximilian University, Munich, Germany, 5Centre for Chronobiology at the Psychiatric University Clinics, Basel,Switzerland, 7Psychiatric Research Unit, Frederiksborg General Hospital, Hilleroed, Denmark, 10Department of GeneralPsychiatry, University Hospital of Psychiatry, Währinger Gürtel, Vienna, Austria, and 11Wellcome Department of ImagingNeuroscience, Institute of Neurology, London, UK

This review summarizes a scientific dialogue betweenrepresentatives in non-pharmacological treatmentoptions of affective disorders. Among the recentlyintroduced somatic treatments for depression thosewith most evidenced efficacy will be discussed. Thefirst part of this article presents current opinionsabout the clinical applications of transcranial mag-netic stimulation in the treatment of depression. Thesecond part explains the most relevant uses of chro-nobiology in mood disorders, while the last part

deals with the main perspectives on brain imagingtechniques in psychiatry. The aim was to bridge gapsbetween the research evidence and clinical decisions,and reach an agreement on several key points of chro-nobiological and brain stimulation techniques, aswell as on relevant objectives for future research.

Key words: chronobiology, depression, neuroimag-ing, transcranial magnetic stimulation.

DEPRESSION IS A debilitating and prevalentdisease; 4–10% of the general population expe-

riences an episode of major depression within a year,

while approximately 30% of men and 40% of womensuffer from at least one episode during their lifetime.1

Different antidepressants are available to treat adepressive episode. Nevertheless, the therapeuticlatency, the non-response rate and the side-effects ofantidepressants are important reasons to search fornew non-pharmacological techniques to treat depres-sive episodes. Among non-pharmacological tech-niques we focused on transcranial brain stimulation

*Correspondence: Raffaella Zanardi, MD, Department of Psychiatry,Vita-Salute University San Raffaele Hospital, Via Stamira d’Ancona,20 Milan 20127, Italy. Email: zanardi.raffaella@hsr.itReceived 17 May 2007; revised 5 May 2008; accepted 2 September2008.

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and chronobiologic treatments and we chose not toinclude such invasive therapies as electroconvulsivetherapy (ECT), magnetic seizure therapy and vagusnerve stimulation. Moreover, we describe functionalbrain imaging, as a tool to investigate neuronal func-tion in vivo, to evaluate the correlation betweenneural function and treatment response and, eventu-ally, the neural predictors of clinical outcome.

TRANSCRANIAL BRAIN STIMULATION:TREATMENT OF DEPRESSION,OBSESSIVE–COMPULSIVE DISORDERAND TOURETTE SYNDROMEWITH TRANSCRANIALMAGNETIC STIMULATIONRepetitive transcranial magnetic stimulation (rTMS)has become a major research tool in experimentalclinical neurophysiology2,3 and cognitive neuro-science4,5 due to its potential to non-invasively andfocally stimulate cortical brain regions. Given that theprefrontal cortex plays a significant role in the controlof mood and emotional behavior, rTMS has beeninvestigated as an experimental tool in healthy vol-unteers and as a therapeutic intervention in patientswith affective disorders. Preclinical and clinical find-ings of functional neuroimaging studies demonstratethat rTMS of the dorsolateral prefrontal cortex(DLPFC) modulates regional brain activity in keyregions of fronto-limbic circuits, for example ante-rior cingulate and mesolimbic areas.6 Moreover,there is robust mainly preclinical evidence that rTMSacts on various neuroendocrine and neurotrans-mitter systems involved in the pathophysiology ofdepression, that is, it exerts effects on the hypo-thalamic–pituitary–thyroid and the hypothalamic–pituitary–adrenal axes, on serotonin receptor levels,and induces glutamate release at the stimulation siteand dopamine release in mesostriatal and mesolim-bic regions.7 Recently, it has been shown that rTMScan also induce striatal dopamine release in patientssuffering from major depression,8 as well as in thoseaffected by Parkinson’s disease.9–11

