Electrostimulation to reduce synaptic scaling driven progression of Alzheimers (Rowan et al. 2014)

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Accession:154096
"... As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. ... The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, ... Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. ... "
Reference:
1 . Rowan MS, Neymotin SA, Lytton WW (2014) Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease. Front Comput Neurosci 8:39 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network;
Brain Region(s)/Organism: Neocortex;
Cell Type(s): Neocortex V1 pyramidal corticothalamic L6 cell; Neocortex V1 pyramidal intratelencephalic L2-5 cell; Neocortex V1 interneuron basket PV cell; Neocortex fast spiking (FS) interneuron; Neocortex spiny stellate cell; Neocortex spiking regular (RS) neuron; Neocortex spiking low threshold (LTS) neuron;
Channel(s):
Gap Junctions:
Receptor(s): GabaA; AMPA; NMDA;
Gene(s):
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON; Python;
Model Concept(s): Long-term Synaptic Plasticity; Aging/Alzheimer`s; Deep brain stimulation; Homeostasis;
Implementer(s): Lytton, William [billl at neurosim.downstate.edu]; Neymotin, Sam [samn at neurosim.downstate.edu]; Rowan, Mark [m.s.rowan at cs.bham.ac.uk];
Search NeuronDB for information about:  Neocortex V1 pyramidal corticothalamic L6 cell; Neocortex V1 pyramidal intratelencephalic L2-5 cell; Neocortex V1 interneuron basket PV cell; GabaA; AMPA; NMDA; Gaba; Glutamate;
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RowanEtAl2014
mod
infot.mod *
intf6.mod *
intfsw.mod *
misc.mod *
myfft.mod *
nstim.mod *
place.mod *
sampen.mod *
staley.mod *
stats.mod *
tsa.mod *
updown.mod *
vecst.mod *
bpf.h *
misc.h *
mkmod *
parameters.multi *
                            
: $Id: updown.mod,v 1.16 2009/02/16 22:56:52 billl Exp $

NEURON {
  SUFFIX nothing
  : BVBASE is bit vector base number (typically 0 or -1)
  GLOBAL UPDOWN_INSTALLED, SHM_UPDOWN, NOV_UPDOWN, DEBUG_UPDOWN
}

PARAMETER {
  UPDOWN_INSTALLED=0
  DEBUG_UPDOWN=0
  SHM_UPDOWN=4   : used in updown() for measuring sharpness
  NOV_UPDOWN=1   : used in updown() to eliminate overlap of spikes
  CREEP_UPDOWN=0 : used in updown() to allow left/right "creep" to local minima
}

VERBATIM
#include <stdlib.h>
#include <math.h>
#include <limits.h> // contains LONG_MAX 
#include <sys/time.h> 
extern double* hoc_pgetarg();
extern double hoc_call_func(Symbol*, int narg);
extern FILE* hoc_obj_file_arg(int narg);
extern Object** hoc_objgetarg();
extern void vector_resize();
extern int vector_instance_px();
extern void* vector_arg();
extern double* vector_vec();
extern double hoc_epsilon;
extern double chkarg();
extern void set_seed();
extern int ivoc_list_count(Object*);
extern Object* ivoc_list_item(Object*, int);
extern int hoc_is_double_arg(int narg);
extern char* hoc_object_name(Object*);
char ** hoc_pgargstr();
int list_vector_px();
int list_vector_px2();
int list_vector_px3();
double *list_vector_resize();
int ismono1();
static void hxe() { hoc_execerror("",0); }
static void hxf(void *ptr) { free(ptr); hoc_execerror("",0); }
ENDVERBATIM

:* src.updown(thresh,dlist,nqslist)
:  dest.updown(src)  -- default thresh=0; returns indices
: look for multiple threshold crossings to define peaks
: creates multiple parallel vectors for an NQS db
: counts peaks pointing upward -- should be all pos
: see eg decnqs.hoc:fudup() for usage
VERBATIM

