Neuron. Neurostimulation 2/8/2011

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1 Direct Current Stimulation Promotes BDNF Dependent Synaptic Plasticity: Potential Implications for Motor Learning B Fritsch, J Reis, K Martinowich, HM Schambra, Yuanyuan Ji, LG Cohen & B Lu Leonardo G. Cohen, MD NINDS Bai Lu, PhD NIMH Keri Martinowich, PhD NIMH Neuron 66, , April 29, Presented by Billy Podlaski BioNB 4200 February 7, 2011 Brita Fritsch, MD University of Freiburg, Germany Janine Reis, MD University of Freiburg, Germany, NIH Heidi Schambra, MD NIH Yuanyuan Ji, PhD NICHHD, Max Planck Inst. Neuron Neuron: published by Cell Press since Impact factor in 2009: Focus is on the neuron as the fundamental unit of neuroscience research. Cell Press also publishes Cell, with an impact factor of , making it third after Science and Nature Direct Current Stimulation Promotes BDNF Dependent Synaptic Plasticity: Potential Implications for Motor Learning Main finding: Coupling direct current stimulation with low frequency synaptic stimulation in the primary motor cortex promotes long term potentiation that is BDNF dependent. Significance: Potential implications for motor learning, inducing plasticity in selective brain regions and in treatment for people with neurodegenerative diseases. Neurostimulation What is tdcs? Transcranial direct current stimulation Low direct current between two electrodes Anodal: excites neurons, Cathodal: inhibits Effect: alters cortical excitability, long duration Used to treat people with neuropsychiatric disorders One flew over the cuckoo s nest, 1975 (Moore SK, 2006) 1

2 History of tdcs Discovered in early 1800s, clinical experimentation by Giovanni Aldini (Horvath JC, 2010) 1930s: tdcs was abandoned as other forms of neurostimulation were thought to have more potential (Utz et al. 2010) 1960s: discovery that tdcs has an effect on cortical excitability (Utz et al. 2010) Current research: tdcs is better understood now, with better imaging and stimulation techniques (Nitsche et al. 2008) Reasons behind current study of tdcs Non invasive, lost cost, easy to use (Utz et al. 2010). Positive effects seen in motor, visual, somatosensory, attentional, vestibular and emotional functioning regions of brain (Utz et al. 2010). Can be used to boost recovery after stroke by enhancing new connections (Singer E, 2009). Methods and Results Part I Methods and Results Part I Rat brain slice preps, primary motor cortex (M1) Coupling of low frequency synaptic activation (LFS) with transcranial direct current stimulation (tdcs) Scientific Systems Design, Inc. (1999) Fritsch et al., (2010), Fig. 1A Methods and Results Part I Recorded amplitude of fepsps (field excitatory post synaptic potentials) in motor cortex of rats 15 mins of 0.75 mv anodal DCS, with 0.1 Hz LFS Showed long term potentiation (LTP) in EPSPs that lasted dfor at least 2 hours. Fritsch et al., (2010), Fig. 1C Fritsch et al., (2010), Fig. 1B 2

3 Summary Part I tdcs coupled with LFS in rat M1 slices causes long term potentiation LTP endures long after DCS is stopped, for at least 2 hours NEXT: could this be related to NMDA receptors? Fritsch et al., (2010), Fig. 1C NMDA receptors N methyl D aspartate Type of glutamate receptor Non specific cation channel: allows Ca2+, Na+ and K+ currents to flow Ligand gated and voltagegated Implicated in synaptic plasticity, such as LTP Methods and Results Part II Added NMDA antagonist (D APV) to see if this stops LTP from occurring NMDA antagonist prevents potentiation, supports hypothesis that DCS is NMDA dependent (IOCB AS CR, 2011) Fritsch et al., (2010), Fig. 1D Methods and Results Part II Local application of GABA A antagonist bicuculline (BIC) in the absence of DCS caused a transient potentiation This negates the possibility that DCS causes disinhibition during stimulation Summary Part II tdcs coupled with LFS in M1 of rat brain slices causes NMDA dependent long term potentiation This is NOT due to disinhibition of GABA This is NOT due to disinhibition of GABA NEXT: Investigating the role that the neurotrophic factor BDNF has on NMDAdependent potentiation Fritsch et al., (2010), Fig. 1E 3