An important issue before introducing rTMS intoclinical practice is the safety of this therapeuticapproach. Several rTMS clinical trials have been con-ducted, not only in depression, but also in otherneuropsychiatric disorders such as schizophrenia,obsessive–compulsive disorder, Parkinson’s disease,stroke, epilepsy, tinnitus and chronic pain. Thesestudies show that rTMS is a safe treatment and is

associated with few, mild and rapidly reversible side-effects, such as headache and neck pain.12 Althoughthere is a concern that rTMS – especially high-frequency rTMS – can induce seizures, this side-effectcan normally be avoided if published safety guide-lines are adhered to.13,14 In single cases, however,where comorbidity and co-medication reduce seizurethresholds the benefit versus risk ratio needs to becarefully considered. Moreover, past trials haveshowed that rTMS treatment induces no long-termchanges in the electroencephalography (EEG) andin the cognitive performance; on the contrary, thereis evidence that rTMS induces an enhancementin some aspects of the cognition that seems moodindependent.

Their is multifold evidence that prefrontal rTMShas considerable antidepressant efficacy,15 but cur-rently published as well as ongoing multicenter trialswill provide more robust data on the issues of anti-depressant efficacy and effectiveness. The first large,multicenter, randomized controlled trial, involving301 medication-free patients with major depressionwho had not benefited from prior treatment, haslargely confirmed the safety and efficacy of rTMS,particularly when administered for at least 4 weeks.16

Compared to other brain stimulation approaches,such as ECT, rTMS might have a similar efficacy innon-psychotic depression, thereby providing a lessinvasive alternative treatment for patients with refrac-tory and severe major depression. In addition, rTMStreatment might be beneficial for a broad spectrum ofdepressive patients. A recent study showed that rTMStherapy in younger and less treatment-resistantpatients is associated with a better outcome, whichleads to the question of whether rTMS treatmentmight be considered also as the first-line treatmentfor depression along with antidepressant.17 More-over, rTMS has been shown to be a useful and safeadjunctive treatment for drug-resistant depressedpatients when compared to sham stimulation.16,18

Two recent trials have also shown that the response toselective serotonin re-uptake inhibitors (SSRI) andtricyclic antidepressants can be accelerated by con-comitant rTMS treatment.19,20

The role of two polymorphisms that influence theresponse to antidepressants has also been analyzed:the polymorphisms of the serotonin transporterpromoter region (SERTPR) and of the 5-HT1A sero-tonergic receptor promoter region (-1019 C/G). Inparticular, C/C patients had a better response torTMS.21

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Although several studies on major depression andrTMS have been published, the optimum parametersof stimulation have not been defined as yet. The mainreasons for this are: (i) previous studies have mainlyused fixed stimulation parameters; and (ii) potentialnew alternatives of stimulation have not been fullyexplored yet. An up-to-date review, however, hasshown that recent trials, which are likely to havebenefited from the insights gained in the earlier trials,have shown larger effect sizes.22 Moreover, differentmethods such as priming 1-Hz rTMS treatment with6-Hz rTMS,23 preconditioning rTMS treatment withtranscranial direct current stimulation (tDCS),24 thetaburst stimulation (TBS)25 and the combination ofrTMS with other antidepressants treatments suchas antidepressant pharmacotherapy and cognitivebehavior therapy (CBT) might further enhance themagnitude and impact of rTMS treatment. In particu-lar, when given after cathodal polarity tDCS (cathodeplaced over M1), 5-Hz rTMS resulted in a markedfacilitation of cortico-spinal excitability.24 TBS, with aburst of three stimuli at 50 Hz (i.e. 20 ms betweeneach stimulus repeated at intervals of 200 ms, i.e.5 Hz), if administered for 190 s (600 pulses) at 80%of the motor threshold, produced a marked increasein cortical excitability.25 Further studies should evalu-ate the tolerability and the effects on cortical excit-ability of TBS with an increased number of pulses anda higher motor threshold. Clinical trials are needed totest if this increase in cortical excitability is correlatedwith a better clinical response. Finally, it is critical toinvestigate whether a dose-adjustment strategy withindividualized stimulation parameters might maxi-mize its clinical benefits. Therefore development ofmethods of monitoring brain activity during rTMStreatment such as online EEG might provide valuableinformation regarding the status of brain corticalexcitability. This information can be used to adjustthe parameters of rTMS treatment.