  //** declarations
#define UDSL 500
#define UDNQ 11
// nq=new NQS("LOC","PEAK","WIDTH","BASE","HEIGHT","START","SLICES","SHARP","INDEX","FILE","NESTED")
#define LOC     nq[0] // loc of peak of spike
#define PEAK  	nq[1] // value at peak (absolute height)
#define WIDTH  	nq[2] // rt flank - lt flanks (? isn't it rt flank - LOC ?)
#define BASE  	nq[3] // height at base
#define HEIGHT  nq[4] // peak - base
#define START  	nq[5] // left flank of spike?
#define SLICES  nq[6] // how many slices found this spike
#define SHARP  	nq[7] // 2nd deriv at peak
#define INDEX  	nq[8] // consecutive numbering of spikes
//        	nq[9] // will use to fill in trace's file name at hoc level
#define NESTED  nq[10] // how many bumps are nested within this one
  //** procedure updown()
static double updown (void* vv) {
  int i, k, m, n, nqsz, nsrc, jj[UDSL], f[UDSL], lc, dsz[UDSL], nqmax, thsz, lc2, done, dbn;
  double *src, *tvec, *th, *dest[UDSL], *nq[UDNQ], *tmp, *dbx, lt, thdist;
  Object *ob, *ob2;
  void *vvd[UDSL], *vvth, *vnq[UDNQ];
  //** read in vectors and verify sizes, etc
  nsrc = vector_instance_px(vv, &src); // trace to analyze
  thsz = vector_arg_px(1, &th);        // vector of thresholds to check
  ob =  *hoc_objgetarg(2);             // storage for values for each threshold
  ob2 = *hoc_objgetarg(3);             // list of NQS vectors for returning values
  tmp = (double *)ecalloc(nsrc, sizeof(double));  // tmp is size of trace
  lc =  ivoc_list_count(ob);
  lc2 = ivoc_list_count(ob2);
  if (lc>UDSL) {printf("updown ERRF mismatch: max slice list:%d %d\n",UDSL,lc); hxf(tmp);}
  if (lc2!=UDNQ){printf("updown ERRB mismatch: NQS sz is %d (%d in list)\n",UDNQ,lc2);hxf(tmp);}
  if (nsrc<lc) {printf("updown ERRC mismatch: %d %d\n",lc,nsrc); hxf(tmp);} // ??
  if (lc!=thsz) {printf("updown ERRA mismatch: %d %d\n",lc,thsz); hxf(tmp);}
  if (!ismono1(th,thsz,-1)) {printf("updown ERRD: not mono dec %g %d\n",th[0],thsz); hxf(tmp);}
  // thdist=(th[thsz-2]-th[thsz-1])/2; // NOT BEING USED: the smallest spike we will accept
  for (k=0;k <lc;k++)  dsz[k] =list_vector_px3(ob , k, &dest[k], &vvd[k]);
  for (k=0;k<lc2;k++) {
    i=list_vector_px3(ob2, k, &nq[k],   &vnq[k]);
    if (k==0) nqmax=i; else if (i!=nqmax) { // all NQ vecs same size
      printf("updown ERRE mismatch: %d %d %d\n",k,i,nqmax); hxf(tmp); }
  }
  //** store crossing points and midpoints in dest[k]
  // dest vectors dest[k] will store crossing points and midpoints at each th[k] slice location
  // as triplets: up/max/down
  for (k=0; k<lc; k++) {   // iterate thru thresholds
    jj[k]=f[k]=0; // jj[k] is ind into dest[k]; f[k] is flag for threshold  crossings
    for (i=0;i<nsrc && src[i]>th[k];i++) {} // start somewhere below this thresh th[k]
    for (; i<nsrc; i++) { // iterate through trace
      if (src[i]>th[k]) { 
        if (f[k]==0) { // ? passing thresh 
          if (jj[k]>=dsz[k]){printf("(%d,%d,%d) :: ",k,jj[k],dsz[k]);
            hoc_execerror("Dest vec too small in updown ", 0); }
          dest[k][jj[k]++] = (i-1) + (th[k]-src[i-1])/(src[i]-src[i-1]); // interpolate
          f[k]=1; 
          tmp[k]=-1e9; dest[k][jj[k]]=-1.; // flag in tmp says that a thresh found here
        }
        if (f[k]==1 && src[i]>tmp[k]) { // use tmp[] even more temporarily
          tmp[k]=src[i]; // pick out max
          dest[k][jj[k]] = (double)i; // location of this peak
        }
      } else {          // below thresh 
        if (f[k]==1) {  // just passed going down 
          jj[k]++;      // triplet will be indices of cross-up/peak/cross-down
          dest[k][jj[k]++] = (i-1) + (src[i-1]-th[k])/(src[i-1]-src[i]);
          f[k]=0; 
        }
      }
    }
  }
  //** truncate dest vectors to multiples of 3:
  for (k=0;k<lc;k++) vector_resize(vvd[k],(int)(floor((double)jj[k]/3.)*3.));
