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

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"... 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. ... "
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;
Gap Junctions:
Receptor(s): GabaA; AMPA; NMDA;
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;
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: staley.mod,v 1.75 2010/04/30 18:59:54 samn Exp $ 

  SUFFIX staley
  GLOBAL installed,verbose,samprate,mindist,minspikes,abovebth
  GLOBAL Lintdur,Bintdur,spkup

::* NEURON stuff 
  samprate=2000    : sampling rate of original data, assumed to be 2KHz as in BPF default
  Lintdur=120      : little interval: duration in ms
  Bintdur=12       : big interval: duration in sec
  Sintdur=2        : smaller interval for checking spike counts for beg and end of sz
  mindist=0.1      : (sec) minimum duration between seizures (for concatenating them)
  minspikes=40     : minimum # of spikes in a 'seizure'
  abovebth=0       : not used currently
  endwting=1       : to weight avgnumspikes for criterion for end of sz
  flag=0           : choose set of criteria
  spkup=12         : duration of upswing to look for
  spklim=0.25      : used in upswing detection - larger means bigger spikes required
  useavgtots=0     : use average max_maxS-min_minS over all intervals for upvalue threshold

  usesharp=0       : use 2nd deriv to test spike
  sharpoff=4       : iff usesharp==1, uses x{tt+sharpoff} - 2*x{tt} + x{tt-sharpoff}
  sharpth=-500     : threshold for sharpness to be considered a spike - only used when usesharp=1

  incby1=0         : inc by 1 in inteval checks


static double gsz(), gszspk();

#include "misc.h"
static  ListVec* pL;

typedef struct SEIZURE {
  int startIntervalIndex;
  int endIntervalIndex;
  int totalSpikesCount;
  int endSpikesCount;
  int ID;
  int startIndex;
  int endIndex;
} sSeizure;

//* utility functions and main struct
//note: not sure initialization of sSeizure is done correctly, need to see original class
// constructor
sSeizure* AllocSeizure (int intervalIndex,int spikesCount)
  sSeizure* p;
  if(!(p = calloc(1,sizeof(sSeizure)))){
    printf("AllocSeizure ERR: out of memory!\n"); hxe();
  p->startIntervalIndex = p->endIntervalIndex = intervalIndex;
  p->endIntervalIndex+=1; // when looking at pairs
  p->totalSpikesCount = spikesCount;
  p->ID = -1; // invalid identifier
  return p;

typedef struct LSEIZURE {
  int bufsz;
  int count;
  sSeizure** pp;
} LSeizure;

int InitLSeizure (LSeizure* pl,int sz) {
  pl->bufsz = sz;
  pl->count = 0;
  if(sz==0) pl->pp=NULL; else pl->pp=calloc(sz,sizeof(sSeizure*));
  return pl->bufsz;

void FreeLSeizure(LSeizure* pl) {
  int i;
  //  for(i=0;i<pl->count;i++) free(pl->pp[i]);

int AddSeizure(LSeizure* pl, sSeizure* ps) {
  if(0) printf("pl=%p , pl->count=%d, pl->bufsz=%d\n",pl,pl->count,pl->bufsz);
  if( pl->count + 1 >= pl->bufsz ) {
    pl->bufsz *= 4;
    if(0)printf("pl=%p, realloc pl->count=%d, pl->bufsz=%d\n",pl,pl->count,pl->bufsz);
    if(! (pl->pp=realloc(pl->pp,sizeof(sSeizure*)*pl->bufsz)) ) {
      printf("AddSeizure: out of memory!\n"); hxe();
  pl->pp[pl->count++] = ps;
  return 1;

int RemoveSeizureAt(LSeizure* pl, int idx) {
  int i,j;
  if( idx < 0 || idx >= pl->count) {
    printf("RemoveSeizureAt: invalid index=%d, count=%d!\n",idx,pl->count); hxe();
  for(i=idx+1;i<pl->count;i++) pl->pp[i-1]=pl->pp[i];
  return 1;

void printSeizure (sSeizure* p) {
  printf("ID:%d, startIntervalIndex:%d, endIntervalIndex:%d, totalSpikes:%d, endSpikes:%d, startIndex:%d, endIndex:%d\n",

void printSeizures (LSeizure* lp) {
  int i;
  for(i=0;i<lp->count;i++) printSeizure(lp->pp[i]);