Limited data are available about the role of TMSas long-term maintenance therapy for mood disor-ders. Recent case series suggested that rTMS mightbe used as an adjunctive maintenance treatmentfor patients with bipolar depression26 or with refrac-tory depression.27 These data are in agreement withthose of the O’Reardon et al. study, which followed10 unipolar patients for a period ranging from6 months to 6 years.28 Clearly, these are preliminarydata and further trials are necessary to better evalu-ate the role of rTMS as maintenance therapy indepression.

CONCLUSIONS

Several rTMS trials have shown that rTMS is a safe andwell-tolerated treatment if administered followingthe published safety guidelines.13,14

The bulk of studies published on rTMS in the treat-ment of depression and the most comprehensive andrecently updated meta-analysis29,30 show that activerTMS is significantly more effective than sham treat-ment, but the optimum set of stimulation parametersis still to be determined. Given the large amount ofpatients who do not achieve response or full remis-sion with antidepressant drugs, the combination withrTMS should be more widely available in clinicalpractice to treat drug-resistant patients as an initialstep until further studies determine whether otherstrategies of rTMS treatment, such as using rTMS as afirst-line therapy, are clinically effective when com-pared to standard treatments. When using rTMS inclinical practice, age should be taken into account,given that younger patients respond better thanelderly patients.17 Another issue that should be con-sidered is the presence of psychotic features, becausethe possible increase of dopamine induced by rTMS8

may worsen these symptoms. Because evidence forthe effectiveness of rTMS in long-term treatment ofdepression is still scarce, TMS should be used as atreatment in the acute phase.26–28 Moreover, it isimportant to consider the relationship betweenclinical benefit and the amount of time needed toregularly undergo rTMS.

CHRONOTHERAPEUTICS OFMOOD DISORDERSA disruption of circadian rhythms has been hypoth-esized to be involved in the pathogenesis of mooddisorders. This disruption is manifested not only inwell-known rhythms such those of cortisol secretion,body temperature or the sleep–wake cycle, but also inother functions such as heart rate.

Circadian rhythms are regulated by a biologicalclock located in the suprachiasmatic nuclei and aresynchronized not only by the external light–darkcycle, but also by other zeitgebers. The genetic com-ponents of the master clock follow a circadian patternof transcriptional–translational feedback loops inorder to produce a circadian rhythm. Clock genes arefound in all cells, and some zeitgebers (light) act onlyon the central clock, others (e.g. food) only onperipheral clocks.31

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Recent observations about clock genes and theirrole in the regulation of mammalian circadian rhyth-micity have raised interest about the possible role ofsuch genetic mechanisms in the circadian rhythmabnormalities that characterize major depressive epi-sodes.32 A first study in healthy human subjects pro-vides evidence to support this hypothesis: CLOCKgene polymorphism plays a role in the regulation oflong-term cyclicity in affective illness.33

The sleep–wake cycle is the most studied rhythmicphenomenon in affective disorders and researchon this topic began prior to the general interest onbiological rhythms. Approximately 90% of depressedpatients complain of bad sleep quality and this clini-cal observation during a depressive episode is notonly a subjective impression but is also reflected inobjective sleep EEG measures, for example in RapidEye Movement (REM) and Non-Rapid Eye Move-ment (NREM) sleep changes.34

Because a dysregulation of the sleep–wake cyclecan induce a manic or a depressive episode, andremission from depression is often accompanied by aregularization of circadian abnormalities, manipula-tions of the sleep–wake cycle have been used for thetreatment of depression for the last 30 years.35

The consensus arrived at for clinical acute manage-ment of a depressive episode using chronotherapeu-tic methods was: wake therapy, dark therapy andbright light therapy.

