2009/11/10 Morning Meeting Reporter R2 黃莉婷 Supervisor 鄧復旦 主任

J Psychiatry Neurosci 2004;29(4):268-79

Introduction Major depression >> 13% in men, 21% in women >> Refractory to drug treatmen: 30%  Electroconvulsive therapy (ECT)  Repetitive transcranial magnetic stimulation (rTMS)

Topics Symptoms and cognition in major depression Neuroimaging studies of depression rTMS as treatment for depression Structure and function of the MDLFC and the ACC Combined TMS / positron emission tomography (PET) studies of frontocortical connectivity

Symptoms and cognition in major depression Depressed mood Decreased drive and motivation Impaired cognitive performance in learning,memory, attention, executive, motor, perceptual functions. Impairement to resist interference or initiate actions.

Neuroimaging studies of depression Left middorsolateral frontal cortex (MDLFC)  Hypometabolism and hypoperfusion   correlated with severity of depression

Neuroimaging studies of depression Anterior cingulate cortex (ACC)  increased metabolic activity   Antidepressant treatment : neural activity ↓

Neuroimaging studies of depression The involvement of the MDLFC / ACC in depression The reversibility of depression-related “abnormalities

Transcranial Magnetic Stimulation (TMS) Stimulate specific cortical regions of the brain   changes in behaviour Apply in trains of pulses: repetitive TMS or rTMS

rTMS as treatment for depression Left MDLFC >> 5 cm anterior to the primary motor cortex (M1) High-frequency stimulation (> 1 Hz) 10 daily session The mean before-versus-after decrease in the Hamilton Depression Rating Scale ( HDRS) scores  34% (range 15%–62%) The Avery-George-Holtzheimer database of rTMS depression studies.

Active rTMS was superior in producing clinical response   number-needed-to-treat : 6

Structure of the MDLFC The middle frontal and superior frontal gyri  areas 46 and 9/46 (middle frontal gyrus)  area 9 (superior frontal gyrus)

Connections of the MDLFC Bidirectional with post. neocortical areas:  visual (prestriate and inferior temporal cortices)  auditory (superior temporal cortex)  somatosensory (parietal cortex) Reciprocal with the ant.and post. cingulate cortices

Function of the MDLFC >> Organize and plan sequences of responses >> Select appropriate strategies >> Monitor self-generated actions Motor planning, organization Integration of sensory and mnemonic information Regulation of intellectual function and action Working memory

Structure of the ACC: heterogeneous

Function of the ACC: heterogeneous CognitiveVisceral Area24 and 3225 Locationsupracallosalsubcallosal ConnectionMDLFCThe post. orbitofrontal area Hypothalamus, Ventral striatum, Periaqueductal grey

Function of supracallosal ACC Volitional control of behaviour Characteristics of speech production during sad affect Bilateral cingulate lesions  akinetic mutism   monotonous intonation a low frequency of spontaneous utterances

Combined TMS/PET studies to assess both potential mechanisms

Possible neural mechanisms of rTMS Modulate activity in the specific neural circuits that mediate a given group of symptoms Facilitation of monoaminergic neurotransmission

The first type of study The corticocortical connectivity of the MDLF and its modulation by brief periods of rTMS PET ligands 15 O-H 2 O > regional distribution of cerebral blood flow (CBF) >> the amount of excitatory neurotransmission

Method Cortical connectivity of the left MDLFC modulatory effect of rTMS

After doublepulse TMS … CBF decreased both at the stimulation site and in several distal regions, including the ACC TMS  γ-aminobutyric acid (GABA) release   a net decrease in excitatory synaptic activity

Following the 2 series of rTMS … “Suppression” response was reversed  increases in cerebral blood flow (CBF)

Regression analyses The blood-flow response to double-pulse TMS covaried with that at the stimulation site, including the contralateral MDLFC and the ACC

Summary Low-frequency TMS  inhibitory response rTMS  cortical excitability and connectivity ↑ “Long-term transformation” GABA mediated inhibitory postsynaptic potentials Depolarizing responses

The second type of study TMS-induced release of dopamine PET ligands : 11 Craclopride >> regional dopamine concentration

Method Hz trains of rTMS * 3 series * 2 day The left MDLFC / the left occipital cortex   Measure regional release of dopamine

rTMS over the left MDLFC Left caudate nucleus 11 C-raclopride binding potential ↓ > > dopamine concentration ↑

rTMS over the left primary motor cortex (M1) Dopamine release in the ipsilateral putamen

Summary Corticostriatal loops 1.Prefrontal cortex  The head of the caudate nucleus 2. Primary motor cortex  Lateral putamen Exp Brain Res 1998;120: rTMSMDLFCM1 Dopamine ↑CaudatePutamen

Discussion

Limited Interpretation of previous studies No detailed information about the coil position Inadequate control stimulation or comparison groups The blood-flow or metabolic measurements were acquired during a resting baseline

The goal of future studies Potential therapeutic effects of rTMS in depression, other psychiatric and neurologic disorders  Improvement of the treatment protocols  Understand the pathophysiology of the brain disorders

Thanks for your attention ~~