//* dgetseizures(double* channelData,int channelsLength) -- main routine
static LSeizure* dgetseizures (double* channelData,int channelsLength) {
  // based on Andy White & Kevin Staley routine for seizure detection
  // currently works for recording freq of 250Hz
  // This subroutine creates a measure of the density of the signal
  // We first find the maxima and minima for groups of 25 points
  //** declarations and allocations
  int intervalIndex, dataIndex, seizureIndex, iS, stopIndex, uplim;
  int intervalLength, channelIndex, i,j, intervalsCount, SgroupCount, true;
  int seizuresCount, spikesCount, totsLen, bufszStart, dbxi, ii, jj, LintCnt;
  double value, min_minS, max_maxS, HV, LV; //int value, min_minS, max_maxS, HV, LV;
  double diffc, totsum, diffthresh;
  int upflag, upcount, avgnumspikes, *spks;
  double upvalue, limit, *diffcor, *percentc, *tots, sharp;
  LSeizure tmpSeizures, *pSeizuresOut;  
  sSeizure *tmpSeizure, *currentSeizure, *nextSeizure; 
  diffcor=percentc=tots=0x0; spks=0x0;
  if(!(pSeizuresOut=calloc(1,sizeof(LSeizure)))){printf("getseizures ERR: out of memory!\n");hxe();}
  InitLSeizure(pSeizuresOut,bufszStart); InitLSeizure(&tmpSeizures,bufszStart);
  intervalLength = (int)Bintdur*samprate;
  intervalsCount = channelsLength / intervalLength; // this is the # of intervals
  uplim=(int)(0.5+spkup*samprate/1e3); // round up
  if(intervalsCount<1) {
    printf("getseizures ERR:invalid intervalsCount:%d %d\n",channelsLength,intervalLength);hxe();}
  SgroupCount = (int)Bintdur/Lintdur*1e3; // Bintdur/Lintdur; intervalLength/30; 
  if(intervalsCount<1 || SgroupCount<1) { 
    printf("Error: Data length too short, cannot process."); hxe(); }
  if((diffcor = (double*) calloc(intervalsCount,sizeof(double)))==0x0) {
    printf("getseizures ERRdfc: out of memory!\n"); hxe();  }
  if(!(percentc = (double*) calloc(intervalsCount,sizeof(double)))) { // not used currently
    printf("getseizures ERRpcc: out of memory!\n"); hxe();  }            // but still calculated
  if(!(tots = (double*) calloc(intervalsCount,sizeof(double)))) {
    printf("getseizures ERRtts: out of memory!\n"); hxe();  }
  if(!(spks=(unsigned int*) calloc((size_t)(jj=intervalsCount*Bintdur/Sintdur),sizeof(int)))) {
    printf("getseizures ERRspk: out of memory!\n"); hxe();  }
  for (ii=0;ii<jj;ii++) spks[ii]=0; // clear
  totsLen = intervalsCount;
  // gsz() calculates the correlation measures
    gsz(channelData,diffcor,percentc,tots, channelsLength, intervalLength,SgroupCount,LintCnt);
  //** 2nd full loop: spike counting; find spikes for cases with high diffcor
  // Now that we have a suspected (intervalLength) 3000 pts interval, 
  // we test how many spikes there are in the interval
  if (verbose==13) {
    if (pL->isz<1||pL->plen[0]!=intervalsCount) {
      printf("For verbose 13 need 1 vec of %d each\n",intervalsCount); hxe(); } 
    for (ii=0;ii<intervalsCount;ii++) pL->pv[0][ii]=(double)spks[ii];
  if(incby1) for (ii=0; ii<intervalsCount; ii++) { // whole trace; ii=intervalIndex
    if (flag==0) {
      true=(spks[ii]>minspikes && diffcor[ii]>diffthresh);
    } else if (flag==1) {true=(spks[ii]>minspikes);
    } else if (flag==2) {true=(diffcor[ii]>diffthresh);
    if (true) {
      if(seizuresCount==0 || tmpSeizure->endIntervalIndex!=ii-1)  { // new one
      } else { // add to current sz
        tmpSeizure->endIntervalIndex = ii; //ending index upddate
        tmpSeizure->totalSpikesCount += spks[ii]; //total spikes count