Wake therapy (total or partial sleep deprivation) isuseful in the treatment of major depression: a singlenight without sleep can restore euthymia in approxi-mately 60% of treated depressed patients.36 A bettereffect has been observed in bipolar than in unipolardepressed patients.37 Because approximately 80% ofresponders relapse shortly after recovery sleep, recentstudies have focused on the possibility of sustainingthese rapid but transient effects of wake therapyover time. A high proportion (50–70%) of sustainedresponse to total sleep deprivation (TSD) has beenattained by combining TSD with other antidepressantor mood stabilizing treatments: both serotonergic,noradrenergic, mixed noradrenergic/serotonergicdrugs, lithium salts and light therapy could success-fully maintain the acute antidepressant effect of sleepdeprivation.38 In particular, ongoing long-term treat-ment with lithium salts was shown to sustain theeffects of repeated TSD, leading to sustained symp-tomatological remission in approximately 60% ofpatients.39 Regimens using repeated sleep deprivation(three times a week) seem to sustain the antidepres-

sive effect as well. Recent data suggest that thecombination of TSD and light therapy is useful inthe treatment of an acute depressive episode intreatment-resistant patients.40

Based on the phase advance hypothesis of depres-sion,41 some European studies indicated that pro-longed manipulations of the sleep–wake cycle, suchas sleep phase advance, are also able to sustain theeffects of TSD both with or without a combined anti-depressant drug treatment.42

Consistent data have linked sleep–wake andlight–dark rhythms with psychopathological status inpatients affected by bipolar disorder, with sleep lossand light exposure elevating mood. These observa-tions led to the hypothesis that sleep disruption dueto multiple types of environmental stimuli could actas triggering factors for mood episodes in bipolarpatients, and that a strict control of the sleep–wakeand light–dark rhythms could act as a mood stabi-lizer.43 Following this perspective, in a recent study 16bipolar inpatients affected by a manic episode wereexposed to a regimen of 14 h of enforced darkness(’dark therapy’, DT) for 3 consecutive days; patientswith a manic episode lasting <2 weeks had an ame-lioration of mood.44 This observation confirms previ-ous findings45 but does not help to clarify whether thetherapeutic effects of treatment are due to the darkenvironment or to improved sleep.

As described here, circadian rhythms are regulatedby a biological clock that is principally synchronizedby the external light–dark cycle. Bright-light therapy(LT) has been established over the last 20 years as thetreatment of choice for seasonal affective disorder.46,47

Morning bright light is more effective than eveningadministration, and the duration of administrationvaries from 0.5 to 2 h. Timed light therapy shiftscircadian phase and thereby modifies the phase rela-tionship between the internal clock, sleep, and theexternal light–dark cycle.48 Morning light is scheduledrelative to the individual’s patients chronotype (laterfor evening types than for morning types) in order tooptimize circadian rhythm phase advances.47,49,50

Many studies have been conducted with the aim ofdefining the parameters of light administration. Mostcommonly used is broad-spectrum white light; thequestion of whether there is any improved efficacy ofblue light as opposed to putative harmful retinal side-effects is under intensive discussion.

Light therapy has been also used more and more innon-seasonal major depression. Light therapy is rec-ommended as an add-on to conventional antidepres-

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sants in unipolar patients,40 or lithium in bipolarpatients. This method provides a viable alternativefor patients who refuse, resist or cannot toleratemedication, or for those in whom drugs may be con-traindicated, as in antepartum depression.