  for (i=0; i<nsrc; i++) tmp[i]=0.; // clear temp space
  //** go through all the slices to find identical peaks and save widths and locations
  // tmp[] uses triplets centered around a location corresponding to a max loc in the
  // original vector; the widest flanks for each are then on either side of this loc
  for (k=0;k<lc;k++) { // need to go from top to bottom to widen flanks
    for (i=1;i<jj[k];i+=3) { // through centers (peaks)
      m=(int)dest[k][i]; // hash: place center at location
      if (tmp[m-2]<0 || tmp[m-1]<0 || tmp[m+1]<0 || tmp[m+2]<0) continue; // ignore; too crowded
      tmp[m]--;  // count how many slices have found this peak (use negative)
      tmp[m-1]=dest[k][i-1]; tmp[m+1]=dest[k][i+1]; // flanks
    }
  }
  //** 1st (of 2) loops through tmp[] -- pick up flanks
  // step through tmp[] looking for negatives which indicate the slice count and pick up 
  // flanks from these
  // nq=new NQS("LOC","PEAK","WIDTH","BASE","HEIGHT","START","SLICES","SHARP","INDEX","FILE")
  for (i=0,k=0; i<nsrc; i++) if (tmp[i]<0.) { // tmp holds neg of count of slices
    if (k>=nqmax) { printf("updown ERRG OOR in NQ db: %d %d\n",k,nqmax); hxf(tmp); }
    LOC[k]=(double)i;  // approx location of the peak of the spike
    WIDTH[k]=tmp[i+1]; // location of right side -- temp storage
    START[k]=tmp[i-1]; // start of spike (left side)
    SLICES[k]=-tmp[i];  // # of slices
    k++;
  }
  nqsz=k;   // k ends up as size of NQS db
  if (DEBUG_UPDOWN && ifarg(4)) { dbn=vector_arg_px(4, &dbx); // DEBUG -- save tmp vector
    if (dbn<nsrc) printf("updown ERRH: Insufficient room in debug vec (%d<%d)\n",dbn,nsrc); 
    else for (i=0;i<nsrc;i++) dbx[i]=tmp[i]; 
  }
  //** adjust flanks to handle nested bumps
  // 3 ways to handle spike nested in a spike or elongated base:
  // NB always using same slice for both L and R flanks; NOV_UPDOWN flag: (no-overlap)
  //   0. nested spike(s) share flanks determined by shared base
  //   1. nested spike(s) have individual bases, 1st and last use flanks from base
  //   2. nested spike(s) have individual bases, base flanks listed separately w/out peak
  // here use 
  // search nq vecs to compare flanks to neighboring centers
  // if flanks overlap the centers on LT or RT side,
  // correct them by going back to original slice loc info (in dest[])
  //*** look at left side -- is this flank to left of center of another bump?
  if (NOV_UPDOWN) for (i=0;i<nqsz;i++) { // iterate through NQS db
    if ((i-1)>0 && START[i] < LOC[i-1]) { // flank is to left of prior center
      if (DEBUG_UPDOWN) printf("LT problem %d %g %g<%g\n",i,LOC[i],START[i],LOC[i-1]);
      for (m=lc-1,done=0;m>=0 && !done;m--) { // m:go from bottom (widest) to top
        for (n=1;n<jj[m] && !done;n+=3) {     // n:through centers
          // pick out lowest slice with this peak LOC whose flank is to RT of prior peak
          if (floor(dest[m][n])==LOC[i] && dest[m][n-1]>LOC[i-1]) {
            // ??[i]=START[i]; // temp storage for L end of this overlap
            // replace both left and right flanks at this level -- #1 above
            START[i]=dest[m][n-1]; WIDTH[i]=dest[m][n+1]; done=1; 
          }
        }
      }
    }
    //*** now look at RT side
    if ((i+1)<nqsz && WIDTH[i]>LOC[i+1]) {
      if (DEBUG_UPDOWN) printf("RT problem %d %g %g>%g\n",i,LOC[i],WIDTH[i],LOC[i+1]);
      for (m=lc-1,done=0;m>=0 && !done;m--) { // m: go from bottom to top
        for (n=1;n<jj[m] && !done;n+=3) {     // n: through centers
          // pick out lowest slice with this peak LOC whose flank is to LT of next peak
          if (floor(dest[m][n])==LOC[i] && dest[m][n+1]<LOC[i+1]) {
            // ??[i]=WIDTH[i]; // end of overlap
            START[i]=dest[m][n-1]; WIDTH[i]=dest[m][n+1]; done=1;
          }
        }
      }        
    }
  }