        tmpSeizure->endSpikesCount = spks[ii]; //end spikes count
  } // full trace loop; next intervalIndex pair
  else  for (ii=0; ii+1<intervalsCount; ii+=2) { // whole trace; ii=intervalIndex
    if (flag==0) {
      true=(spks[ii]>minspikes && spks[ii+1]>minspikes && diffcor[ii]>diffthresh && diffcor[ii+1]>diffthresh);
    } else if (flag==1) {true=(spks[ii]>minspikes && spks[ii+1]>minspikes);
    } else if (flag==2) {true=(diffcor[ii]>diffthresh && diffcor[ii+1]>diffthresh);
    if (true) {
      if(seizuresCount==0 || tmpSeizure->endIntervalIndex!=ii-1)  { // new one
      } else { // add to current sz
        tmpSeizure->endIntervalIndex = ii+1; //ending index upddate
        tmpSeizure->totalSpikesCount += spks[ii]+spks[ii+1]; //total spikes count
        tmpSeizure->endSpikesCount = spks[ii+1]; //end spikes count
  } // full trace loop; next intervalIndex pair
  if(verbose==-1) {
    printf("before tmpSeizures %d:\n",tmpSeizures.count);  printSeizures(&tmpSeizures); }
  //** find the end points of the seizure. to do this compute the number of spikes in 2 second
  // intervals.  There will be a dramatic drop at the end of a seizure
  for (seizureIndex=0; seizureIndex<seizuresCount; seizureIndex++) { 
    tmpSeizure = tmpSeizures.pp[seizureIndex];
    currentSeizure = pSeizuresOut->pp[seizureIndex];
    currentSeizure->ID = seizureIndex;
    currentSeizure->totalSpikesCount = tmpSeizure->totalSpikesCount;
    if(seizureIndex < seizuresCount-1) { //start of next seizure (to prevent overlap)
      //potential problem for seizure overlap:
      //endIntervalIndex marks the beginning of interval and stop condition looks at it
      //so seizures overlap within 4s; next seizure start dataIndex
      stopIndex = (tmpSeizures.pp[seizureIndex+1])->startIntervalIndex * intervalLength; 
    } else stopIndex = channelsLength;
    intervalIndex = tmpSeizure->endIntervalIndex + 1; //current seizure end point 
    // (next seizure doesn't start in next interval), otherwise would be the same seizure
    dataIndex = intervalIndex * intervalLength; 
    if (intervalIndex >= totsLen) intervalIndex = totsLen-1;
    limit = tots[intervalIndex]/50.; // 50 hardcoded; count many more spikes than orig
      (Bintdur*(tmpSeizure->endIntervalIndex - tmpSeizure->startIntervalIndex+1));
    if (verbose==-2) printf("avgnumspikes: %d\n",avgnumspikes);
    for (j=1; j<minspikes; j++) { // j not used
      spikesCount = 0;
      for (i=0; i<samprate*Sintdur; i++, dataIndex++) { // 2s interval; i not used
        if(dataIndex>=stopIndex) { //start of next seizure reached -> stop
          dataIndex = stopIndex-1; break; }
        if (dataIndex+1 >= channelsLength) break;
          if(value>0) { upflag = 1; // true;
            upcount++; //count of how many periods was increasing
            upvalue+=value; // total value of increase
          } else	{ 
            if (upflag && upvalue>limit && upcount>uplim) {
              if(usesharp && dataIndex-sharpoff>=0.0 && dataIndex+sharpoff<channelsLength) {
                sharp = channelData[dataIndex+(int)sharpoff]-2*channelData[dataIndex]+channelData[dataIndex-(int)sharpoff];
                if(sharp < sharpth) spikesCount++; // only sharp spikes count
              } else spikesCount++;
      } //Loop
      if (spikesCount/Sintdur < endwting*avgnumspikes) break; // spikes/sec
    } //Loop
    currentSeizure->endIndex=dataIndex; //update seizure end dataIndex
    currentSeizure->endIntervalIndex = (int)dataIndex/intervalLength; 