CONCLUSIONS

In clinical practice wake therapy is quite more effec-tive in bipolar than in unipolar patients,37 while lighttherapy has a better documented effectiveness onseasonal disorders.46 Nevertheless, recent studiesshowed a good efficacy of LT in other depressivesyndromes as well.51 In the last few years the combi-nation of antidepressant drugs and lithium salts withsleep–wake rhythm manipulation and light therapy,have provided clinicians with new ways to achieverapid and sustained antidepressant responses. Giventhe urgent need for new strategies to treat patientswith residual depressive symptoms, further clinicaltrials of wake therapy and/or adjuvant light therapy,coupled with follow-up studies of long-term recur-rence, are a high priority.

NEW TECHNOLOGIES: PSYCHIATRICBRAIN IMAGINGPsychiatric disorders have a very complex etiology,with known interactions among genetic, psychologi-cal, and environmental factors. Despite their clinicalimpact, the specific neurophysiologic basis of psy-chiatric disorders are still unknown. Considerableprogress, however, has been made in identifying thebrain regions and neural circuits that underlie normaland abnormal emotion processing, cognitive func-tioning, perceptions and mood regulation. In thepast years neuroimaging research has emerged as avaluable tool in enlarging our knowledge and under-standing of mental diseases. Of the several neuroim-aging modalities, including positron emissiontomography, functional magnetic resonance imag-ing (fMRI), and single-photon emission computedtomography (SPECT), magnetic resonance spectros-copy (MRS) provides unique information on thetissue concentration in vivo of some 25–30 biochemi-cal constituents in anatomically distinct areas of thebrain. Importantly, MRS is non-invasive, has highspatial resolution, and requires neither radioactivetracers nor ionizing radiation. Although MRS hasbeen used primarily as a research tool, the recentimprovements in technology make MRS a valuable

tool for both researchers and clinicians. In fact, MRShas demonstrated utility for both diagnosis and treat-ment assessment in numerous central nervous systemdisorders.52,53

Because neurochemical information of the braincan be obtained in vivo, MRS holds considerablepromise to illuminate brain mechanisms involvedin depression.54,55 In psychiatry, investigators areprimarily using proton (1H) MRS. 1H spectroscopycan distinguish N-aspartate (NAA), creatine andphosphocreatine, and phosphatidylcholine. Signalscan be obtained from glutamate, glutamine,g-aminobutyric acid, lactate and inositol phosphates.NAA is found in neurons and is absent in most glialcell lines. Decreases in NAA may reflect a diminishednumber or density of neurons. Creatine and phos-phocreatine are important energy substrates, andphosphatidylcholine is an important component ofcell membranes. Comparisons have been made of theconcentrations of substances between healthy brainsand brains with neuropsychiatric abnormalities.56,57

With respect to treatment strategies for depression,MRS may prove ideal for longitudinal studies aimedat defining the neurochemical correlates of differenttherapeutic strategies, the contribution of the differ-ent neurotransmitters to the functioning of brainareas putatively involved in the pathogenesis of thedisease, or the differences between mood pathologyand euthymic state.58,59

fMRI research, with its superior resolution com-pared to other imaging techniques, has providedunprecedented opportunities for elucidating theanatomical correlates of major depression. Indeed,functional neuroimaging studies have proved to be auseful method for investigating the neural correlatesof some of the core features of major depression, suchas sustained negative emotion processing, specificmood congruent bias to negative information, rumi-nation, and cognitive impairment.60

The acute tryptophan depletion (ATD) techniquehas been used to probe 5-HT function in severalpopulations, most commonly in patients recoveredfrom depression. A consistent finding is that ATDcauses a partial return of symptoms in some patientsrecovered from depression, particularly those stabi-lized on SSRI. Several studies have investigated theeffect of ATD on regional blood oxygen-level depen-dent (BOLD) responses during cognitive paradigmsusing fMRI in healthy volunteers.61 Roiser et al.62 per-formed a double-blind, placebo-controlled crossover-design study. Participants attended two testing days

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during which their only dietary intake consisted of a33-g amino acid mixture that either contained orlacked tryptophan. Five hours following amino acidingestion (T5), participants performed the AffectiveGo/No-Go test during fMRI. Patients and controlsdiffered in terms of the effect of ATD on BOLDresponses to emotional stimuli, as shown bytreatment ¥ diagnosis interactions in several regionspreviously implicated in depression. These includedthe right frontal polar cortex, left anterior insula, leftventrolateral prefrontal cortex, left posterior orbitalcortex, anterior cingulate cortex (ACC), posterior cin-gulate cortex, right parahippocampal gyrus and leftcaudate.