  //make sure left and right sides of bump occur at local minima
  //shouldn't creeping be before NOV_UPDOWN=1 overlap check???
  //creeping can result only in equal borders btwn two bumps
  //on one side, so it should be ok here...
  if(CREEP_UPDOWN) for(i=0,k=0;i<nsrc;i++) if(tmp[i]<0.){

    //move left side to local minima
    int idx = (int)START[k];
    while(idx >= 1 && src[idx] >= src[idx-1]) idx--;
    START[k] = idx;

    //move right side to local minima
    idx = (int)WIDTH[k];
    while(idx < nsrc-1 && src[idx] >= src[idx+1]) idx++;
    WIDTH[k] = idx;

    k++;
  }

  //** 2nd loop through tmp[] used to fill in the rest of NQS
  // needed to split into 2 loops so that could check for overlaps and correct those
  // before filling in the rest of nq
  for (i=0,k=0; i<nsrc; i++) if (tmp[i]<0.) { // tmp holds neg of count of slices
    // calculate a base voltage lt as interpolated value on left side
    lt=src[(int)floor(START[k])]+(START[k]-floor(START[k]))*\
      (src[(int)floor(START[k]+1.)]-src[(int)floor(START[k])]);
    BASE[k]=lt;         // base voltage
    PEAK[k]=src[i];     // peak voltage
    WIDTH[k] = WIDTH[k] - START[k]; // width = RT_flank-LT_flank
    HEIGHT[k]=PEAK[k]-BASE[k]; // redund measure -- can eliminate
    // measure of sharpness diff of 1st derivs btwn peak and SHM_UPDOWN dist from peak
    // to get 2nd deriv would be normalized by 2*SHM_UPDOWN*tstep
    // ??could take an ave. or max first deriv for certain distance on either side
    SHARP[k]=(src[i]-src[i-(int)SHM_UPDOWN])-(src[i+(int)SHM_UPDOWN]-src[i]);
    INDEX[k]=(double)k;
    k++;
  }
  
  int iNumBumps = k;

  //count # of other bumps nested within each bump
  if(!NOV_UPDOWN){
    for(i=0; i<iNumBumps; i++){
      NESTED[i] = 0;
      int j = 0;
      for(;j<iNumBumps;j++){
        if(i!=j && LOC[j] >= START[i] && LOC[j] <= START[i]+WIDTH[i]){
          NESTED[i]+=1.0;
        }
      }
    }
  } else for(i=0;i<iNumBumps;i++) NESTED[i]=0.0;

  //** finish up
  for (i=0;i<lc2;i++) vector_resize(vnq[i], nqsz);
  if (k!=nqsz) { printf("updown ERRI INT ERR: %d %d\n",k,nqsz); hxf(tmp); }
  free(tmp);
  return jj[0];
}


ENDVERBATIM

:* PROCEDURE install_updown()
PROCEDURE install_updown () {
  if (UPDOWN_INSTALLED==1) {
    printf("$Id: updown.mod,v 1.16 2009/02/16 22:56:52 billl Exp $\n")
  } else {
  UPDOWN_INSTALLED=1
  VERBATIM {
  install_vector_method("updown", updown);
  }
  ENDVERBATIM
  }
}

Rowan MS, Neymotin SA, Lytton WW (2014) Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease. Front Comput Neurosci 8:39[PubMed]

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