  //** search/update the start of the seizure index. 
  // do this by computing the number of significant spikes and
  //determining where that changes significantly. use 2 second intervals
  seizuresCount = pSeizuresOut->count; 
  for (seizureIndex = 0; seizureIndex<seizuresCount; seizureIndex++) { 
    tmpSeizure = tmpSeizures.pp[seizureIndex];
    currentSeizure = pSeizuresOut->pp[seizureIndex];
    if (seizureIndex>0) { //end of previous seizure (to prevent overlap)
      //!! ?? here is potential problem for seizure overlap !!!
      //endIntervalIndex marks the beginning of interval and stop condition looks at it
      //so seizures overlap within 4s !!!
      //stopIndex = ((seizureTmp^)tmpSeizures[seizureIndex-1])->endIntervalIndex * intervalLength; 
      stopIndex = (pSeizuresOut->pp[seizureIndex-1])->endIndex;
    else stopIndex = 0;
    intervalIndex = tmpSeizure->startIntervalIndex; //current seizure start point
    if(intervalIndex >= totsLen) intervalIndex = totsLen-1;
    dataIndex = intervalIndex * intervalLength; 
    limit= tots[intervalIndex]/50; // *0.02 hardcoded 50
    avgnumspikes = tmpSeizure->totalSpikesCount/\
    upcount=0.0; upvalue=upflag=0; 
    for(j=1; j<minspikes; j++) { 
      spikesCount = 0;
      for(i=0; i<samprate*Sintdur; i++, dataIndex--) { //2s interval; hardcoded 2
	if(dataIndex<=stopIndex) { //end of previous seizure reached -> stop
	  dataIndex = stopIndex + 1; break; }
        if(dataIndex+1 >= channelsLength) break;
        if(value>0) { 
          upflag=1; upcount++; upvalue+=value;
        } else { 
          if (upflag && upvalue>limit && upcount>uplim) {
            if(usesharp && dataIndex-sharpoff>=0.0 && dataIndex+sharpoff<channelsLength) {
              sharp = channelData[dataIndex+(int)sharpoff]-2*channelData[dataIndex]+channelData[dataIndex-(int)sharpoff];
              if(sharp < sharpth) spikesCount++; // only count sharp spikes
            } else spikesCount++;
      } //Loop
      if (spikesCount/Sintdur<endwting*avgnumspikes) break;
    currentSeizure->startIndex = dataIndex; // update seizure start dataIndex
    currentSeizure->startIntervalIndex = (int)dataIndex/intervalLength; 
  //** connect overlapping seizures
  for(seizureIndex = seizuresCount-1; seizureIndex>0; seizureIndex--) { 
    currentSeizure = pSeizuresOut->pp[seizureIndex-1];
    nextSeizure =    pSeizuresOut->pp[seizureIndex]; 
    if(currentSeizure->endIndex >= (nextSeizure->startIndex - mindist)) {//overlap ??
      //connect overlapping seizures
      currentSeizure->endIndex = nextSeizure->endIndex; //copy end to start
      currentSeizure->totalSpikesCount += nextSeizure->totalSpikesCount;
      free(nextSeizure);     // comment by sam : do we need to delete this seizure here?
  //** deallocations
  if(verbose==-1) {
    printf("after tmpSeizures %d:\n",tmpSeizures.count);  printSeizures(&tmpSeizures);
    printf("after pSeizuresOut %d:\n",pSeizuresOut->count); printSeizures(pSeizuresOut); }
  if(diffcor) free(diffcor);
  if(percentc) free(percentc);
  if(tots) free(tots);
  for(i=0; i<tmpSeizures.count; i++) { //delete tmpSeizures
    if(tmpSeizures.pp[i]==0x0) printf("tmpSeizures.pp[%d]=0x0",i);
  return pSeizuresOut;