Models of emotion perception in depression do notalways entirely accord to findings because there isconflicting evidence of increased or decreased indicesof brain activation in depression, such as metabolicchanges, regional cerebral blood flow (rCBF), andBOLD contrast.63,64 These inconsistencies are partlydue to variations in sample size, sample charac-teristics (e.g. age and gender), medication status(treatment-naive, unmedicated, or medicated), chro-nicity of illness, and the imaging techniques andparameters used. The definition of a phenotype,however, which is homogenous with respect toimaging abnormalities, still represents the majorlimit in comparing the results available in the litera-ture. Clinical neuroscientific investigations into thebiology of mood disorders struggle with the limita-tion that psychiatric nosology remains at a syndromiclevel, in which non-specific behavioral and neuroveg-etative signs, rather than pathophysiology, are used todefine major depression. There are regions, however,that have been consistently identified to have meta-bolic changes in sadness and depression.65,66 Mayberget al. found that sadness in healthy subjects was asso-ciated with both increases and decreases in rCBF,compared with rest: increases were seen in ventrallimbic and paralimbic sites (subgenual cingulate[Brodmann area 25] and ventral, mid-, and posteriorinsula); decreases were predominantly in dorsal cor-tical regions (right dorsal prefrontal [Brodmann area46/9], inferior parietal [Brodmann area 40], dorsalanterior cingulate [Brodmann area 24b], and poste-rior cingulate [Brodmann area 23/31]).67 Moreover,some of the most interesting findings of neuroimag-ing studies are the correlates of response to treatmentin depression. In a subset of patients given pharma-cological treatment for depression, post-treatmentmetabolism relative to pretreatment metabolism was

associated with both increases and decreases in spe-cific limbic-paralimbic and neocortical sites, but in apattern inverse to that seen with provoked sadness.Remission of depression was characterized by meta-bolic increases in dorsal cortical regions (right dorso-lateral prefrontal [Brodmann area 46/9], inferiorparietal [Brodmann area 40], dorsal anterior cingulate[Brodmann area 24b], and posterior cingulate [Brod-mann area 23/31]) and concomitant decreases inventral limbic and paralimbic sites (subgenual cingu-late [Brodmann area 25] and ventral, mid-, and pos-terior insula).67 Mayberg et al. reported that metabolicactivity in ventral anterior cingulate was elevatedbefore treatment and reduced after clinical improve-ment in responders to antidepressant medications.68

Davidson et al. found that neural responses toblocks of negative and positive affective stimuli inACC and insula were associated with response tovenlafaxine antidepressant treatment.69 Changes infMRI activation in the amygdala with ongoing bupro-pion extended release (XL) medication correlatedwith improvements on the Hamilton Rating Scale forDepression.70

A fundamental neuropsychological impairment indepression is a mood-congruent processing bias suchthat ambiguous or positive events tend to be per-ceived as negative. In particular, depressed patientsshow a diminished ability to discern affective facialexpressions. In a study by Fu et al., depressed subjectshad reduced capacity for activation in the leftamygdala, ventral striatum, and frontoparietal cortexover time, and a negatively correlated increase ofdifferential response to variable affective intensity(dynamic range) in the prefrontal cortex.71 Symptom-atic improvement after treatment with fluoxetine wasassociated with reduction of dynamic range in thepregenual cingulate cortex, ventral striatum, and cer-ebellum. Chen et al. evaluated fMRI and structuralMRI (sMRI) data as predictors of symptom change inpeople with depression.72 Faster improvement waspredicted by greater functional activation of ACC.Faster rates of symptom improvement were stronglyassociated with greater gray matter volume in ACC,insula, and right temporo-parietal cortex. BecauseMRI is a less expensive and complex technique, theseresults could facilitate study of antidepressant predic-tors of response on a larger scale.