4 Proteins / growth factors that promote the survival and development of neurons BDNF: Brain derived neurotrophic factor, secretion depends on calcium and NMDA activation (Balkowiec and Katz, 2002) Neurotrophins Methods and Results Part III 1) BDNF flox/flox, cre : knockout mice with a forebrain specific deletion of the BDNF gene. + Cre : absence of BDNF Cre : control BDNF knockouts with Cre+ do not show potentiation 2) Used TrkB IgG to diminish BDNF present in the cortex: this also inhibits potentiation (Kizilova A, 2009) Fritsch et al. (2010), fig. 2A Fritsch et al. (2010), fig. 2B Methods and Results Part III Possible role of TrkB (BDNF receptor)? TrkB F616A knock in mice: allows for selective inhibition i of receptor kinase activity ii of TrkB receptor by the molecule 1NMPP1 Fritsch et al. (2010), fig. 2C 4

5 Methods and Results Part III Does DCS increase secretion of BDNF? Method: western blotting with antibodies against phospho TrkB and total TrkB. Check kfor TrkB levels l before bf and after DCS Result: DCS increases BDNF levels over twofold Fritsch et al. (2010), fig. 2D Summary Part III tdcs and LFS induces NDMA dependent, BDNF dependent long term potentiation TrkB (BDNF receptor) is important for LTP induction DCS/LFS increases BDNF secretion in the brain FINALLY: How does this relate to human motor learning? Methods and Results Part IV Motor skill acquisition tests in humans: sequential visual isometric pinch force task. Studied humans with BDNF Val66Met polymorphism: Val/Val: control Met carriers: 18 30% reduction in BDNF Fritsch et al. (2010), fig. S3A,B Fritsch et al. (2010), fig. 3A 5

6 2/8/2011 Methods and Results Part IV Compared human and mouse motor acquisition tasks BDNF knock in mice: accelerating rotarod task Mice: i Wild type : normal BDNF levels BDNFMet/Met : reduces activity dependent BDNF by 30% BDNFflox/flox, cre : BDNF is absent Fritsch et al. (2010), fig. 3B,C The Accelerating Rotarod Test Fritsch et al. (2010), fig. 3D Fritsch et al. (2010), fig. 3E,F Fritsch et al. (2010), fig. 3G 6

7 Overall conclusions Anodal DCS / LFS in M1 induces LTP that requires activity dependent BDNF Does DCS/LFS trigger the release of probdnf? Factors other thanbdnfstillmust be considered: Possible involvement of spike timing dependent plasticity Future work must be done, exploring effects of other molecules and neuromodulators Fritsch et al. (2010), fig. 3H,I Can be used in vitro to induce plasticity Implications in treatment of neurodegenerative disorders neurorehabilitation. Future of tdcs References Fritsch et al. (2010) Direct current stimulation promotes BDNF dependent synaptic plasticity: potential implications for motor learning. Neuron 66, Horvath JC et al (2010). Transcranial magnetic stimulation: a historical evaluation and future prognosis of therapeutically relevant ethical concerns. J Med Ethics: doi: /jme Kizilova A, (2009). Early diagnostics of schizophrenia is now possible. Russia IC. Moore SK (2006). Psychiatry s shocking new tools. IEEE Spectrum. shocking new tools/0 Nitsche MA et al (2008). Transcranial direct current stimulation: state of the art Brain stimulation. 1(3): Singer, E (2009) Repairing the stroke damaged brain. Technology Review. Utz KS et al (2010). Electrified minds: transcranial direct current stimulation (tdcs) and galvanic vestibular stimulation (GVS) as methods of non invasive brain stimulation in neuropsychology a review of current data and future implications. Neuropsychologia, 48(10): Scientific systems design, inc. (1999). Four or six channel brain slicer BSC3. Institute of Biochemistry and Organic Chemistry, Neuroactive steroids (2011). Singer, E (2009) 7