//* gsz()
static double gsz (double* channelData,double* diffcor,double* percentc,double* tots,\
          int channelsLength,int intervalLength, int SgroupCount,int LintCnt) {
  int intervalIndex, dataIndex, iS, intervalsCount;
  int i,j, ii, SgroupCount4, dbxi;
  double value, min_minS, max_maxS, HV, LV; //int value, min_minS, max_maxS, HV, LV;
  double diffc, totsum, avg1, sdev1, avg2, sdev2;
  double upvalue, limit, *minS, *maxS;
  double bintdur,lintdur; // lower case are local versions
  //** redund variable definitions from calling routine
  intervalsCount = channelsLength / intervalLength; // this is the # of intervals
  SgroupCount4 = SgroupCount/4;  //and this is the # of sub-sub-groups?? hardcoded 4
  //minS=gcnew array<float>(SgroupCount+2);//minS=gcnew array<int>(SgroupCount+2);
  //100 => (averages over 30 values) * 100 = 3000 
  if((minS = (double*) calloc(SgroupCount+2,sizeof(double)))==0x0) {
    printf("getseizures ERR: out of memory!\n"); hxe();  }
  //maxS=gcnew array<float>(SgroupCount+2);//maxS=gcnew array<int>(SgroupCount+2);
  //102 to make correct sum at the end of 100 (maxS(i+1) maxS(i+2))
  if((maxS = (double*) calloc(SgroupCount+2,sizeof(double)))==0x0){
    printf("getseizures ERR: out of memory!\n"); hxe();  }