The effect on brain activation of non-pharmacological intervention for the treatment ofdepression, such as CBT, has also been tested throughan emotional words task.73 Improved response to

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CBT was associated with lower pretreatment reactiv-ity in the subgenual cingulate cortex and higher pre-treatment reactivity in the amygdala.

Also studies on sleep deprivation have found thatpatients who underwent this treatment had consistentcerebral metabolic changes. Ebert et al. first reportedin a SPECT study that one of the markers that differ-entiates depressed responders from depressed non-responders at baseline is higher cingulate activity inthe responders, which is decreased with sleep depri-vation response.74 Further, three different groupsreported that responders had increased relative local-ized metabolic activity in the general location ofthe ventral ACC compared with non-responders ornormal controls at baseline.75–77 All the studies inwhich patients, both before and after sleep depriva-tion, were compared, reported that clinical improve-ment was associated with normalization of theincreased metabolic activity in the area of the ventralanterior cingulate/medial prefrontal regions.74–77

SPECT has been used also to study predictors andcorrelates of the response to TMS in depression. Lang-guth et al. have shown that high pretreatment ante-rior cingulated cortex activity was a positive predictorof treatment response to 2 weeks of 10-Hz rTMS overleft DLPFC.78 Shinsuke et al. have found that a suc-cessful rTMS treatment was associated with a signifi-cant increase in rCBF in the left DLPFC in thestimulated region.79 Moreover, there was a relation-ship between the improvement in symptoms ofdepression and the increase in rCBF in the leftDLPFC, the left subgenual cingulate, the anterior cin-gulated cortex, the ventrolateral prefrontal cortex, theorbitofrontal cortex, the anterior insula, and theright putamen/pallidum.

The recent mapping of the human genome hasprompted a new series of questions that include thefunction of individual genes at the level of brainphysiology, the contribution of genetic factors to sus-ceptibility to psychiatric disorders, and their relatedneurobiology. Within the framework of these ques-tions, recent studies are beginning to explain the rela-tionship between genes, neurons, brain networks, andbehavior, as well as to shed light on the basis of theindividual variability with regard to this relation-ship.80,81 Current brain imaging techniques providenovel tools to study more specifically the relationshipbetween behavior, pathophysiology, genetics, andtreatment.82 The major contribution of these tech-niques is that they permit the creation and analysis ofstatistical maps of brain activity in single subjects as

well as in groups of individuals. Thus, functional brainimaging allows statistical exploration of the maineffect of genes at the brain systems level during specificbehaviors. Furthermore, once the physiological effectof genetic variants is known, the effect of the samegenetic variants can be measured in brain disorders.

Brain-derived neurotrophic factor (BDNF) andserotonin transporter (SERT) genes, both of whichhave been associated with psychopathological states,are important in brain development and in functionsrelated to memory and emotion. Genetic variationsof the BDNF (val66met) and SERT gene (5-HTTLPR)affect the function of these proteins in neurons andpredict variation in human memory and in fearbehavior. In a previous work Pezawas et al. showedthat the S allele of 5-HTTLPR affects the integrity,function and connectivity, and presumably develop-ment of a neural circuit linking amygdala and rostralanterior cingulate circuitry, a circuitry related toanxious temperament and depression in the presenceof environmental adversity.83 Additionally, theycould show that val66met BDNF affects the develop-ment and function of brain circuitries (hippocampus,DLPFC) prominently implicated in aspects of cogni-tive functioning (e.g. working memory).84 Conver-gent evidence links BDNF to depression, such as datashowing an association of the functional val66metBDNF polymorphism with increased risk for mooddisorders, for temperamental traits related to mooddisorders, and associated increases of BDNF expres-sion after ECT and antidepressive SSRI treatment.85