  //** first loop: search for seizures; for each period of bintdur detect correlations
  for (dbxi=0,intervalIndex=0; intervalIndex<intervalsCount; intervalIndex++) { //thru trace
    //find minS(i) and maxS(i)  also max(maxS) and min(minS) for all intervals			
    // (100+2)*30 == 3060; we need 2 more since maxS(i+1) maxS(i+2)
    for (dataIndex=intervalIndex*intervalLength, iS=0; iS<SgroupCount+2; iS++) { // Big Int.
      minS[iS]= 1e22; maxS[iS]= -1e22; 
      for(i=0; i<LintCnt; i++, dataIndex++) {  // find min/max on Little Interval
	if(dataIndex < channelsLength) value = channelData[dataIndex];
        if (minS[iS] > value)  minS[iS] = value;
        if (maxS[iS] < value)  maxS[iS] = value;
    if (verbose==11) {
      if (dbxi==0 && (pL->isz<2 || pL->plen[0]!=intervalsCount*(SgroupCount+2)\
          || pL->plen[1]!=intervalsCount*(SgroupCount+2))) {
        printf("For verbose 11 need 2 vecs of %d each\n",intervalsCount*(SgroupCount+2)); hxe();} 
      for (iS=0; iS<SgroupCount+2; iS++,dbxi++) {
        pL->pv[0][dbxi]=minS[iS]; pL->pv[1][dbxi]=maxS[iS];
    // calculate metrics for each group
    for (iS=0; iS<SgroupCount; iS++) {
      HV = MIN(maxS[iS], MAX(maxS[iS+1],maxS[iS+2])); // compare to how it ends
      LV = MAX(minS[iS], MIN(minS[iS+1],minS[iS+2]));
      //metric3 = sum of differences over 100 intervals Si 
      diffc += (HV - LV); //!!! metric3
      totsum += (maxS[iS]-minS[iS]); //sum (max(Si)-min(Si))
    //Now produce the metrics
    diffcor[intervalIndex] = diffc;	//metric3
    percentc[intervalIndex] = diffc/totsum; // almost metric4; should be SUM(a/b) not SUM(a)/SUM(b)
    // recompute totsum using quartile maxima
    for(totsum=0, iS=0, j=0; j<4; j++)  {  // smoothing over 4
      min_minS = 1e22;  max_maxS = -1e22; 
      for(i=0; i<SgroupCount4; i++, iS++) { 
        if (max_maxS < maxS[iS])  max_maxS = maxS[iS];
        if (min_minS > minS[iS])  min_minS = minS[iS];
      totsum += (max_maxS - min_minS);
    tots[intervalIndex] = totsum/4;
    if (verbose==12) {
      if (dbxi==0) {
        for (ii=0;ii<3;ii++) if (pL->isz<3||pL->plen[ii]!=intervalsCount) {
          printf("For verbose 12 need 3 vecs of %d each\n",intervalsCount); hxe(); } 
        printf("Verbose 12: diffcor,percentc,tots\n");
      pL->pv[0][dbxi]=diffcor[ii]; pL->pv[1][dbxi]=percentc[ii]; pL->pv[2][dbxi]=tots[ii];
  } // whole trace; next intervalIndex
  //** Calculate the standard deviation of the high and low values
  // This is a measure of the correlation of the items - for a seizure the value should be low -
  // it will be higher for random processes.
  //  Review the results for this slice of time
  //  calculate mean and std-dev for percentc and diffcor
  for(intervalIndex=0; intervalIndex<intervalsCount; intervalIndex++)  { 
    avg1 += diffcor[intervalIndex];  // avg1 for diffcor 
    avg2 += percentc[intervalIndex]; // avg2 for percentc
    sdev1 += diffcor[intervalIndex]*diffcor[intervalIndex];   //for standard-deviations
    sdev2 += percentc[intervalIndex]*percentc[intervalIndex];
  avg1 = avg1/intervalsCount; avg2 = avg2/intervalsCount; 
  sdev1 = sdev1/intervalsCount - avg1*avg1; // standard-deviations
  if(sdev1>0.) sdev1=sqrt(sdev1); else sdev1=avg1;
  sdev2 = sdev2/intervalsCount - avg2*avg2;
  if(sdev2>0.) sdev2=sqrt(sdev2); else sdev2=avg2;
  if (verbose>1) printf("diffcor: %g (%g,%g), percentc: %g (%g)\n",\
  if(minS) free(minS);
  if(maxS) free(maxS);
  return avg1+abovebth*sdev1;

#ifdef MYSPUD

int dspud (double* src, int nsrc, int lc) {
  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
          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]);
  //** 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
  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
  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;


  //** 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
    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
  int iNumBumps = k;

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


static double gszspk (double* channelData, int* spks,\
                      double* tots, int channelsLength, int intervalLength) {
  int intervalIndex, dataIndex, intervalsCount, foundspk;
  int i,j, ii, upflag, upcount, spikesCount, uplim, dbgSpikes,didpr,cnt;
  double value, upvalue, limit, sum, sharp; // lower case are local versions
  //** redund variable definitions from calling routine
  intervalsCount = channelsLength / intervalLength; // this is the # of intervals

  if(useavgtots) {
    for(intervalIndex=0; intervalIndex<intervalsCount; intervalIndex++) sum += tots[intervalIndex];
    sum /= (double) intervalsCount;
    limit= sum*spklim;

  for (intervalIndex=0; intervalIndex<intervalsCount; intervalIndex++) { // whole trace
    dataIndex = intervalIndex * intervalLength;
    if(!useavgtots) limit= tots[intervalIndex]*spklim; // 0.25 of average difference max_maxS-min_minS
    if(verbose>=15 && !didpr){ printf("limit = %g\n",limit); didpr=1; }
    for (j=0; j<intervalLength; j++, dataIndex++)  {  // Bintdur ~12sec
      if (dataIndex > channelsLength) continue; // bounds-check added by Sam
      value = channelData[dataIndex+1]-channelData[dataIndex];
      if(value>0) { // increasing value
        upflag=1; upcount++; upvalue+=value;
      } else { // not increasing value
        foundspk=0; sharp=0.0;
        if(upflag && upvalue>limit && upcount>uplim) {
          if(usesharp && dataIndex-sharpoff>=0.0 && dataIndex+sharpoff<channelsLength) {
            sharp = channelData[dataIndex+(int)sharpoff]-2*channelData[dataIndex]+channelData[dataIndex-(int)sharpoff];
            if(sharp > sharpth) foundspk=0; // only count sharp spikes
        if (foundspk) { // found a spike
          spikesCount++;  // increase the spike count
          if(verbose>=14) { // save spike x,y ?
            if(pL->isz < 3 || pL->plen[0]<channelsLength || pL->plen[1]<channelsLength || pL->plen[2]<1) {
              printf("need at least 2 vectors of size %d for verbose==14!\n",channelsLength); hxe();
            } else { 
              if(usesharp && dataIndex-sharpoff>=0.0 && dataIndex+sharpoff<channelsLength) {
                sharp = channelData[dataIndex+(int)sharpoff]-2*channelData[dataIndex]+channelData[dataIndex-(int)sharpoff];
                if(verbose>=15) printf("spike found (x,y,upcount,upvalue,sharp)=(%d,%g,%d,%g,%g)\n",dataIndex,channelData[dataIndex],upcount,upvalue,sharp);
              } else {
                if(verbose>=15) printf("spike found (x,y,upcount,upvalue)=(%d,%g,%d,%g)\n",dataIndex,channelData[dataIndex],upcount,upvalue);
              pL->pv[0][dbgSpikes]=dataIndex; pL->pv[1][dbgSpikes++]=channelData[dataIndex];}
        upflag=upcount=upvalue=0; // not increasing so reset counts
    } // Bintdur loop; next j,dataIndex
  if(verbose>=14) pL->pv[2][0]=dbgSpikes;
  return 0.;

// veceeg.getseizures(totalSpikesCount,startIndex,endIndex)
// the 3 input args are Vectors to store results
static double getseizures (void* vv) {
  int n, cnt,i; LSeizure* pSeizures;
  double *p,*totalSpikesCount,*startIndex,*endIndex;
  n = vector_instance_px(vv,&p);
  if(verbose>10) {
    if (!ifarg(4)) { printf("Use veclist for dbx with verbose>10\n");hxe();
    } else pL=AllocListVec(*hoc_objgetarg(4));
  if(!(pSeizures=dgetseizures(p,n))) return 0.0;

  for(i=0;i<cnt;i++) {
    totalSpikesCount[i] =   (double)pSeizures->pp[i]->totalSpikesCount;
    startIndex[i] =         (double)pSeizures->pp[i]->startIndex;
    endIndex[i] =           (double)pSeizures->pp[i]->endIndex;
  for(i=0;i<pSeizures->count;i++) free(pSeizures->pp[i]);
  if (pL) FreeListVec(&pL);
  return (double)cnt;

PROCEDURE install () {
  if(!installed) {
  } else printf("%s\n","$Id: staley.mod,v 1.75 2010/04/30 18:59:54 samn Exp $");

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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