These data implicating a biological interaction ofBDNF with 5-HTTLPR-dependent signaling suggest amolecular mechanism that could support an epistaticinteraction between the functional variants in thesegenes in risk for depression. Recently, Benedetti et al.focused on the interaction between genotype, antide-pressant response and a BOLD fMRI moral valencetask.86 The search for genetic factors predisposing toantidepressant response in affective disorders showedthat a polymorphism in SERTPR predicted efficacy fora range of treatments,87 including TSD alone or incombination with LT in patients affected by bipolardepression. The same SERTPR has been shown toinfluence core features of affective illness, such as ageat onset and recurrence of mood episodes, and, inhealthy subjects, the neural response of limbic struc-tures to emotional stimuli88 and the functional cou-pling of ACC and medial prefrontal cortex withamygdala.83 The effect of TSD combined with lighttherapy on event-related neural responses to a

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go/no-go task with emotional words in a homo-geneous sample of patients affected by bipolardepression was assessed. Significant interactions oftreatment, response to treatment, and moral valenceof the stimuli were found in ACC, DLPFC, insula, andparietal cortex. In these areas responders changedtheir BOLD responses to emotional stimuli in apattern opposite to that of non-responders. Genotypeof the promoter for the serotonin transporter pre-dicted response to treatment: at end-point, but not atbaseline, homozygotes for the short allele had signifi-cantly worse Hamilton rating scale for depression(HDRS) scores. Genotype of the promoter for theserotonin transporter also influenced baseline neuralresponses in anterior cingulated cortex and DLPFC.86

Brain volume was investigated for regions that hada significant interaction of SERTPR polymorphism(l/l, l/s, and s/s) and moral valence of the stimuli(positive–negative) at baseline in order to see if thepredictive value of SERTPR genotype could be corre-lated to a baseline influence on neural responses tothe task. Two of these voxels were located in the apriori regions of interest: right ACC (Brodmann area24) and right DLPFC (Brodmann area 46).

Furthermore, in both ACC and DLPFC baselineactivations for negative and for positive stimulivaried according to SERTPR genotype, with l/l sub-jects having minimal activations for negative, andmaximal for positive stimuli; s/s subjects having theopposite pattern; and heterozygotes l/s having inter-mediate values.86

CONCLUSIONS

Nowadays, agreement about the future key role ofneuroimaging techniques, especially those that arenon-invasive such as fMRI, has been reached. Theability of fMRI to investigate the function of integratedneural networks within the human brain makes it theoptimal tool to elucidate individual differences inbehavior, psychopathology and personality.

FINAL REMARKSTMS and chronotherapeutics are non-pharmacological techniques to treat depressive epi-sodes that could be used to enhance or to replaceantidepressants. Neuroimaging techniques show thatthe antidepressant response to these treatments mayshare common biological substrates. The optimaltarget for chronotherapeutics seems to be the classical

depressive syndrome; moreover, consistent findingsshowed that diagnosis is a predictor of response, withbipolar depressed patients receiving higher benefitthan unipolar depressed patients from sleep depriva-tion.37 In contrast, TMS has been longer evaluated asa treatment for patients with refractory and severemajor depression but recent trials have also shownthat the response to antidepressants can be acceler-ated by concomitant rTMS treatment.16,18,20

Nevertheless, available evidence does not allow thecreation of a treatment algorithm to unmistakablyselect and combine these treatments in different typesof depression. All these therapies can be combinedwith traditional antidepressants when drugs do notproduce a satisfying clinical effect, giving a wideapplication in clinical practice.

Future perspective is to better analyze these treat-ments, to search for optimum parameters and todevelop a treatment algorithm for the choice of thebest non-pharmacological antidepressant therapy foreach patient.

Brain imaging techniques examine the relationshipbetween behavior, pathophysiology, genetics, andtreatment, and the development of this area wouldhelp to optimize the application both of rTMS and ofchronotherapeutics.

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